Pediatric Chronic Anemia

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

• Decreased red cell production
• Increased red cell destruction (hemolysis)
• Combined etiologies - Decreased red cell production and increased hemolysis
• Blood loss

Decreased red cell production

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

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

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) in TEC is not elevated and the anemia is normocytic and normochromic.

Nutritional anemia can take the form of the following:

• Iron deficiency - Extremely common; vulnerable ages are between 6 and 24 months, particularly in infants who are strictly breastfed without iron supplements
• Copper deficiency - In children exclusively on jejunal tube feeding ^[8]
• Folic acid deficiency - Most common in infants fed strictly with goat milk
• Vitamin B12, transcobalamin deficiency - Common in infants breastfed by vegetarian or vegan mothers
• Protein-energy malnutrition is also associated with chronic anemia

A growing number of hereditary anemias caused by genetic mutations have been described, with the list including the following:

• Fanconi anemia (ie, congenital aplastic anemia) - This is hereditary (autosomal recessive) and is usually, but not always, associated with phenotypic abnormalities (see Physical Examination); although it is a congenital anemia, hematologic abnormalities, including anemia, may not be apparent until age 7-8 years
• Diamond-Blackfan anemia - Anemia is present at birth and, if not, occurs during the first 3 months of life; usually macrocytic anemia; heterozygous mutations in ribosomal protein genes are involved in 75% of patients with Diamond-Blackfan anemia ^[9]
• Loss of function variants in DNA polymerase epsilon 1 - In two children (siblings) described by Takeuchi et al, the patients had short stature and facial dysmorphism, transfusion-dependent severe anemia, and reticulocytopenia; the bone marrow showed erythroid hypoplasia ^[10]
• Infantile malignant osteopetrosis - The common clinical features are hepatosplenomegaly and visual and hearing impairment; skeletal radiographs show extensive increased bone density ^[11]
• Thiamine-responsive megaloblastic anemia (Rogers syndrome) - Macrocytic anemia, bilateral sensorineural hearing loss, and diabetes mellitus; results from a mutation in the SLC19A2 gene ^[12]
• Congenital dyserythropoietic anemia (CDA) type 1 - Moderate-to-severe macrocytic anemia; can cause dysplastic erythropoiesis and ineffective erythropoiesis, characterized by abnormal-appearing red cell precursors (multinucleated and/or giant erythroblasts) in the bone marrow; anemia may be present at birth or during childhood, or it may exist later, during adulthood; affected infants may show hepatomegaly, jaundice, and intrauterine growth retardation; autosomal recessive inheritance; genetic investigation will show biallelic pathogenic variants in CDAN1 or CDIN1 ^[13]
• Imerslund-Grasbeck syndrome - Congenital macrocytic anemia due to malabsorption of vitamin B12; autosomal recessive inheritance due to mutations in the gene CUBN (encoding cubilin) or AMN (encoding amnionless) ^[14]
• Pearson pancreatic syndrome ^[15]
• Rare, inherited microcytic hypochromic anemias ^[16]

With regard to the last item, a group of rare congenital, hypochromic, microcytic anemias that do not respond to iron therapy has been described, including the following:

•  X-linked sideroblastic anemia - This results from mutations in the erythroid-specific ALAS2 gene, situated at Xp11.21; anemia may not be present until later in life; bone marrow shows ringed sideroblasts
• Divalent metal transporter 1 (DMT1) mutation - This anemia caused by a defect in iron uptake in the intestine as well as by, in the peripheral tissues, defective iron acquisition and employment; anemia is present at birth; it manifests in early infancy as iron deficiency anemia refractory to iron therapy and is characterized by increased or normal serum ferritin, increased serum iron, and iron saturation ^[17]
• TMPRSS6 mutation - The TMPRSS6 gene controls hepcidin production, with the mutated gene increasing such production, thereby preventing iron absorption from the intestine and release of iron from macrophages
• Hereditary atransferrinemia - Iron overload in the liver, pancreas, and heart.
• Hereditary  aceruloplasminemia - Iron overload and progressive neurodegeneration; patients show iron deposition in the liver, pancreas, basal ganglia, and other organs; diabetes mellitus, retinal degeneration, ataxia, and, late in life, dementia develop

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 in patients of any age with miliary tuberculosis.

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

Hemoglobinopathies of the underproduction type include heterozygous thalassemia syndromes. Normal hemoglobin is underproduced because of mutations affecting production of α-globin or β-globin chains.

Long-term maintenance chemotherapy can cause suppression of DNA synthesis.

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], hereditary hemorrhagic telangiectasia, ^[18] cardiac valve defects [usually prosthetic], ^[19] thermal burns); (2) antibodies (chronic autoimmune hemolysis [warm or cold]); ^[20] (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), (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, Hb Nottingham, and Hb Zürich).

Anemia due to decreased red cell production and increased hemolysis

This includes the following:

• Anemia of infection and inflammation
• Anemia of chronic kidney disease
• Anemia of inflammatory bowel disease - Such as Crohn disease and ulcerative colitis
• Anemia of autoimmune disease - Such as systemic lupus erythematosus and idiopathic rheumatoid arthritis

Anemia due to blood loss

The following may cause anemia:

• Occult bleeding, usually in unrecognizable quantities via the gastrointestinal (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

The overall prevalence of chronic anemia varies with 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 nations, with the prevalence being much higher than in developed countries. 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.

Nonetheless, according to a report by Stevens et al, while 48% of children worldwide aged 6-59 months had anemia in 2000, by 2019 this figure had fallen to 40%. The investigators stated that about 25-50% of children in this age group and women aged 15-49 years, with anemia, have iron deficiency; however, in populations in which the burden of anemia and infections is high, the proportion of anemia related to iron deficiency may be lower. ^[21]

The treatment and prevention of chronic anemia require a global endeavor to raise general nutritional status and eliminate common infections. An additional important factor is hemoglobinopathies prevalent in malaria-infested areas.

The 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. ^{[22, 23]} The endemic areas of hemoglobinopathies are Mediterranean countries, Asian Indian countries, Southeast Asian countries, and sub-Saharan African countries. ^[23] The hemoglobinopathies with significant frequencies in these regions are α- and β-thalassemia, sickle cell anemia, hemoglobin C and hemoglobin E diseases, and combinations of these hemoglobinopathies. ^[24] 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. β-thalassemias are seen in Mediterranean, Middle Eastern, 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 (an acute hemolytic episode, not chronic anemia) upon exposure to a strong oxidant, such as 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 2 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 mutations 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; such exposure to lead may result in anemia owing to impaired heme synthesis, red cell hemolysis, and shortened survival of red cells.

Onset of menses leads to susceptibility to iron deficiency.

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 straightforward 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.

Keep mothballs and naphthalene out of all children’s reach, in case they 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, 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 their 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.

Blue sclerae occur in several conditions, including iron deficiency, and thus when caregivers notice them, iron should be checked.