Hema Dave and Alan S. Wayne
Despite some overlap with disorders encountered in adults, many congenital and acquired hematologic diseases manifest primarily during childhood. In addition, pediatric hematology is distinguished by developmental differences in normal physiology and blood parameters.1 The purpose of this chapter is to highlight unique features in the evaluation, diagnosis, and treatment of common pediatric hematologic conditions. The reader is referred to other chapters in this edition for additional details of the management of specific disorders.
ANEMIA
Normal red blood cell (RBC) values vary with age and are affected by factors such as race, sex, and altitude (Table 10.1). The RBC count is highest at birth and continues to decrease gradually to a physiologic nadir at 2 to 4 months (earlier for premature infants), at which point erythropoiesis is stimulated. Anemia is defined as an overall reduction in red cell mass or hemoglobin (Hb) concentration, 2 standard deviations below the mean normal value for the specific population.
Pediatric anemia is commonly classified according to RBC size (Table 10.2). Microcytic anemias account for the majority of cases of anemia in early childhood (Table 10.3). Current recommendations by the American Academy of Pediatrics include screening for anemia testing Hb and serum transferrin receptor between the ages of 9 to 12 months with additional screening between the ages of 1 and 5 years for patients at risk and adolescent females post-puberty (Table 10.4).2-5
The initial diagnostic evaluation of a child with anemia should consist of a detailed history and physical examination and the following minimal laboratory testing: complete blood count (CBC), reticulocyte count, and examination of the peripheral blood smear. Consideration of the physiologic basis for anemia can be helpful in guiding further investigation (Table 10.5).
Microcytic Anemias
Iron deficiency is the most common cause of anemia during childhood and may result from a combination of low stores at birth, high requirements because of growth and blood volume expansion, inadequate nutrition, and poor bioavailability of dietary iron. Iron deficiency due to blood loss is usually a result of gastrointestinal tract irritation and occult hemorrhage associated with introduction of cow’s milk before the first year of life or menstruation during adolescence. On history, additional risk factors for iron deficiency may include prematurity, limited or prolonged breast-feeding, non-iron-fortified formula or excessive intake of whole milk (generally more than 1 quart per day). Early iron deficiency may result only in a low ferritin level. Falling iron stores leads to decreased serum iron and transferrin saturation and an increase in total iron-binding capacity (TIBC) and free erythrocyte protoporphyrin (FEP). With frank deficiency, there is hypochromia, microcytosis, and anisocytosis on the blood smear. The platelet count also may be increased. A response to a trial of elemental iron (3 mg/kg/day) is often helpful in differentiating iron deficiency from thalassemia trait: a Hb increase of more than 1 g/dL at 1 month and reticulocyte peak at 10 to 14 days is diagnostic. Iron supplementation (3 mg/kg/day for mild anemia, 6 mg/kg/day for moderate to severe anemia) should be provided for 3 to 6 months.2-6 The most common reason for a lack of response to oral iron therapy is lack of compliance. If anemia persists, other causes of microcytic anemia should be considered (Table 10.2).
Table 10.4 Recommendations for Anemia Screening
American Academy of Pediatrics (AAP) Recommendations4
Option 1: Universal screening (communities with high-risk populations) 9–12 mo, 15–18 mo
Adolescents: Males at peak growth, Females at routine exams
Option 2: Selective screening (communities with low-risk populations) Screen high-risk patients at 9–12 mo, 15–18 mo, yearly until 5 Adolescents: Males at peak growth, Females at routine exams
Center for Disease Control (CDC)5
High-risk populations: 9–12 mo, 15–18 mo, yearly until 5
Adolescent females every 5–10 yr, yearly if risk factors
Adolescent males at peak growth
Lead toxicity often coexists with iron deficiency in at-risk populations and may further inhibit gastrointestinal absorption of iron. Lead poisoning should be suspected if there is a history of pica or exposure to lead-based paint, particularly in children with developmental delay or autism as these can be comorbid conditions. An elevated FEP and basophilic stippling on peripheral smear may be seen. Therapy should include oral treatment with succimer or, in severe cases, parenteral treatment with dimercaprol (BAL) or calcium-sodium ethylenediaminetetraacetic acid (EDTA).7 Center for Disease Control (CDC) recommendations for management of children with elevated lead levels can be found in Table 10.6.
Thalassemia syndromes are common causes of microcytic anemia in childhood. They are classified into α and β thalassemias based on the affected globin chain. The α-thalassemias present in utero or at birth, while the β-thalassemias are not evident until 6 months of age, when β-globin synthesis becomes predominant. Thalassemia trait is often mistaken for iron deficiency.8 In contrast to iron deficiency, β-thalassemia trait is associated with a normal red cell distribution width (RDW), basophilic stippling and targeting on the blood smear, and an elevated Hb A2 on electrophoresis. α-thalassemia trait is associated a normal Hb electrophoresis outside of the newborn period, although Hb Bart’s (γ4) is present on newborn screening samples. In the evaluation of thalassemias, ethnic heritage is often suggestive and microcytosis should be present in at least one parent. Thalassemia trait (heterozygous β-1 and 2 gene deletion α-thalassemias) requires no therapy. In contrast, in thalassemia major, aggressive packed RBC transfusion should be initiated early in life to eliminate the increased erythropoietic drive and allow normal linear growth and bone development. In utero transfusion has been used to prevent hydrops fetalis in 4-gene deletion α-thalassemia (Hb Bart’s disease), which is otherwise fatal. Care should be given to address iron overload and chelation therapy in transfusion-dependent children to prevent end-organ damage later in life. As an alternative to life-long transfusion and chelation therapy, allogeneic hematopoietic stem cell transplantation (SCT) is a curative approach for children with thalassemia major who have human leukocyte antigen (HLA)-matched sibling donors. Prenatal diagnosis of thalassemia can be made as early as the 10th week of gestation using chorionic villus sampling.9
Normocytic Anemias
Anemia is a common manifestation of numerous systemic conditions in pediatrics. The anemia of acute inflammation and chronic disease is frequently mild and usually normocytic, although the mean cell volume (MCV) is occasionally low. Transferrin is frequently diminished (Table 10.3). Treatment is aimed at the primary condition. Viral infection is the most common cause of transient bone marrow suppression in children and may result in both anemia and leukopenia. The hallmark of viral suppression is failure of the reticulocyte count to increase in the face of anemia. Usually, only close observation is required because the bone marrow suppression is self-limited.
Transient erythroblastopenia of childhood (TEC) is an acquired pure red cell aplasia that can also follow viral illness in previously healthy children.10 The median age for presentation is 2 years, in contrast to congenital pure red cell aplasia, which commonly presents in infancy. Reticulocytopenia and, occasionally, leukopenia and thrombocytopenia are seen. Most children with TEC recover in 1 to 2 months. Observation alone is usually sufficient, although short-term transfusion therapy may be required for cardiovascular compromise associated with severe anemia.
Hemolysis usually results in normocytic anemia. There are a large number of congenital and acquired hemolytic conditions of childhood, including membrane disorders, hemoglobinopathies, metabolic defects, enzymopathies, and immune-mediated hemolysis. Immune-mediated hemolysis, either isoimmune or alloimmune, may present in neonates; autoimmune hemolytic anemia is seen in older children. Hemoglobinopathies such as sickle cell disease, enzyme deficiencies such as glucose-6-phosphate dehydrogenase deficiency, and membrane disorders such as hereditary spherocytosis (HS) should be considered in the differential diagnosis of hemolysis. Microangiopathic hemolysis may be seen in hemolytic uremic syndrome (HUS) and disseminated intravascular coagulation (DIC). Laboratory features consistent with hemolysis include reticulocytosis, elevated lactate dehydrogenase (LDH), indirect hyperbilirubinemia, decreased serum haptoglobin, and, in severe cases, hemoglobinuria. A positive direct Coomb’s test indicates immune-mediated hemolysis. Examination of the peripheral smear may reveal characteristic red cell morphology. Thrombocytopenia and renal impairment are additional features of HUS. Treatment of hemolysis should be directed toward the underlying cause, with transfusions reserved for severe anemia and cardiovascular compromise. Immune hemolysis often requires corticosteroids and/or other immunosuppressive medications.
The diagnosis of sickle cell disease is usually made during routine newborn screening by Hb electrophoresis. Children diagnosed with sickle cell disease should be cared for by practitioners with specific expertise in the management and prevention of its complications.11,12 Consultation with a pediatric hematologist is strongly recommended. One early presentation of sickle cell crisis in pediatric patients is dactylitis, due to vaso-occlusive crisis of the hands and feet. Children should receive influenza vaccine annually starting at six months of age, the 7-valent conjugated pneumococcal vaccine series in the first year of life, and 23-valent polysaccharide pneumococcal vaccine and meningococcal vaccine at 2 years. Penicillin prophylaxis should begin at diagnosis and continue until age five years and completion of the pneumococcal vaccination series. Of importance, the risk of pneumococcal sepsis is lifelong and individuals with sickle cell disease require immediate medical attention for fever or signs of infection. Because of the risk of cerebrovascular accident and the difficulty of clinical diagnosis in the pediatric population, children should undergo annual transcranial Doppler ultrasound (TCD) starting at the age of 2 years.11Chronic blood transfusions can prevent stroke in children with abnormal TCD (velocities ≥200cm/sec)11,13,14 Hydroxyurea increases fetal Hb and reduces vaso-occlusive pain crises, acute chest syndrome and need for transfusion.15 Annual echocardiogram to detect pulmonary hypertension is recommended starting at 15 years and annual eye examination at 10 years to evaluate for retinopathy.12
Macrocytic Anemias
Vitamin B12 deficiency causes megaloblastic changes in the bone marrow.16 In infants, B12 deficiency may be the result of maternal depletion and decreased stores at birth. In older children and adolescents, etiologies include pernicious anemia, malabsorption, dietary deficiency, and inborn errors of metabolism. Unrecognized, severe deficiency early in life may cause failure to thrive and even permanent neurologic damage. Symptoms in older children may include anorexia, weight loss, diarrhea, constipation, weakness, glossitis, peripheral neuropathy, ataxia, and dementia. Anemia is commonly accompanied by neutropenia, hypersegmented neutrophils, and thrombocytopenia. A low serum B12 level and a response to replacement therapy are confirmatory.
Folate deficiency also results in a megaloblastic bone marrow.16 The newborn infant has increased demands for folate. Risk factors for early deficiency include prematurity, low levels in maternal breast milk, and a predominance of goat’s milk intake. In older children, folate deficiency is usually the result of malnutrition, although it may also be caused by certain medications, chronic hemolysis, malabsorption, and inborn errors of metabolism. Serum and erythrocyte folate levels will be low and the anemia should respond to small replacement doses of folic acid.
Diamond-Blackfan anemia (DBA) or congenital pure red cell aplasia is usually noted soon after birth or during the first year of life. The main competing entity in the differential diagnosis is TEC, but TEC more commonly presents after the first year of life. Twenty-five percent of patients with DBA have associated anomalies, such as short stature and/or abnormalities of the head, face, and upper limbs. Laboratory features include reticulocytopenia, high MCV (often only mildly elevated), increased Hb F, elevated adenosine deaminase activity, normal or decreased white blood cell (WBC) count, and normal or increased platelet count. Mutations in genes that encode ribosomal proteins have been found in about 50% of patients,17 and large deletions or changes in regulatory regions likely account for the remainder. The bone marrow shows erythroid hypoplasia. In considering the differential diagnosis, a normal CBC in the past supports TEC and an abnormal chromosomal breakage study confirms Fanconi anemia (FA). The majority of children with DBA respond to corticosteroids. Prednisone is begun at a dosage of 2 mg/kg/day with a response usually seen within 1 month. Once the Hb has reached a satisfactory level, steroids should be tapered to the lowest possible dose (ideally on an alternate day schedule). Although spontaneous remissions have occurred, corticosteroid dependence is the rule and chronic transfusion and chelation therapy should be considered for those with associated toxicity. Allogeneic SCT can be curative.18
FA can often be differentiated from acquired aplastic anemia by characteristics such as impaired growth and/or anomalies of the thumbs, radii, kidneys, head, eyes, ears, skin, and/or genitourinary system. Inheritance is autosomal recessive and the family history may be positive for marrow failure and leukemia. There is a 10% to 35% risk of developing leukemia or myelodysplastic syndrome.19 Although the mean age of diagnosis is between eight and nine years, the first hematologic signs of FA may develop in infancy and often includes macrocytosis, elevated Hb F and/or mild cytopenia(s). Severe pancytopenia usually develops later in life. The differential includes other familial or acquired bone marrow failure syndromes. Abnormal chromosomal breakage analysis or FA genotyping confirms the diagnosis. Anemia is frequently responsive to androgen therapy. Only SCT is curative for the hematologic manifestations of FA, but a modified pretransplant conditioning is critical to avoid severe toxicity caused by chemotherapy and radiation sensitivity.
BLEEDING
Many congenital and acquired disorders of hemostasis, including platelet abnormalities, present in infancy and childhood. Hemorrhagic disorders in infancy may manifest as bleeding from the umbilicus, circumcision site, unusually large cephalohematomas, and more serious but fortunately rare intracranial hemorrhages. The normal ranges for coagulation assays are age dependent and differ greatly from the neonatal period to infancy and later childhood (Table 10.7). Most coagulation proteins increase in parallel with gestational age. Because physiologic levels of many clotting factors are low at birth, it is often difficult to diagnose disorders of hemostasis in newborns.
Acquired Factor Deficiencies
Hemorrhagic disease of the newborn (HDN) is a complication of physiologically low levels of vitamin K-dependent factors in the newborn.20 Classic HDN presents on days 2 to 7 of life in otherwise healthy, full-term infants and occurs in 1/10,000 live births without vitamin K prophylaxis. Risk factors include poor placental transfer of vitamin K, marginal levels in breast milk, inadequate milk intake, and the sterile newborn gut. Although rarely necessary, diagnosis can be confirmed by screening coagulation tests and vitamin K-dependent factor levels. Determination of decarboxylated forms of vitamin K-dependent factors or protein induced by vitamin K antagonists also may be helpful. HDN should be prevented in all newborns by prophylactic administration of vitamin K at birth with a single dose of 0.5 to 1 mg intramuscularly (preferred route) or an oral dose of 2 to 4 mg, followed by continued supplementation in breast-fed infants.
Vitamin K deficiency can also be seen in children with liver disease, with chronic antibiotic use, and due to inadequate intake or disorders that interfere with vitamin K absorption, such as chronic diarrhea, cystic fibrosis, or other fat malabsorption syndromes. Therapy should include vitamin K administration as well as measures directed to the underlying disease.
DIC can be differentiated from vitamin K deficiency and liver disease by assaying coagulation factor levels. DIC decreases all clotting factors due to consumption. In contrast, factor VIII, the only clotting protein not synthesized solely in the liver, is normal or elevated in liver disease. Therapy should be directed at the underlying cause, although supportive measures may include treatment with fresh-frozen plasma (FFP).
Inherited Factor Deficiencies
Hemophilias A and B often present in early childhood. Newborns with hemophilia can bleed with circumcision and, rarely, may suffer an intracranial hemorrhage after delivery. In the absence of a family history, the diagnosis of hemophilia is most often made when a child with moderate to severe factor deficiency begins to crawl or walk. Common symptoms include easy bruising, hemarthrosis in weightbearing joints, and deep intramuscular hemorrhage. Central nervous system (CNS) bleeding is the usual cause of early mortality. Laboratory evidence for hemophilia includes a prolonged partial thromboplastin time (PTT), which corrects on mixing studies. An abnormally low factor VIII or IX level confirms the diagnosis. Care should be taken to evaluate and treat hemarthroses aggressively in children to prevent the later development of chronic arthropathy. The treatment of hemophilia in children is similar to that in adults and includes factor replacement dosed according to the site, type, and severity of hemorrhage.21 The availability of recombinant factor concentrates has increased the safety and feasibility of prophylaxis in children with frequent hemorrhagic episodes. For dose determination of factor concentrates, factor VIII levels will typically increase by approximately 2% for every 1 unit/kg given and factor IX levels by about 1% for every 1 unit/kg administered. In patients with mild hemophilia A, desmopressin is often effective for short-term management of mild bleeding. As in adults, routine screening for inhibitors should be conducted.
Von Willebrand disease (vWD) usually presents with less severe bleeding, primarily mucocutaneous, as compared to hemophilia. Because recurrent bruising and epistaxis are relatively common in children, history should be directed toward the presence of prolonged, unusual, or severe bleeding. A careful family history may reveal similar symptoms in parents or siblings. The diagnosis is confirmed by abnormal assays for factor VIII, von Willebrand factor (vWF) antigen and activity, and multimer analysis. Factor VIII and vWF are acute phase reactants and, in children, falsely elevated levels caused by interval illnesses may obscure the diagnosis. Thus, repeat testing should be considered if the diagnosis of vWD is suspected. Therapy is as in adults.22
Platelet Disorders
Neonatal alloimmune thrombocytopenia (NAIT) results from the placental transfer of maternal alloantibodies against paternally inherited antigens (most commonly HPA-1a) on fetal platelets. Newborns present with transient, isolated but severe thrombocytopenia that must be distinguished from other causes, including maternal immune thrombocytopenic purpura (ITP), severe infection, DIC, hypersplenism, and Kasabach-Merritt syndrome. Approximately 15% of affected neonates experience intracranial hemorrhage, either in utero or in the immediate postnatal period. Unlike Rh disease of the newborn, prior sensitization is not required, and thus NAIT may occur with the first pregnancy. A normal platelet count in the mother helps to differentiate NAIT from maternal ITP. Immunophenotyping of maternal and paternal platelets is useful to confirm the diagnosis. The treatment of choice in severe NAIT is transfusion of maternal platelets. When they are not readily available, platelets obtained from a known HPA-1a-negative donor or from random donors may be used for active bleeding. Intravenous immunoglobulin (IVIG) or corticosteroids may also be used as a temporary measure either in the antenatal or postnatal periods, with dosing as in ITP.
ITP affects approximately 1 in 10,000 children annually in the United States. In contrast to the disease in adults, ITP in childhood is usually a self-limited, benign condition. Children typically present under the age of 10. Eighty percent have spontaneous resolution within 6 months. Infants and older children are more likely to have prolonged thrombocytopenia. The typical presentation in acute ITP is the abrupt onset of mucosal bleeding, petechiae, and bruising in healthy children, often preceded by a viral illness. Most children have severe thrombocytopenia (platelet counts less than 20,000/µL) but an otherwise normal CBC. Large platelets are usual on the peripheral blood smear. Although acute ITP is a diagnosis of exclusion, otherwise healthy children with no significant medical history or findings on physical examination rarely require extensive laboratory testing. Testing for human immunodeficiency virus (HIV) infection can be considered. The diagnostic utility of bone marrow examination in suspected acute ITP is low. Evaluation for chronic ITP should include bone marrow studies and testing for immunodeficiency and autoimmune disease. The need for treatment in acute ITP is often debated; current guidelines recommend therapy for significant bleeding (Table 10.8).23 Although the risk of intracranial hemorrhage is small, precautions should be taken to prevent head trauma and helmets are recommended for toddlers just learning to walk.
Inherited platelet disorders may be qualitative or quantitative; they are a rare cause of thrombocytopenia in infancy and childhood. The variety of qualitative disorders includes Glanzmann thrombasthenia (GT), Bernard-Soulier syndrome (BSS), platelet-type pseudo-vWD, and platelet storage granule defects. Quantitative defects are seen in congenital amegakaryocytic thrombocytopenia, thrombocytopenia-absent radii (TAR), X-linked thrombocytopenia, Wiskott-Aldrich syndrome (WAS), and May-Hegglin anomaly. Children with these disorders present with petechiae, easy bruising, or mucocutaneous bleeding. Rarely, gastrointestinal or intracranial bleeding may occur. Screening for qualitative disorders requires platelet aggregation studies. Characteristic features of specific disorders should be sought, such as forearm deformities in TAR, immunodeficiency in WAS, and macrothrombocytes in May-Hegglin anomaly. Treatment for bleeding is usually supportive. Platelet transfusions should be avoided if possible in patients with BSS and GT because of the risk of developing alloantibodies to the missing platelet antigens GPIb–IX and αIIb-β3, respectively.
Table 10.8 Treatment Regimens for Childhood ITP
IVIG: 0.8–1 g/kg × 1 d OR
Prednisone 2 mg/kg/d × 14 d with taper OR
Anti-D: 50–75 µg/kg × 1 d (Rh positive, non-splenectomized patients only)
Modified from Neunert C, Lim W, Crowther M, et al.The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117(16):4190-4207.
THROMBOSIS
As with coagulation factor levels, normal ranges for endogenous antithrombotic proteins are age- and gestation-dependent (Table 10.7). Venous thromboembolic events (TEE) are less common in children than in adults, with the exception of specific at-risk patient populations.24 Unless risk factors are identified, arterial thrombosis is extremely infrequent.
Anticoagulant and thrombolytic therapy should be dosed according to age and weight (Tables 10.9 and 10.10). The duration, monitoring, efficacy, and long-term effects of anticoagulation in the management of TEE in children require further study. The treatment of children with oral anticoagulants is complicated by the risk of bleeding complications. As in adults, caution is required when instituting warfarin therapy. To avoid paradoxical thrombosis, heparinization should be continued until the international normalized ratio (INR) is in the therapeutic range.
Congenital Prothrombotic Disorders
Children who are homozygous or compound heterozygous for deficiencies of anticoagulant proteins usually present in the neonatal or early childhood period. In the absence of additional risk factors, however, individuals who are heterozygous for thrombophilic conditions infrequently experience their first TEE early in life. In general, evaluation for possible inherited deficiency is recommended for children with a family history of congenital thrombophilia, and if thromboses are unexplained, occur in unusual sites, are particularly severe, and/or are recurrent.
Protein C and S deficiencies, in the homozygous state, classically present as purpura fulminans within hours or days of birth. Purpura fulminans is more common with protein C deficiency and is characterized by acute DIC with rapidly progressive hemorrhagic necrosis of the skin and other thrombotic/hemorrhagic complications, including death. Homozygous infants usually have undetectable levels of protein C or S, and their parents have heterozygous deficiency. Both functional and immunologic assays for protein C and S should be utilized. Acquired causes of protein C and S deficiency, such as liver disease and sepsis, should be excluded. Purpura fulminans should be treated with FFP and, if available, purified protein C concentrate. Warfarin-induced skin necrosis has been described in children with heterozygous protein C and S deficiency, and extreme caution is required when converting such individuals from heparin to warfarin anticoagulation.
Other inherited thrombophilic states including antithrombin III deficiency, factor V Leiden, prothrombin G20210A mutations, and homocysteinemia also have been associated with recurrent thromboembolism in children and adolescents.24 The incidence of deep vein thrombosis related to those conditions is low and the value of an extensive evaluation of the first TEE has been questioned.
Acquired Prothrombotic Disorders
As in adult patients, thromboembolism in children is usually secondary; central venous catheters are the most common cause. Neonates are at particularly high risk, and the use of umbilical lines may be associated with portal venous system thrombosis. Other risk factors include malignancy, surgery, trauma, pregnancy, congenital heart disease, Kawasaki disease, nephrotic syndrome, and systemic lupus erythematosus (SLE). Complete evaluation for possible underlying conditions should be undertaken. The laboratory examination should be guided by clinical findings and risk factors, and in most cases should include lupus anticoagulant or antiphospholipid antibody assay.
NEUTROPENIA
Normal neutrophil counts vary with age and are affected by race and other factors (Table 10.1). For example, the lower limit of normal in blacks may be 200 to 600/µL less than in whites.
Neutropenia is commonly encountered in pediatrics, most often caused by viral suppression. Children, like adults, are at increased risk for life-threatening bacterial infection when the absolute neutrophil count (ANC) falls below 500/µL. Common pyogenic infections seen in association with neutropenia include cellulitis, superficial or deep abscesses, pneumonia, sepsis, and recurrent or chronic otitis media and sinusitis.
General management recommendations include aggressive monitoring for and treatment of infection, judicious use of antibiotics, rapid institution of empiric broad-spectrum parenteral antibiotics for fever or possible infection, and maintenance of good skin and oral hygiene. Granulocyte-colony stimulating factor (G-CSF, filgrastim) is often effective in increasing the rate of ANC recovery in certain disorders.
Viral infections are the most common cause of transient neutropenia in childhood. Neutropenia usually develops during the first 24 to 48 hours of illness and commonly lasts up to a week or longer. Neutropenia may also occur with serious bacterial infections, especially in neonates.
Autoimmune neutropenia of childhood is the most common cause of chronic neutropenia in pediatrics, primarily affecting children younger than 3 years of age. The ANC at presentation is usually below 250/µL. Associated monocytosis is common and antineutrophil antibodies can be detected in most patients.25 Other causes of neutropenia should be excluded, such as immunodeficiency, drug-related, transient postinfectious, and congenital neutrophil disorders. Although the ANC is often extremely low or absent, most children experience only minor infections and thus, this condition is sometimes referred to as chronic benign neutropenia of childhood. Nonetheless, empiric, broad-spectrum parenteral antibiotics are recommended for the first few episodes of fever. If a child appears to have a benign course, subsequent febrile episodes might be managed more routinely unless there is documented infection or signs of sepsis. Daily trimethoprim/sulfamethoxazole may be useful in preventing recurrent minor bacterial infections. G-CSF is usually effective in low doses (1 to 2 µg/kg/day) and should be considered for children with recurrent, severe neutropenic complications. Spontaneous remission within the first few years of diagnosis is common, especially in young children.
Cyclic neutropenia is characterized by periodic oscillations in the ANC. Cycles commonly occur every 21 days and the nadir is usually below 200/µL. Symptoms typically begin in the first year of life and commonly include recurrent fever, gingivitis, stomatitis with oral aphthous ulcers and pharyngitis. Diagnosis is confirmed by monitoring serial CBCs twice per week for 6 to 8 weeks to establish the periodicity of the neutropenia, which may also be accompanied by asymptomatic oscillations in other blood counts. Cyclic neutropenia is an autosomal dominant disorder caused by mutation in the gene encoding neutrophil elastase (ELANE). Parental history and/or CBCs may be helpful. Although in most cases cyclic neutropenia is a benign condition, serious infectious complications may occur and treatment with G-CSF is sometimes indicated. Low doses of G-CSF often suffice, and doses of 2 to 3 µg/kg daily or every other day can be titrated to maintain the neutrophil count above 500/µL.
Severe congenital neutropenia (Kostmann disease) is a disorder associated with severe, chronic neutropenia from birth. The ANC is usually less than 200/µL and recurrent bacterial infections are common, including those seen in more benign neutropenic conditions, as well as life-threatening sepsis, meningitis, and gastrointestinal tract infection. Neonates may present with omphalitis. Bone marrow examination reveals neutrophil developmental arrest. Inheritance is most often due to autosomal recessive mutations in ELANE, although other genetic defects and inheritance patterns are well described.26 Standard therapy consists of daily G-CSF, but high doses may be required and patients undergoing long-term therapy are at risk for myelodysplastic syndrome and acute myelogenous leukemia. SCT should be considered as a curative approach.
Shwachman-Diamond syndrome and Chédiak-Higashi syndrome are both autosomal recessive constitutional neutropenias. Shwachman-Diamond, caused by compound heterozygous or homozygous mutations in the SBDS gene, is characterized by progressive marrow failure, pancreatic exocrine insufficiency, short stature, skeletal deformities, and predisposition to myelodysplastic syndrome and acute myeloid leukemia. Two-thirds of patients have a moderate neutropenia that can be intermittent and responsive to G-CSF. Chédiak-Higashi is also a multiorgan disease that includes oculocutaneous albinism, recurrent bacterial infection, a mild bleeding disorder due to platelet dysfunction, and neuropathy. The accumulation of giant granules in neutrophils leads to premature destruction. This disorder is caused by homozygous or compound heterozygous mutations in the lysosomal trafficking regulator gene (LYST or CHS1). Affected individuals commonly progress to an accelerated phase characterized by hemophagocytic lymphohistiocytosis, which is often fatal. Therapy is mostly supportive and SCT is the only known cure for the hematologic manifestations.
Other causes of neutropenia include drug-induced, inborn errors of metabolism, nutritional deficiency, or bone marrow infiltration. Treatment should be directed at the underlying etiology.
LEUKOCYTOSIS
Leukocytosis refers to an increase in total WBC count for age. Neutrophilia is an increase in the ANC above 7,500/µL, but the upper limit of normal may be higher in newborns and infants (Table 10.1). Neutrophilia may result from increased production, mobilization from the bone marrow, or peripheral demargination. In children, acute neutrophilia is most often due to bacterial or viral infection. Absolute lymphocytosis usually indicates an acute or chronic viral process. Evaluation of leukocytosis should include a detailed history and physical examination directed to symptoms and signs of infection and for lymphadenopathy and hepatosplenomegaly. Examination of the peripheral blood smear is essential to distinguish normal from atypical and malignant WBCs.
Leukocyte adhesion deficiency type I (LAD I) is a disorder of impaired phagocyte adhesion, chemotaxis, and ingestion, caused by partial or total deficiency of CD18-related surface glycoproteins due to deficiency of the gene encoding the beta-2 integrin chain (ITGB2).27 The hallmark of this disorder is the occurrence of repeated, severe bacterial or fungal infections in the absence of pus despite persistent neutrophilia. Infants typically present in the newborn period with omphalitis or delayed umbilical cord separation. The diagnosis of LAD can be confirmed by flow cytometry, which reveals deficiency of surface expression of the CD18/CD11 molecules. Treatment is supportive, consisting primarily of prophylaxis against and treatment of infection. SCT may be curative, and more recently investigational gene therapy has been studied.
Infectious mononucleosis (IM) is classically associated with atypical lymphocytosis and is caused by infection with Epstein-Barr virus (EBV). In adolescents and young adults, a prodrome of fatigue and anorexia usually precedes development of fever, lymphadenopathy, exudative pharyngitis, and hepatosplenomegaly. Young children commonly present with a mild respiratory illness only. A muco-cutaneous eruption can occur, especially after treatment with penicillin or ampicillin. Hematologic complications, including immune-mediated hemolytic anemia, thrombocytopenia, aplastic anemia, and hemophagocytosis can be seen, as many other rare complications of CNS involvement, myocarditis, orchitis, and splenic rupture. Children with acquired or congenital immunodeficiency states can develop EBV-associated lymphoproliferative syndrome, which can evolve into non-Hodgkin’s lymphoma. EBV in boys with X-linked lymphoproliferative syndrome, results in fulminant IM, hemophagocytic lymphohistiocytosis, lymphoma, and/or other severe EBV-associated complications that are fatal in the majority of cases.28
Atypical lymphocytosis and early immunologic evidence of EBV infection, either by heterophil or EBV-specific antibody testing, are the most consistent laboratory findings. Nonspecific heterophil antibody tests are often negative in children younger than 4 years of age. Other infections, such as cytomegalovirus (CMV), pertussis, and cat-scratch disease, should be excluded in the setting of EBV-negative IM.
Therapy of IM is supportive. Rarely, short course corticosteroids are used to manage life-threatening manifestations, such as upper airway obstruction from tonsillar/adenoidal hypertrophy. To reduce the risk of splenic rupture, contact sports should be avoided until splenomegaly resolves.
HEMATOLOGIC MANIFESTATIONS OF SYSTEMIC CONDITIONS
Many systemic conditions can result in secondary hematologic abnormalities. Evaluation of the CBC and peripheral smear may also provide important clues during the evaluation of a diagnostic dilemma. Systemic disorders that have prominent hematologic findings and present predominantly in childhood are detailed below.
Lysosomal storage diseases are caused by a deficiency in specific enzymes of the lysosomal metabolic pathway and result in pathologic accumulation of normal substrate, leading to dramatic changes in the central nervous and hematologic systems as well as enlargement of organs that comprise the reticuloendothelial system, including the liver and spleen. Vacuolated lymphocytes and hypergranulated neutrophils in the peripheral blood and lipid-laden macrophages (“foam” or “storage” cells) in the bone marrow are commonly observed. Other characteristic cell types include the sea-blue histiocyte in Niemann-Pick disease and the Gaucher cell. Specific enzyme replacement therapy is available for some of these disorders, while therapy is only supportive for others and SCT curative in certain conditions.29
Autoimmune lymphoproliferative syndrome (ALPS) is a rare disorder of early childhood caused by defective lymphocyte apoptosis.30 Symptoms include lymphadenopathy, splenomegaly, autoimmunity, and an increased risk of lymphoid malignancy. Autoimmune cytopenias are common. The presence of increased numbers of double negative (CD4−/CD8−) T-cells on flow cytometry supports the diagnosis. A number of molecular defects have been identified, most commonly mutations in Fas (TNFRSF6, CD95). Therapy is mainly supportive, although immunosuppressive drugs may be needed to manage complications of autoimmunity and lymphoproliferation. SCT can be curative.
Collagen vascular diseases commonly have hematologic manifestations, most often anemia of chronic illness and/or autoimmune-mediated cytopenias. Aplastic anemia has been described in SLE. Patients with autoimmune disorders are at increased risk for developing antiphospholipid antibodies, although such lupus anticoagulants result in prolongation of prothrombin time (PT) and PTT, they predispose to thromboembolism rather than bleeding.
TRANSFUSION SUPPORT
The indications for transfusion in infants and children are similar to those in adults. Patient size, blood volume, and underlying condition mandate special precautions in regard to dosing and risks. In all cases, careful consideration should be given to the indication for, appropriate dose of, and potential toxicities of the specific blood product. Formulas to calculate pediatric transfusion requirements are detailed in Table 10.11.
Packed red blood cells (PRBCs) should be transfused in children according to age-specific blood volumes and target Hb levels. Unless rapid replacement is required for shock or rapid loss, the recommended infusion rate is 2 to 4 mL/kg/hour or 10 to 15 mL/kg aliquots over 4 hours. With volume intolerance, gradual correction can be achieved by infusing small aliquots (5 to 10 mL/kg) over 4 to 6 hours. Diuretics may be helpful. When rapid correction is required but is limited by fluid intolerance, partial exchange transfusion can be utilized with whole blood removed in small aliquots and replaced with equal volumes of PRBCs.
Platelets transfused at a dose of 0.1 U/kg are expected to increase the platelet count by approximately 50,000/µL in most infants and children. The target post-transfusion platelet count varies with the clinical scenario. In general, the aim should be to raise the count to a level at which bleeding stops. Values of around 50,000/µL usually suffice, although normal counts should be maintained for life-threatening circumstances, such as CNS, vascular, or surgical hemorrhage. In the setting of myelosuppression without additional risk factors for severe bleeding, prophylactic platelet transfusion is recommended at a level of 10,000/µL. To minimize the risk of bleeding in newborns, standard recommendations are to maintain the platelet count above 30,000/µL for full-term and 50,000/µL for premature infants. Prophylactic transfusions are not indicated in the setting of ITP and other antibody-mediated forms of platelet destruction where no transfusion-related increment is expected; rather, transfusions should be reserved for life-threatening bleeding. To decrease the risk of alloimmunization in children who require multiple transfusions, single-donor (apheresis) and leukocyte-depleted platelets should be used whenever possible.
FFP is recommended for children with coagulopathy, as evidenced by prolonged PT and/or PTT, who have active bleeding or to prevent hemorrhage in those at high risk (e.g., preoperatively). FFP should be used to replace clotting factors for which specific concentrates are not available and a dose of 10 to 15 mL/kg usually raises the clotting activity by approximately 20%. Multiple doses may be required if there is ongoing consumption. The rate of transfusion is limited by citrate toxicity, and vital signs and ionized calcium levels should be monitored closely when large or rapid infusions are used.
Cryoprecipitate is used primarily to combat bleeding with hypofibrinogenemia. A dose of 0.3 U/kg will increase the fibrinogen level by approximately 200 mg/dL.
Specialized Blood Products to Prevent Toxicities
WBC removal by leukofiltration should be performed for recipients of blood products who require multiple transfusions in order to decrease the risk of sensitization to leukocyte antigens. Leukodepletion also decreases the risks of febrile reactions and CMV transmission. Irradiation of cellular blood products with 2,500 cGy should be used to prevent transfusion-associated graft-versus-host disease in the following situations: (i) potential immunocompromised host, including very low birth weight infants, immunodeficiency, malignancy, marrow or organ transplantation; (ii) blood from first-degree family members or HLA-matched donors; and (iii) all granulocyte transfusions.
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