Pallor, Pediatric

Basics

Description

- Ages between 6 months and 3 years or adolescent females - Peak age ranges for iron deficiency

- Race - African: hemoglobins S and C,α- and ²-thalassemia trait, G6PD deficiency - Southeast Asian: hemoglobin E andα-thalassemia - Mediterranean descent: ²-thalassemia and G6PD deficiency

- Premature infant - Increased risk of both iron and vitamin E deficiency - Exaggerated hyperbilirubinemia can be the presenting symptom of isoimmune hemolytic or other congenital hemolytic anemia.

- Milk intake - Introduction of cow 's milk at <12 months of age is associated with iron deficiency. - Drinking a lot of cow 's milk (>24 oz/day) puts a toddler at risk for iron deficiency.

- Frontal bossing and prominence of the malar and maxillary bones - Extramedullary erythropoiesis

- CBC with red cell indices - Establishes the diagnosis of anemia, distinguishes by size: normocytic, macrocytic, microcytic

- Coombs test and antibody screen - Identifies immune-mediated red cell destruction - Can have false positives and negatives

- Quantitative red cell " enzyme assays - Inherited RBC enzyme deficiencies

- Congenital - Hemoglobinopathies: sickle cell syndromes, thalassemia syndromes, other unstable hemoglobins - Erythrocyte membrane defects: hereditary spherocytosis, elliptocytosis, stomatocytosis, pyropoikilocytosis, infantile pyknocytosis - Erythrocyte enzyme defects: G6PD deficiency, pyruvate kinase deficiency - Diamond-Blackfan anemia: congenital pure red cell aplasia (rare) - Fanconi anemia: constellation of varied cytopenias, multiple congenital anomalies, abnormal bone marrow chromosomal fragility

- Infectious - Septic shock - Can get mild anemia after mild infections in childhood (anemia of inflammation) - Infection-related bone marrow suppression: parvovirus B19 infection - Infection-related hemolytic anemias: Epstein-Barr virus, influenza, coxsackievirus, varicella, cytomegalovirus, Escherichia coli, Pneumococcus species, Streptococcus species, Salmonella typhi, Mycoplasma species

- Nutritional/toxic/drugs - Iron deficiency anemia: common cause of anemia in children, especially those <3 years of age and in female adolescents - Plumbism: anemia usually due to coexisting iron deficiency; very high lead levels associated with altered heme synthesis - Vitamin B12 and/or folate deficiency: results in a megaloblastic anemia - Medication-induced bone marrow suppression: chemotherapy; antibiotics, especially trimethoprim-sulfamethoxazole - Drug-related hemolytic anemia: antibiotics, antiepileptics, azathioprine, isoniazid, nonsteroidal anti-inflammatory drugs

- Trauma - Tumor - Leukemia with bone marrow infiltration - Metastatic tumors with bone marrow infiltration

- Genetic/metabolic - Metabolic derangements: severe electrolyte disturbance, pH disturbance, inborn errors - Shwachman-Diamond syndrome: marrow hypoplasia with associated pancreatic insufficiency and associated failure to thrive

- Other: - Transient erythroblastopenia of childhood: acquired pure RBC aplasia - Aplastic anemia: bone marrow failure syndrome with at least 2 of the 3 blood cell lines eventually affected - Systemic diseases: anemia of chronic disease, chronic renal disease, uremia - Hypothyroidism - Sideroblastic anemia: defective iron use within the developing erythrocytes - Autoimmune and isoimmune hemolytic anemias - Microangiopathic hemolytic anemias: thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), disseminated intravascular coagulation (DIC) - Mechanical destruction: vascular malformation, abnormal or prosthetic cardiac valves

- Circulatory failure without anemia - Requires intensive monitoring and access to critical care in an emergency department or intensive care unit - Fluid resuscitation and/or inotropic pressor support as needed

Pallor is defined as paleness of the skin and may be a reflection of anemia or poor peripheral perfusion.
The normal range for hemoglobin is age dependent.
Anemia can be defined functionally as the inability of hemoglobin to meet cellular oxygen demand.
Parents often fail to notice pallor of gradual onset.Grandparents or others who see the child less often may be the first to suspect pallor.

Risk Factors

Ages between 6 months and 3 years or adolescent femalesPeak age ranges for iron deficiency
GenderSome red cell " enzyme X-linked defects such as glucose-6-phosphate dehydrogenase (G6PD) and phosphoglycerate kinase deficiencies are sex linked.
RaceAfrican: hemoglobins S and C,α- and ²-thalassemia trait, G6PD deficiencySoutheast Asian: hemoglobin E andα-thalassemiaMediterranean descent: ²-thalassemia and G6PD deficiency

Genetics

Familial history: Some of the congenital hemolytic anemias are autosomal dominant.

Diagnosis

Determine first that the child appears pale, not simply fair skinned. Second, decide if there is a medical emergency associated with circulatory failure. If not, the goal is to investigate the etiology and intervene appropriately.
Phase 1: Assess for signs of shock.If present, initiate emergency procedures as required to stabilize the patient, such as airway, breathing, and circulation.
Phase 2: If patient is stable, perform history, physical examination, and CBC with reticulocyte count to establish time of onset of pallor, associated symptoms, and level of anemia.
Phase 3: Follow specific diagnostic workup based on findings in phase 2.

Signs and Symptoms

Pallor
Other signs and symptoms dependent on etiology

History

Acute versus chronic onsetHelps with differential diagnosis
Associated symptoms: weight loss, fever, night sweats, cough, and/or bone painSuggest an underlying systemic illness, such as leukemia, infection, or rheumatologic disorder
Jaundice, scleral icterus, dark urine
Age <6 monthsMay represent a congenital anemia or isoimmunization
Premature infantIncreased risk of both iron and vitamin E deficiencyExaggerated hyperbilirubinemia can be the presenting symptom of isoimmune hemolytic or other congenital hemolytic anemia.
PicaOften associated with plumbism and iron deficiency
MedicationsCan cause bone marrow suppression and/or hemolysis
Milk intakeIntroduction of cow 's milk at <12 months of age is associated with iron deficiency.Drinking a lot of cow 's milk (>24 oz/day) puts a toddler at risk for iron deficiency.
Recent trauma and/or surgeryBlood loss can result in iron deficiency.
Recent infectionCan be associated with hemolysis or bone marrow suppressionMost common form of mild anemia in childhood
Family historyFamilial history of splenectomy and/or early cholecystectomy can be a clue for a previously undiagnosed hemolytic anemia.

Physical Exam

Rapid respiratory rate, decreased BP, weak pulses, slow capillary refillIndications of uncompensated anemia and/or shock
Frontal bossing and prominence of the malar and maxillary bonesExtramedullary erythropoiesis
Enlarged spleenHemolytic anemias, malignancy, infection
GlossitisVitamin B12 deficiencyIron deficiency
Scleral icterus or jaundice
Systolic flow murmur
BruitsMay indicate vascular malformations
Petechiae and bruisingMay indicate an associated thrombocytopenia, coagulopathy, or vasculitis
Dysmorphic featuresDiamond-Blackfan and Fanconi anemia are associated with other congenital defects, including thumb abnormalities, short stature, and congenital heart disease.

Diagnostic Tests & Interpretation

Lab

CBC with red cell indicesEstablishes the diagnosis of anemia, distinguishes by size: normocytic, macrocytic, microcytic
Reticulocyte countDistinguishes between decreased production and increased destruction of red cells
Coombs test and antibody screenIdentifies immune-mediated red cell destructionCan have false positives and negatives
Peripheral blood smearSpecific morphologic findings can be diagnostic.
Iron studies: iron-binding capacity, serum iron, ferritin, transferrinIron deficiency anemia or anemia of chronic disease
Hemoglobin electrophoresis with quantification
Lead studies: serum lead, free erythrocyte protoporphyrin
Stool guaiac
Osmotic fragilityRed cell membrane defects (spherocytosis)Any spherocytic anemia may be positive.
Quantitative red cell " enzyme assaysInherited RBC enzyme deficiencies
Serum folate, RBC folate, and serum vitamin B12 levels

Diagnostic Procedures/Other

Bone marrow aspiration and biopsy: if malignancy or bone marrow failure syndrome suspected

Differential Diagnosis

CongenitalHemoglobinopathies: sickle cell syndromes, thalassemia syndromes, other unstable hemoglobinsErythrocyte membrane defects: hereditary spherocytosis, elliptocytosis, stomatocytosis, pyropoikilocytosis, infantile pyknocytosisErythrocyte enzyme defects: G6PD deficiency, pyruvate kinase deficiencyDiamond-Blackfan anemia: congenital pure red cell aplasia (rare)Fanconi anemia: constellation of varied cytopenias, multiple congenital anomalies, abnormal bone marrow chromosomal fragility
InfectiousSeptic shockCan get mild anemia after mild infections in childhood (anemia of inflammation)Infection-related bone marrow suppression: parvovirus B19 infectionInfection-related hemolytic anemias: Epstein-Barr virus, influenza, coxsackievirus, varicella, cytomegalovirus, Escherichia coli, Pneumococcus species, Streptococcus species, Salmonella typhi, Mycoplasma species
Nutritional/toxic/drugsIron deficiency anemia: common cause of anemia in children, especially those <3 years of age and in female adolescentsPlumbism: anemia usually due to coexisting iron deficiency; very high lead levels associated with altered heme synthesisVitamin B12 and/or folate deficiency: results in a megaloblastic anemiaMedication-induced bone marrow suppression: chemotherapy; antibiotics, especially trimethoprim-sulfamethoxazoleDrug-related hemolytic anemia: antibiotics, antiepileptics, azathioprine, isoniazid, nonsteroidal anti-inflammatory drugs
Trauma
TumorLeukemia with bone marrow infiltrationMetastatic tumors with bone marrow infiltration
Genetic/metabolicMetabolic derangements: severe electrolyte disturbance, pH disturbance, inborn errorsShwachman-Diamond syndrome: marrow hypoplasia with associated pancreatic insufficiency and associated failure to thrive
Other:Transient erythroblastopenia of childhood: acquired pure RBC aplasiaAplastic anemia: bone marrow failure syndrome with at least 2 of the 3 blood cell lines eventually affectedSystemic diseases: anemia of chronic disease, chronic renal disease, uremiaHypothyroidismSideroblastic anemia: defective iron use within the developing erythrocytesAutoimmune and isoimmune hemolytic anemiasMicroangiopathic hemolytic anemias: thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), disseminated intravascular coagulation (DIC)Mechanical destruction: vascular malformation, abnormal or prosthetic cardiac valves

Treatment

Initial Stabilization

Severe anemia of unclear etiology with hemodynamic instabilityTransfuse with packed RBCs cautiously.In an autoimmune hemolytic process, the child is at risk for a transfusion reaction, and there may be delay in obtaining cross-matched blood.Obtain blood for diagnostic studies before transfusion if possible.
Circulatory failure without anemiaRequires intensive monitoring and access to critical care in an emergency department or intensive care unitFluid resuscitation and/or inotropic pressor support as needed
Acute blood lossTreat circulatory failure as described.Transfuse with packed RBCs, platelets, and fresh frozen plasma as needed.
MalignanciesEmergency care should be directed toward treatment of circulatory failure and possible associated infection and then to rapid diagnosis and treatment of the malignancy.Consultation with an oncologist should be sought as soon as possible.

General Measures

Treat underlying cause.
Consider packed RBC transfusion if in extremis or severe anemia and low likelihood of recovery in near future.
Consider emergent plasmapheresis if with microangiopathic hemolytic anemia.
Consider immunosuppressive medications (corticosteroids, intravenous immunoglobulin (IVIG) if with autoimmune hemolytic anemia.
Iron deficiency anemia

Medication

Elemental iron for patients with iron deficiency

4 " 6 mg/kg/24 h PO divided b.i.d. " t.i.d.
Absorbed best with acidic drinks, including orange juice; dairy products decrease absorption.
Reticulocyte should improve 72 hours after starting iron therapy; the hemoglobin may take a week to rise.
Iron should be continued for at least 3 months to replenish iron stores.

Ongoing Care

Issues for Referral

Severe or unexplained anemia
Anemias other than dietary iron deficiency or thalassemia trait
Recurrent iron deficiencyMay suggest ongoing bleeding or iron malabsorption
All bone marrow failure or infiltrative processes

Additional Reading

Baker RD, Greer FR, Committee on Nutrition, American Academy of Pediatrics. Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0-3 years of age). Pediatrics. 2010;126(5):1040 " 1050. [View Abstract]
Glader BE. Hemolytic anemia in children. Clin Lab Med. 1999;19(1):87 " 111. [View Abstract]
Graham EA. The changing face of anemia in infancy. Pediatr Rev. 1994;15(5):175 " 183. [View Abstract]
Monzon CM, Beaver D, Dillon TD. Evaluation of erythrocyte disorders with mean corpuscular volume (MCV) and red cell distribution width (RDW). Clin Pediatr. 1987;26(12):632 " 638. [View Abstract]
Segal G, Hirsh M, Feig S. Managing anemia in pediatric office practice: part 2. Pediatr Rev. 2002;23(4):111 " 122. [View Abstract]
Sills RH. Indications for bone marrow examination. Pediatr Rev. 1995;16(6):226 " 228. [View Abstract]