Pediatric Chronic Anemia 

Updated: Oct 31, 2019
Author: Susumu Inoue, MD; Chief Editor: Max J Coppes, MD, PhD, MBA 

Overview

Background

Chronic anemia has no precise definition. Anemia that persists for 6 months or more (eg, hereditary spherocytosis [HS]) is clearly chronic; however, anemia that lasts only 2 months (eg, iron deficiency that is being treated) should also be considered chronic anemia, and the reasons for it must be sought.

In contrast, acute anemia develops suddenly, in a matter of hours or days. Acute anemia is usually due to acute blood loss or acute hemolysis. Because the life span of normal erythrocytes is about 120 days, bone marrow failure as the cause of anemia always results in chronic, slow-developing anemia. An exception is acute anemia that occurs in patients with existing chronic anemia. For example, patients with sickle cell anemia who already have chronic anemia may develop additional acute anemia due to bone marrow failure (aplastic crisis).

Go to Anemia and Anemia of Prematurity for complete information on these topics.

Chronic anemia can be primary or secondary.

Primary chronic anemia

Primary chronic anemias are the true chronic anemias, in which anemia (defined as a hemoglobin level more than 2 standard deviations below the mean reference value for age) is part of the basic disease process. The basic disease process is hematologic (eg, sickle cell disease, HS), and the degree of anemia varies markedly from etiology to etiology and from patient to patient, even with the same etiology. (See Etiology and Workup.)

Secondary chronic anemia

Secondary chronic anemias are chronic anemias that may provide a diagnostic clue to an underlying pathology. They are the consequence of a nonhematologic problem (eg, chronic blood loss, chronic renal failure, osteomyelitis, inflammatory bowel disease, tuberculosis). (See Etiology.)

For example, a retrospective study by Aljomah et al found that in pediatric patients with inflammatory bowel disease, 67.31% had anemia at diagnosis, with 38.46% having anemia of chronic disease by itself and 28.85% having iron deficiency anemia alone or suffering from both iron deficiency anemia and anemia of chronic disease.[1]

Complications

Complications that pose a threat to long-term health are often a function of the primary condition that is causing secondary anemia. (See Prognosis and History.)

See the following:

  • Iron overload: Monitor patients with primary chronic anemias to avoid iron overload (which can sometimes arise because of increased iron absorption, even in the absence of chronic transfusions) or expansion of the marrow cavity, as with thalassemia.

  • Aplastic crisis: The so-called aplastic crisis may occur in any patients with chronic hemolytic anemia. This is characterized by a sudden drop in hemoglobin levels with reticulocytopenia. Patients who are usually well compensated for anemia may develop heart failure due to the sudden drop in hemoglobin. In most cases, patients require blood transfusion. The cause is commonly the result of parvovirus B19 infection and cessation of erythropoiesis. As the patients develop antibodies to the virus, they spontaneously recover. Detection of parvovirus DNA by polymerase-chain reaction (PCR) assay or demonstration of parvovirus B19 immunoglobulin M (IgM) antibodies is diagnostic. The name, aplastic crisis is a misnomer, because leukopenia and thrombocytopenia are not observed.

  • Hypersplenism: Monitor any patient with significant splenomegaly (palpable spleen by physical examination) for hypersplenism.

  • Folate deficiency: Avoid folic acid deficiency by using supplementation in any patient with chronic hemolytic anemia.

  • Cholelithiasis and cholecystitis: Ask patients about symptoms of cholelithiasis.

  • Failure to thrive

  • Heart failure

  • Cerebral infarction: In a small number of severely anemic children (Hb 2.4 and 3.7), silent cerebral infarction lesions were demonstrated on MRI that was performed as a part of a research study.[2] Some of them showed subtle neurological abnormalities with careful neurological examination. The long-term consequences of these lesions are unknown in terms of the child's neurological function.

  • Ischemic stroke: A study by Baker et al determined that among hospital discharges of African-American children, sickle cell disease is most prevalently related to ischemic stroke, being present in 29% of such cases.[3]

Etiology

As with acute anemia, chronic anemia is classified into the following 3 primary categories:

  • Decreased red cell production

  • Increased red cell destruction (hemolysis)

  • Blood loss

Decreased red cell production

Marrow aplasia may involve a single cell line, as in Diamond-Blackfan anemia (ie, pure red cell aplasia), or it may involve all cell lines, as in aplastic anemia.

Transient erythroblastopenia of childhood (TEC) is the most common form of childhood pure red cell aplasia. The peak age range for TEC is 6 months to 6 years. It is usually triggered by a viral illness. In most cases, specific viruses have not been identified,[4] although human herpesvirus type 6[5] and parvovirus B19[6] have been thought to be the cause in some instances. Spontaneous recovery is the rule, but recovery is sometimes prolonged, necessitating blood transfusion. Typically, the reticulocyte count is zero. Unlike Diamond-Blackfan anemia, mean corpuscular volume (MCV) is not elevated.

Fanconi anemia (ie, congenital aplastic anemia) is hereditary (autosomal recessive) and is associated with other phenotypic abnormalities (see Physical Examination). Although it is a congenital anemia, hematologic abnormalities including anemia may not be apparent until age 7-8 years.

Acquired aplastic anemia is seen at any age in an otherwise healthy patient.

Marrow replacement may involve tumor cells, fibrous tissue, or granulomas. Malignancies that metastasize to bone marrow resulting in anemia include neuroblastoma, Hodgkin disease, non-Hodgkin lymphoma (although extensive involvement of the marrow results in a change of definition to leukemia), rhabdomyosarcoma, and primary bone tumors.

Leukemia is the most common malignancy in childhood and may present with just anemia. In infants and young children, neuroblastoma must be considered. Chronic myelocytic leukemia, although rare, may also present as a chronic anemia.

Myelofibrosis with myeloid metaplasia may manifest as fibrous tissue invading the marrow in an uncontrolled fashion; this is one of the conditions within the myeloproliferative spectrum of premalignancies.

Granulomas may occur with any of the TORCH (ie, toxoplasmosis, other infections, rubella, cytomegalovirus infection, herpes simplex) infections in neonates or patients of any age with miliary tuberculosis.

Impaired erythropoietin production occurs in the anemia of renal failure and may be a partial explanation of anemia of chronic disease.

Nutritional deficiency occurs, as seen in iron deficiency or in folic acid or vitamin B-12 deficiency. Protein-energy malnutrition is also associated with chronic anemia.

Hemoglobinopathies of the underproduction type occur, as seen in heterozygous thalassemia syndromes. Normal hemoglobin is underproduced because of mutations affecting production of α-globin or β-globin chains.

Chemotherapy (long-term maintenance chemotherapy) can cause suppression of deoxyribonucleic acid (DNA) synthesis.

Congenital dyserythropoietic anemia can cause dysplastic erythropoiesis and ineffective erythropoiesis, characterized by abnormal-appearing red cell precursors (multinucleated and/or giant erythroblasts) in the bone marrow.

A group of rare congenital, hypochromic, microcytic anemias that does not respond to iron therapy has been described. One of them is due to a mutation of an iron processing protein gene, dimeric metal transporter 1 (DMT-1). It manifests in early infancy as iron deficiency anemia refractory to iron therapy. It is characterized by increased serum ferritin, serum iron, and iron saturation.[7] A similar anemia (iron refractory iron deficiency anemia [IRIDA]), due to mutations in the gene TMPRSS6 (which encodes transmembrane serine protease), has been described in many patients. These patients express inappropriately increased amount of hepcidin, thereby preventing iron absorption from the intestine and release of iron from macrophages.

Increased red cell destruction (hemolysis)

Extracorpuscular causes of hemolysis include (1) mechanical injury to red blood cells (eg, hemolytic-uremic syndrome [HUS], thrombotic thrombocytopenic purpura [TTP], chronic disseminated intravascular coagulopathy [DIC], giant hemangioma [Kasabach-Merritt phenomenon], cardiac valve defects [usually prosthetic], thermal burn); (2) antibodies (chronic autoimmune hemolysis [warm or cold]); (3) infections, drugs, and toxins; and (4) hypersplenism (secondary to splenomegaly of any cause).

Intrinsic causes of hemolysis include (1) red cell membrane defects (HS, elliptocytosis, stomatocytosis, acanthocytosis, paroxysmal nocturnal hemoglobinuria), (2) red cell enzyme abnormalities (glucose-6-phosphate dehydrogenase [G-6-PD] deficiency, pyruvate kinase deficiency, glutathione synthetase deficiency), and (3) hemoglobinopathies (homozygotes of hemoglobins S, C, D, E or the thalassemias or double heterozygotes of the above and unstable hemoglobin, such as Hb Köln).

Anemia due to blood loss

The following may cause anemia:

  • Occult bleeding, usually in unrecognizable quantities via the GI tract

  • Blood loss through the lungs (eg, idiopathic pulmonary hemosiderosis)

  • Blood loss through the kidneys (eg, paroxysmal nocturnal hemoglobinuria)

  • Excessive menstrual blood loss resulting from a coagulopathy (eg, von Willebrand disease) or dysmenorrhea

Epidemiology

Overall prevalence of chronic anemia varies with the ethnic group, geographic location, sex, age, and other factors. Worldwide, undiagnosed iron deficiency is probably the most common cause of isolated chronic anemia, especially in children aged 1-5 years and in teenagers. This may reflect inadequate nutritional iron and/or the effects of chronic parasitic infestations (eg, hookworm). (Anemia is also seen in persons with generalized malnutrition states but not as an isolated finding.)

In Mediterranean and Middle Eastern populations, β-thalassemia trait is an important consideration in the differential diagnosis of chronic anemia at any age; α-thalassemia is seen more commonly in Southeast Asia, India, and the Middle East).

Chronic anemia is a major public health problem in developing and underdeveloped countries. The prevalence is much higher than in developed counties. It is most often due to nutritional deficiency, including iron deficiency, and compounded by parasitic infestations, malaria, human immunodeficiency virus (HIV) disease, and other infections. The Global Burden of Disease 2013 study found that iron deficiency anemia affected 619 million children and adolescents in 2013, making it the primary cause of years lived with disability in this age group.[8] The treatment and prevention of chronic anemia require a global endeavor to raise general nutritional status and eliminate the common infections. An additional important factor is hemoglobinopathies prevalent in malaria-infested areas.

The recently increasing population migration from the endemic areas of hemoglobinopathies to Northern European and North American countries has created new diagnostic and management problems for those countries that have not previously experienced this type of challenge.[9, 10] The endemic areas of hemoglobinopathies are Mediterranean countries, Asian Indian countries, Southeast Asian countries, and sub-Saharan African countries.[10] The hemoglobinopathies with significant frequencies in these regions are both alpha and beta thalassemia, sickle cell anemia, hemoglobin C and hemoglobin E diseases, and combinations of these hemoglobinopathies.[11] Patients with these hemoglobinopathies present with chronic anemia.

Race-related demographics

Certain racial groups are much more likely than others to have inherited anemias. Hemoglobin S syndromes are usually (although not invariably) seen in populations of central African origin; hemoglobin C syndromes are seen in populations of western African origin. Hemoglobin D syndromes are usually seen in populations of northern India, and hemoglobin E syndromes are seen in populations of Southeast Asia. Beta-thalassemias are seen in Mediterranean, Middle Eastern, and Southeast Asian, African, and Indian populations, while α-thalassemias are seen in African, Middle Eastern, and Asian populations.

Chronic anemia due to G-6-PD deficiency is more likely in individuals of Mediterranean, Middle Eastern, or Southeast Asian origin. However, black males have a high prevalence of G-6-PD deficiency that causes a hemolytic episode (acute hemolytic episode, not chronic anemia) upon exposure to a strong oxidant, such as a moth balls.

Sex-related demographics

Males are much more likely to have G-6-PD deficiency than are females, although chronic anemia due to this enzyme deficiency in blacks is rare.

Immune hemolytic anemias are more common in adolescent females because of the higher prevalence of autoimmune diseases.

Chronic iron deficiency or chronic iron deficiency anemia is relatively common in menstruating teenagers.

Age-related demographics

The most common pediatric anemia is dietary iron deficiency anemia. It is most prevalent from age 6 months to 3 years. Onset of Diamond-Blackfan anemia is usually in early infancy. Transient erythroblastopenia of childhood (TEC) typically affects patients aged 6 months to 6 years.

Onset of homozygous or doubly heterozygous hemoglobinopathies (β-chain mutation such as sickle cell disease, hemoglobin E disease, β-thalassemia trait) occurs in later infancy, while α-chain mutation (α-thalassemia, hemoglobin H disease) manifests shortly after birth.

The toddler years are the period of lead poisoning.

Onset of menses leads to susceptibility to iron deficiency.

Prognosis

The prognosis is a function of the underlying cause of secondary anemia. Generally, the prognosis in patients with stable chronic anemia is good.

Death resulting from chronic anemia is extremely uncommon because of the adaptive ability of the cardiovascular system.

Morbidity is also uncommon and is usually related to the primary disease process rather than to the anemia per se. Shortness of breath and easy fatigability are unpredictable, because some children tolerate extremely low hemoglobin concentrations, in the range of 4-5 g/dL, without any problem, whereas other children are symptomatic with values at 2 times that concentration. No evidence suggests that such low hemoglobin concentrations pose any systemic problems, but low concentrations can be distressing to children and families.

There is a remarkable paucity of data regarding what hemoglobin level is good enough for a patient with chronic anemia to maintain a normal growth rate. Although patients with β-thalassemia major are known to have growth failure, the confounding factor of iron overload and endocrinopathy prevents a straight forward interpretation of the relationship between hemoglobin level and growth.

In situations of true red blood cell (RBC) aplasia, the anemia eventually reaches a point at which compensatory mechanisms are no longer adequate, and congestive heart failure or syncope can result.

Patient Education

Keep mothballs and naphthalene out of all children’s reach, in case he or she may have G-6-PD deficiency.

Avoid strenuous activities, particularly contact sports if a child has splenomegaly, to avoid rupture.

Teach parents to palpate the spleen in patients with sickle cell disease to detect splenic sequestration.

Remember to give folic acid daily to children with chronic hemolytic anemia.

Educate parents regarding the possibility of aplastic crisis in children with sickle cell disease and HS (sudden pallor, lethargy, and anorexia).

α-Thalassemia trait is most commonly confused with iron deficiency anemia. It would be helpful to write the diagnosis on a paper and give it to parents so that the children will not be given iron therapy unnecessarily by other physicians.

Provide appropriate genetic counseling to patients with hereditary forms of anemia.

Advise parents regarding the risks of blood transfusion.

Parents should also be made aware that in children older than 8 months, nourishment through breastfeeding alone results in iron deficiency and iron deficiency anemia.

For patient education information, see the Skin Conditions and Beauty Center, as well as Anemia and Bruises.

 

Presentation

History

Patients with chronic anemia are usually asymptomatic, even with remarkably low levels of hemoglobin.

Symptoms more often relate to the underlying cause; for example, irritability, pagophagia (ice eating), and lethargy can occur if the anemia is secondary to iron deficiency; paresthesia of hands and feet, if the anemia is due to vitamin B-12 deficiency; left upper quadrant pain, if the anemia is the result of HS and splenomegaly; intolerance to fatty foods, if the anemia is caused by chronic hemolysis with subsequent cholelithiasis; and constipation and cold intolerance, if the anemia is the result of hypothyroidism. Undetected celiac disease or renal failure sometimes manifest as chronic anemia and failure to thrive. Diarrhea and intermittent abdominal pain and chronic anemia may be due to Crohn disease or celiac disease.

Hemoglobin levels as low as 5-6 g/dL are well tolerated in most patients, and patients do not require transfusion. Parents, however, frequently note that patients become much more active following a transfusion.

Inquire carefully regarding any evidence of blood loss (eg, hemoptysis, hematochezia, melena, tarry stools, hematuria, menorrhagia). In endemic areas, a history of papulovesicular skin lesions on the feet may suggest a diagnosis of hookworm infestation.

Age is always an important consideration. Nutritional iron deficiency is seen in older infants and toddlers (aged 6 mo to 3 y), whereas iron deficiency due to blood loss occurs in menstruating girls. The deficiency can be surprisingly severe, but transfusion is indicated only in the rare circumstance of impending high-output cardiac failure.

The patient's sex must always be considered in hemolytic anemias. Severe G-6-PD deficiency may be seen as a chronic nonspherocytic anemia, usually in males.

Ethnicity is a factor in the hemoglobinopathies. Hemoglobin S syndromes are usually seen in populations of central African origin. Hemoglobin C syndromes are seen in populations of western African origin. Hemoglobin D syndromes are usually seen in the population of northern India. Hemoglobin E syndromes are seen in populations of Southeast Asia. Beta-thalassemias are seen in Mediterranean, Middle Eastern, Indian, and Southeast Asian populations. Thalassemias involving the β chain are clinically silent in the first months of life and become apparent only after 6-9 months because of cessation of γ-chain production. Alpha-thalassemias are seen in African, Middle Eastern, and Asian populations.

Dietary history is important with regard to the amount and source of milk ingested by infants and toddlers and to their risk of chronic iron deficiency (24 oz of milk/d or more is a clear risk factor for nutritional iron deficiency in infants and young children). Food aversions (eg, to leafy vegetables) can cause predisposition to folic acid deficiency. Folic acid deficiency also occurs in children fed exclusively with goat's milk. Certain diets (eg, vegan diet) can result in vitamin B-12 deficiency if continued over several years.

Blood loss over an extended period results in iron deficiency. Chronic infection or inflammation, such as chronic pyelonephritis, bacterial endocarditis, osteomyelitis, or juvenile idiopathic arthritis, results in the anemia of chronic disease. Any inflammatory process, such as chronic renal failure or a chronic collagen vascular disease, also results in the anemia of chronic disease. Episodic pain in the chest, abdomen, or extremities may be due to a vasoocclusive crisis of sickle cell disease.

Drugs with oxidant properties trigger hemolysis because of a G-6-PD deficiency, and hemolysis may become chronic if the drugs are continued for an extended period. Exposure to known marrow toxins, such as benzene or the antibiotic chloramphenicol, may result in aplastic anemia months after actual exposure.

Neonatal history may provide useful information regarding a possibly overlooked congenital process that manifested after birth. Exaggerated jaundice as a newborn may be a clue for HS or G-6-PD deficiency.

Family history is critical in any hereditary anemia. Anemia occurs in families with thalassemia syndromes. Gallstones, early cholecystectomy, and splenomegaly are common in families with HS.

Physical Examination

Vital signs, in contrast to those in acute anemia (such as anemia due to acute blood loss), are rarely abnormal in patients with chronic anemias, because adaptive mechanisms are well developed. Tachycardia on exertion is usually the only exception to this rule.

Growth curves may be affected by chronic anemia, usually in a symmetrical fashion, although head circumference is not affected.

Fanconi anemia is characterized by some or all of the following dysmorphic features: small stature, small head, absent thumbs, and café-au-lait spots.

Chronic hemolysis with extramedullary hematopoiesis, such as in β-thalassemia major or sickle cell anemia, may result in frontal bossing and prominent cheeks.

Pallor may be difficult to appreciate unless carefully sought. Pallor of the conjunctivae, nail beds, palm creases, or gums may be recognized. Parents and friends usually do not notice any difference, because the problem is chronic.

Scleral icterus is common in chronic hemolytic anemia. The icterus waxes and wanes.

Petechiae and excessive bruises may indicate thrombocytopenia resulting from marrow aplasia or replacement by malignant cells. Less commonly, the same findings may reflect vasculitis resulting from infection or collagen vascular disease.

Papulovesicular lesions on the feet may suggest hookworm infestation.

Systolic murmur may be apparent and is usually loudest along the left sternal border, as is appropriate in any flow murmur.

Gallop rhythm, cardiomegaly, and hepatic enlargement may indicate early congestive heart failure.

Splenomegaly may indicate chronic hemolysis, as in HS, or elliptocytosis. It may also suggest hypersplenism due to many causes, such as portal hypertension or storage disease. Hypersplenism usually causes mild leukopenia and thrombocytopenia as well. Splenomegaly may also indicate leukemia, myelofibrosis, myeloproliferative disorder, or myelodysplastic syndrome.

 

DDx

Diagnostic Considerations

Conditions to consider in the differential diagnosis of pediatric chronic anemia, in addition to those in the next section, include the following:

  • Acquired immunodeficiency syndrome (AIDS)

  • Congenital dyserythropoietic anemia

  • Diamond-Blackfan anemia

  • Red cell enzyme deficiencies, including G-6-PD deficiency, pyruvate kinase deficiency, and glutathione synthetase deficiency

  • Hemophagocytic lymphohistiocytosis (HLH), congenital or acquired

  • Iron refractory iron deficiency anemia (IRIDA)

  • Nutritional iron deficiency

  • Paroxysmal nocturnal hemoglobinuria

  • Pure red cell aplasia

  • Rheumatoid arthritis

  • Sideroblastic anemia

  • Unstable hemoglobinopathies

  • Hookworm infection

  • Hypothyroidism

  • Myelodysplastic syndrome

  • Myelofibrosis

  • Systemic lupus erythematosus

  • Thalassemia

  • Red cell membrane protein abnormalities, including HS, hereditary elliptocytosis, pyropoikilocytosis, and hereditary xerocytosis

Differential Diagnoses

 

Workup

Approach Considerations

To evaluate anemia, obtain initial laboratory tests, including a complete blood count (CBC), a reticulocyte count, and a review of the peripheral smear. Imaging studies can play a role in the diagnosis of underlying disease, while bone marrow aspiration and biopsy can be used to identify the presence of tumor cells and determine cellular morphology.

Screening for anemia

American Academy of Pediatrics (AAP) guidelines recommend universal screening for anemia in children at about age 12 months, for a hemoglobin threshold of 110 g/L.[12]  However, this has been challenged in a study performed on well children in Toronto. That report found a correspondence between a hemoglobin level of 110 g/L and an undesirably low serum ferritin level of 4.6 μg/L. A hemoglobin threshold to 120 g/L, however, corresponded to a serum ferritin level of 17.9 μg/L, an apparently rational cutoff level.[13]

With ever-increasing evidence that during brain development, iron deficiency itself, not anemia, causes irreversible neurocognitive deficiency,[14] one needs to be certain that infants and toddlers not only do not have iron deficiency anemia but also do not have iron deficiency without anemia.

 

CBC Count

Note different normal ranges for different ages. Some laboratories provide only a uniform reference range for the entire pediatric age group and not for specific age groups. Interpret this carefully to avoid misdiagnosis. Hemoglobin and hematocrit levels can be used interchangeably, depending on professional preference and familiarity. Essentially, the hematocrit level is 3 times the hemoglobin value.

Red cell indices are quite informative, particularly mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), and red cell distribution width (RDW).

Note that reference ranges for these parameters also vary with age. Because of this, the author suggests using the MCV cut-off point of 70 plus age in years for patients aged 7 years or younger (eg, MCV < 72 is abnormal for a patient aged 2 y).

A high RDW (eg, ≥19-20) with microcytic picture is most often indicative of iron deficiency anemia in the pediatric population. The RDW is also very high in anemia with reticulocytosis, including sickle cell disease.

Macrocytosis suggests folate/vitamin B-12 deficiency or hypothyroidism; however, nutritional deficiencies of these vitamins are rare. (The author encountered a 7-year-old boy with chronic abdominal pain and persistent MCV of between 90 and 100. This child turned out to have primary hypothyroidism; his newborn screening was allegedly normal.) Diamond-Blackfan anemia, aplastic anemia, and myelodysplastic syndrome often present with macrocytic anemia. Patients with sickle cell anemia who have been on hydroxyurea also show macrocytosis.

Note that in newborns, MCV is physiologically in the range of 120-102. Beyond the immediate newborn period, MCV exceeding 98 is very uncommon in children; if the volume exceeds 98, it usually indicates a serious hematologic problem, such as myelodysplastic syndrome, leukemia, aplastic anemia, Diamond-Blackfan anemia, or metabolic disorder.

In most, but not all cases of HS, the MCHC exceeds the upper limit of the reference range.

Reticulocyte Count

Reticulocytes are immature, nonnucleated RBCs. An increase in the reticulocyte count (in particular, the absolute reticulocyte count) indicates active erythropoiesis.

The relative reticulocyte count is useful in determining whether anemia is caused by decreased production, increased destruction, or loss of RBCs. An elevated number of reticulocytes is (eventually) observed in individuals with anemia caused by hemolysis or blood loss; note that the absence of reticulocytosis may simply reflect a lag in the response to the acute onset of anemia.

The term reticulocyte count is often inaccurately used to refer to the percentage of reticulocytes, a value that must be interpreted in light of the degree of anemia. Thus, a finding of 2-3% reticulocytes (vs the reference value of approximately 1%) in a patient in whom the hemoglobin level is only one third to one half of reference range does not indicate a reticulocyte response.

Some clinicians prefer to use either the absolute number of reticulocytes/μL of blood or a reticulocyte percentage that is corrected for the degree of anemia. The corrected reticulocyte count equals (patient hematocrit)/(reference range hematocrit) multiplied by the percentage reticulocyte count.

Peripheral Smear

Examination of the peripheral smear is particularly helpful in normocytic anemia. The red cell morphology itself is quite often diagnostic. The following are examples of abnormal cell morphology in normocytic picture:

  • Ghost, bite, blister, or helmet cells (G-6-PD), as depicted in the image below

    Blood smear from a black male with glucose-6-phosp Blood smear from a black male with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency that resulted in acute hemolysis. Note blister (helmet or bite) cells and very dense spherocytic cells. The blood smear is virtually pathognomic of this disorder.
  • Spherocytes (HS, autoimmune hemolytic anemia, ABO hemolytic anemia in newborns), as depicted in the image below

    Blood smear of hereditary spherocytosis (HS). Note Blood smear of hereditary spherocytosis (HS). Note many spherocytic cells. Not all patients with HS are anemic.
  • Target cells (hemoglobin C, liver disease, thalassemia), as depicted in the image below

    Blood smear of hemoglobin C trait. Note numerous t Blood smear of hemoglobin C trait. Note numerous target cells. Target cells are a characteristic of this hemoglobinopathy. The trait patient has no anemia. Target cells are also seen in patients with iron deficiency anemia, thalassemia, sickle cell disease, and liver disease.
  • Sickle-shaped cells (drepanocytes) (sickle cell disease), as depicted in the image below

    Blood smear of a patient with homozygous sickle ce Blood smear of a patient with homozygous sickle cell disease. Note several sickle cells, a nucleated RBC, and a red cell with Howell-Jolly body (indicated by an arrow), evidence of functional asplenia.
  • Schistocytes or fragmented cells (microangiopathic hemolytic anemia), as depicted in the image below

    A blood smear showing a few schistocytes. This pat A blood smear showing a few schistocytes. This patient had Kaposi type hemangioendothelioma with periodic microangiopathic hemolysis and disseminated coagulopathy (Kasabach-Merritt phenomenon).
  • Stippled RBCs, basophilic stippling (in all conditions with increased reticulocyte count and in lead poisoning and 5' nucleotidase deficiency), as depicted in the image below

    A blood smear of a patient with beta thalassemia t A blood smear of a patient with beta thalassemia trait. Note red cells pointed by arrows. Multiple bluish dots in the cells are called basophilic stipplings and consist of aggregated ribosomes. They are often present in immature red cells such as reticulocytes.
  • Increased polychromasia (reticulocytosis)

Normal RBC morphology does not exclude hemolysis.

Additional Laboratory Tests

Additional laboratory tests that may be indicated in the diagnosis and treatment of patients with acute anemia include the following:

  • Bilirubin level, lactate dehydrogenase (LDH) level (hemolytic anemia), and serum haptoglobulin level (decreased or none in chronic hemolytic anemia)

  • Direct antiglobulin or Coombs test (autoimmune hemolytic anemia)

  • Hemoglobin electrophoresis (hemoglobinopathies)

  • Hemoglobin A2 quantitation (β-thalassemia trait, increased above 3.5%)

  • Red cell enzyme studies (eg, G-6-PD, pyruvate kinase), osmotic fragility (spherocytosis) (G-6-PD-deficient red cells may show a normal G-6-PD screening result in the presence of reticulocytosis, and therefore, actual enzyme quantitation is strongly recommended; a normal enzyme level in the presence of reticulocytosis indicates a deficiency)

  • Iron, total iron-binding capacity, and ferritin levels (iron deficiency anemia); soluble (serum) transferrin receptor (differentiation of iron deficiency anemia [increased] from anemia of chronic disease [normal]); free erythrocyte protoporphyrin (FEP) or zinc erythrocyte protoporphyrin (for partially treated iron-deficiency anemia), increased in the presence of normal serum iron)

  • Stool for occult blood (examine at least 3 specimens; in the presence of demonstrated intestinal blood loss, any given stool specimen finding may be negative, which is why multiple specimens are required before one can conclude a negative finding.)

  • Folate and vitamin B-12 levels (macrocytic/megaloblastic anemia)

  • Blood typing and cross matching to assess possible isoimmune anemia in a neonate and to prepare for transfusion

  • Viral antibody titers and viral DNA by PCR assay (eg, Epstein-Barr virus, cytomegalovirus, parvovirus B19, HIV)

  • Urinalysis and blood urea nitrogen (BUN)/creatinine levels to assess renal function

  • Thyroxine (T4)/thyroid-stimulating hormone (TSH) levels to exclude hypothyroidism

A report by Abdullah et al convincingly argued against the appropriateness of screening tests using hemoglobin and serum ferritin levels of 110 g/L and 12 μg/L, respectively, as thresholds for detecting iron deficiency. In children aged 12-36 months with a hemoglobin level of 110g/L, the serum ferritin level may be as low as 2.4 μg, indicating iron deficiency. A linear relationship exists between serum ferritin level and blood hemoglobin concentration until—at a hemoglobin level of 121g/L and a ferritin concentration of 17.9 μg/L—ferritin increases no longer raise hemoglobin levels. The investigators therefore suggest that 121 g/L, rather than 110 g/L, serve as the hemoglobin threshold for iron deficiency.[13]

Radiography and Echocardiography

Chest radiography and echocardiography are indicated for suspected congestive heart failure.

Skull films and films of the hands and wrists may show expanded marrow space. Spine radiography may reveal a paraspinal (vertebral) pseudotumor due to marked expansion of the bone marrow (usually in thalassemia major).

Ultrasonography and CT Scanning

In cases of suspected hypersplenism, using ultrasonography or computed tomography (CT) scanning to detect a large spleen is not recommended. If a thorough physical examination does not detect a palpable spleen, hypersplenism is not a likely diagnosis.

Ultrasonography of the gallbladder for the presence of gallstones in patients with chronic hemolytic anemia may be valuable if the patient has recurrent abdominal pain. Abdominal pain due to gallstones in children is not always in the right upper quadrant. The author has received reports of left upper quadrant pain in children with gallstones that subsided after cholecystectomy.

Additional Studies

Other imaging studies are indicated to detect underlying pathology, including the following:

  • Magnetic resonance imaging (MRI) of bones for suspected osteomyelitis

  • Positron emission tomography (PET) scanning for suspected lymphoma (Hodgkin lymphoma and non-Hodgkin lymphoma)

  • Endoscopy for GI ulcers, inflammatory bowel disease, celiac disease

Exclude impending high-output congestive heart failure using electrocardiography (ECG).

Specimens from bone marrow aspiration and biopsy are often essential in helping to characterize overall cellularity, the presence or absence of tumor cells, the morphology and maturation of red cell precursors, and the presence or absence of stainable iron.

Bone marrow aspiration and biopsy can be used to rule out leukemia, aplastic anemia, tumor cells in the marrow (such as neuroblastoma), megaloblastosis, marrow dysplasia, and hemophagocytosis. It can also be employed in detection of the absence of 1 cell line due to pure red cell aplasia or parvovirus infection.

 

Treatment

Approach Considerations

Chronic anemia merits prompt, if not immediate, attention.

Common sense should prevail in recognizing that, although anemia may be quite profound, the patient is usually well. In this circumstance, it is prudent not to follow the hemoglobin level too closely and thereby create unnecessary apprehension in the family. When physiologic adaptive mechanisms are in place, most children do well, and what is abnormal in others becomes normal in these children. At this point, the art of medicine takes precedence over the science of medicine.

Patients with chronic anemias rarely need inpatient care, even during the diagnostic process. Deal with complications on an ad hoc basis.

Go to Anemia and Anemia of Prematurity for complete information on these topics.

Transfusion

Exclusion of impending high-output cardiac failure is the most important issue. High-output failure is the only reason that blood transfusion is necessary.

RBC transfusions must be performed cautiously; rapid expansion of intravascular volume may cause congestive heart failure in a well-compensated patient. Two or more small aliquots of RBCs may need to be administered, with a few hours of reequilibration between transfusions.

Rapid volume expansion with normal saline, usually performed in the emergency department in chronically anemic children, also may cause congestive heart failure. One needs to assess the benefits and risks of volume expansion in this situation before one decides to give a normal saline bolus.

Elective surgery can usually be performed without preoperative transfusion as long as blood is available.

For patients who require long-term transfusional support, identification of a limited number of dedicated blood donors is desirable. Donors are selected on the basis of detailed antigenic crossmatching with the patient in hopes of avoiding development of immune-mediated hemolysis. Obtain serum ferritin values every 6-10 units of transfusion. If ferritin exceeds 1000 µg/L, start deferasirox or deferoxamine therapy.

Splenectomy

Splenectomy is often indicated in patients with HS, but not necessarily during the pediatric age. Delay splenectomy until patients are aged 8-9 years, by which time immunity to encapsulated bacteria is well established. Typically, this is also before hemolysis sufficient to result in bilirubin gallstones has occurred. However, in some patients, repetitive splenic sequestration occurs, necessitating earlier splenectomy. Intrafamilial variation is common in terms of severity of anemia; thus, history of childhood splenectomy in a parent does not necessarily indicate a need for splenectomy in the affected child.

Prevention of Anemia

Dietary iron deficiency anemia can be prevented by starting supplemental iron when infants are weaned off breast milk or regular formula at age 8-12 months; 1-2 mg/kg/d of elemental iron is usually sufficient to prevent iron deficiency anemia. (See current American Academy of Pediatrics guidelines.[12] ) This should be continued until the child more or less eats regular table foods as the main source of calories. Treatment of iron deficiency anemia needs a higher dose of iron, usually 6 mg/kg/d of elemental iron, for at least 3 months.

Infants of vegan mothers who exclusively breast feed may develop megaloblastic anemia and neurologic signs due to B12 deficiency. These infants should be given B12 supplementation.

There are concerns regarding the potential deleterious developmental effects of excess iron exposure in early childhood. In a randomized evaluation of low-iron versus iron-supplemented formulas in Chile, a 10-year follow-up suggests the presence of subtle neurocognitive deficits specifically in those infants with higher hemoglobin levels at the time of randomization.[15]

Consultations

Many chronic anemias can be diagnosed and managed by generalists. However, when subtle distinctions in morphology or interpretation of laboratory data relative to hemolytic anemia are important, a pediatric hematologist is usually needed. Certainly, when bone marrow aspiration and biopsy are contemplated, the experience of a pediatric hematologist is essential.

Unless readily explained by an increased reticulocyte count or another physiologic condition, macrocytosis usually warrants consultation with a hematologist.

A number of children with hypochromic anemia outside the dietary iron deficiency age are ultimately found to have chronic GI bleeding. It is essential in this situation to work closely with a pediatric gastroenterologist.

Although rare, congenital sideroblastic anemia may present as hypochromic, microcytic anemia in infants. Ringed sideroblasts, ie, erythroid precursors with pathologic, perinuclear iron-loaded mitochondria, occur in bone marrow, characterizing this disorder of abnormal erythropoiesis. Bone marrow examination is necessary to establish the diagnosis.[16]  

Long-Term Monitoring

Monitor growth and development, nutritional status, degree of splenomegaly, formation of gallstones, onset of puberty, endocrine status, and any potential complications related to underlying disorders.

 

Medication

Medication Summary

Medications are dictated by underlying disorders.

Chronic anemia due to intrinsic RBC abnormalities such as hemoglobinopathies, unstable hemoglobins, red cell membrane abnormalities, and red cell enzyme abnormalities do not warrant specific medications.

Nutritional anemia can be treated with supplements of deficient factors.

Recombinant erythropoietin has been useful in managing anemia related to chronic renal failure, rheumatoid arthritis, AIDS, and more recently in patients with DMT1 mutation.[17] Hemoglobin levels and general feelings of well-being have been much improved in patients since recombinant erythropoietin became commercially available.

Vitamins

Class Summary

These agents are essential for normal metabolism and DNA synthesis.

Cyanocobalamin (Vitamin B12, Athlete, CaloMist)

This agent is used to treat megaloblastic anemia resulting from vitamin B-12 deficiency. Deoxyadenosylcobalamin and hydroxocobalamin are active forms of vitamin B-12 in humans. Vitamin B-12 synthesized by microbes but not humans or plants. Deficiency may result from intrinsic factor deficiency (pernicious anemia), partial or total gastrectomy, or diseases of the distal ileum. Deficiency initially and typically manifests as macrocytic anemia, although neurologic symptoms may be present. They can also cause confusion or delirium in elderly patients.

It is essential for normal erythropoiesis and is required for healthy neuronal function and normal function of rapidly growing cells.

Iron Salts

Class Summary

These agents are useful for the treatment of iron deficiency anemia.

Ferrous sulfate

This is the mainstay treatment for patients with iron deficiency anemia. It is used as a building block for hemoglobin synthesis in treating anemia. It allows transportation of oxygen via hemoglobin and is necessary for oxidative processes of living tissue. Treatment should continue for about 2 months after correction of anemia and the etiological cause in order to replenish the body stores of iron. Ferrous sulfate is the most common and inexpensive form of iron used. Tablets contain 50-60 mg of iron salt. Other ferrous salts are used and may cause less intestinal discomfort because they contain smaller doses of iron (25-50 mg). Oral solutions of ferrous iron salts are available for use in pediatric populations.

Dietary iron deficiency anemia can be prevented by starting supplemental iron when infants are weaned off breast milk or regular formula at age 8-12 months.

The authors recommend 6 mg/kg/d of elemental iron for 6 months for infants and children with severe iron deficiency anemia. Please note the dose is based on the weight of elemental iron, not of iron salts.

Colony Stimulating Factors

Class Summary

These agents are used to manage anemia related to chronic renal failure, rheumatoid arthritis, and AIDS.

Epoetin alfa (Procrit, Epogen)

This is a purified glycoprotein produced from mammalian cells and modified with the gene coding for human erythropoietin (EPO). The amino acid sequence is identical to that of endogenous EPO. Its biological activity mimics human urinary EPO, which stimulates division and differentiation of committed erythroid progenitor cells and induces the release of reticulocytes from bone marrow into the blood stream.

Chelation Agents

Class Summary

Iron overload (usually from multiple transfusions) may require chelation therapy, which usually begins when the ferritin level is greater than 1000 ng/mL.

Deferoxamine mesylate (Desferal)

Deferoxamine is freely soluble in water. Approximately 8 mg of iron is bound by 100 mg of deferoxamine. Deferoxamine is excreted in urine and bile and discolors the urine red. It readily chelates iron from ferritin and hemosiderin but not from transferrin. It is most effective when provided to the circulation continuously by means of infusion. Deferoxamine may be administered by IM injection, slow infusion, SC bolus, or continuous infusion. It does not effectively chelate other trace metals of nutritional importance.

Deferasirox (Exjade, Jadenu, Jadenu Sprinkle)

Deferasirox is available as a tablet for oral suspension. It is an oral iron-chelating agent demonstrated to reduce liver iron concentration in adults and children who receive repeated RBC transfusions. Deferasirox binds iron with high affinity in a 2:1 ratio. It is approved for treatment of treat chronic iron overload due to multiple blood transfusions. Treatment initiation is recommended when evidence of chronic iron overload (ie, transfusion of about 100 mL/kg packed RBCs [about 20 U for 40-kg person] and serum ferritin level consistently >1000 µg/L) is noted.

Deferiprone (Ferriprox)

1,2 dimethyl-3-hydroxypyridine-4-one is a member of a family of hydroxypyridine-4-one (HPO) chelators that requires 3 molecules to fully bind iron (III), each molecule providing 2 coordination sites (bidentate chelation). Its half-life is approximately 2 hours. The inactive metabolite is predominantly excreted in urine. Deferiprone is indicated for transfusional iron overload caused by thalassemia syndromes when current chelation therapy is inadequate.