Pediatric Chronic Anemia

Updated: Aug 29, 2022
  • Author: Susumu Inoue, MD; Chief Editor: Lawrence C Wolfe, MD  more...
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Overview

Practice Essentials

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.)

Complications associated with chronic anemia include 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 oxygen reduction - A study by Vu et al indicated that in patients with chronic anemia, the cerebral oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO 2) are reduced compared with controls. Moreover, CMRO 2 impairment corresponded with anemia severity, “independent of transfusion status and anemia subtype.” The reduced cerebral oxygen consumption could potentially result in cerebral hypoxia and ischemia. [2]
  • Cerebral infarction - In a small number of severely anemic children (Hb 2.4 and 3.7), silent cerebral infarction lesions were demonstrated on magnetic resonance imaging (MRI) that was performed as a part of a research study. [3]  Some of them showed subtle neurologic abnormalities with careful neurological examination. The long-term consequences of these lesions are unknown in terms of the child's neurologic 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. [4]

Signs and symptoms of pediatric chronic anemia

The following points should be taken into consideration:

  • Growth curves may be affected by chronic anemia, usually in a symmetrical fashion
  • 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
  • Scleral icterus is common in chronic hemolytic anemia
  • Petechiae and excessive bruises may indicate thrombocytopenia resulting from marrow aplasia or replacement by malignant cells
  • Papulovesicular lesions on the feet may suggest hookworm infestation
  • Systolic murmur may be apparent
  • 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; splenomegaly may also indicate leukemia, myelofibrosis, myeloproliferative disorder, or myelodysplastic syndrome

Workup in pediatric chronic anemia

Laboratory tests include the following:

  • Complete blood count (CBC)
  • Reticulocyte count
  • Review of the peripheral smear

Imaging studies include the following:

  • Chest radiography and echocardiography - 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 - Imaging of the gallbladder for the presence of gallstones in patients with chronic hemolytic anemia may be valuable if the patient has recurrent abdominal pain
  • Other imaging studies are indicated to detect underlying pathology, including the following - MRI of bones for suspected osteomyelitis, positron emission tomography (PET) scanning for suspected lymphoma (Hodgkin lymphoma and non-Hodgkin lymphoma), endoscopy for gastrointestinal (GI) ulcers, inflammatory bowel disease, and celiac disease

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.

Management of pediatric chronic anemia

Management strategies include the following:

  • Transfusion - High-output cardiac failure is the only reason that blood transfusion would be needed
  • Splenectomy - Often indicated in patients with HS, but not necessarily during the pediatric age

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. 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.

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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, [5] although human herpesvirus type 6 [6] and parvovirus B19 [7] 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. [8] 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

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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. [9] 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. [10, 11] The endemic areas of hemoglobinopathies are Mediterranean countries, Asian Indian countries, Southeast Asian countries, and sub-Saharan African countries. [11] 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. [12] 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.

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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.

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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.

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