Leukopenia

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Chapter 125 Leukopenia

Marked developmental changes in normal values for the total white blood cell (WBC) count occur during childhood (Chapter 708). The mean WBC count at birth is high, followed by a rapid fall beginning at 12 hr until the end of the 1st wk. Thereafter, values are stable until 1 yr of age. A slow, steady decline in the WBC count continues throughout childhood until reaching the adult value during adolescence. Leukopenia in adolescents and adults is defined as a total WBC count <4,000/µL. Evaluation of patients with leukopenia, neutropenia, or lymphopenia begins with a thorough history, physical examination, family history, and screening laboratory tests (Table 125-1).

Table 125-1 DIAGNOSTIC APPROACH FOR PATIENTS WITH LEUKOPENIA

EVALUATION ASSOCIATED CLINICAL DIAGNOSES
INITIAL EVALUATION
• History of acute or chronic leukopenia  
• General medical history Congenital syndromes (Shwachman-Diamond, Wiskott-Aldrich, Fanconi anemia, dyskeratosis congenita, glycogen storage disease type Ib, disorders of vesicular transport)
• Physical examination: stomatitis, gingivitis, dental defects, congenital anomalies
• Spleen size Hypersplenism
• History of drug exposure Drug-associated neutropenia
• Complete blood count with differential and reticulocyte counts Neutropenia, aplastic anemia, autoimmune cytopenias
IF ANC <1,000/µL
EVALUATION OF ACUTE ONSET NEUTROPENIA
• Repeat blood counts in 3-4 weeks Transient myelosuppression (e.g., viral)
• Serology and cultures for infectious agents Active or chronic infection with viruses (e.g., EBV, CMV), bacteria, mycobacteria, rickettsia
• Discontinue drug(s) associated with neutropenia Drug-associated neutropenia
• Test for antineutrophil antibodies Autoimmune neutropenia
• Measure quantitative immunoglobulins (G, A, and M), lymphocyte subsets Neutropenia associated with disorders of immune function
IF ANC <500/µL ON 3 SEPARATE TESTS
• Bone marrow aspiration and biopsy, with cytogenetics Severe congenital neutropenia, Shwachman-Diamond syndrome, myelokathexis; chronic benign or idiopathic neutropenia
• Serial CBCs (3/week for 6 weeks) Cyclic neutropenia
• Exocrine pancreatic function Shwachman-Diamond syndrome
• Skeletal radiographs Shwachman-Diamond syndrome, cartilage-hair hypoplasia, Fanconi anemia
IF ABSOLUTE LYMPHOCYTE COUNT <1000/µL
• Repeat blood counts in 3-4 weeks Transient leukopenia (e.g., viral)
IF ALC <1000/µL ON 3 SEPARATE TESTS
• HIV-1 antibody test HIV-1 infection, AIDS
• Quantitative immunoglobulins (G, A, and M), lymphocyte subsets Congenital or acquired disorders of immune function
IF THERE IS PANCYTOPENIA
• Bone marrow aspiration and biopsy Bone marrow replacement by malignancy, fibrosis, granulomata, storage cells
• Bone marrow cytogenetics Myelodysplasia, leukemia
• Vitamin B12 and folate levels Vitamin deficiencies

ANC, absolute neutrophil count; CBC, complete blood count; CMV, cytomegalovirus; EBV, Epstein-Barr virus.

Neutropenia

Neutropenia is an absolute neutrophil count (ANC), calculated as the WBC count × % of neutrophils and bands, more than 2 standard deviations below the normal mean. Normal neutrophil counts must be stratified for age and race. For whites over the age of 12 mo, the lower limit of normal for the neutrophil count is 1,500/µL, and for blacks over 12 mo old, the lower limit of normal is 1,200/µL. The relatively lower limit in blacks probably reflects a relative decrease in neutrophils in the storage compartment of the bone marrow. Neutropenia may be characterized as mild neutropenia, with an ANC of 1,000-1,500/µL; moderate neutropenia, with an ANC of 500-1,000/µL; or severe neutropenia, with an ANC <500/µL. This stratification aids in predicting the risk of pyogenic infection; only patients with severe neutropenia have significantly increased susceptibility to life-threatening infections.

Etiology

Acute neutropenia evolving over a few days often occurs when neutrophil use is rapid and production is compromised. Chronic neutropenia lasting months or years can arise from reduced production, increased destruction, or excessive splenic sequestration of neutrophils. Neutropenia may be classified by whether it arises secondary to factors extrinsic to marrow myeloid cells (Table 125-2), which is common; as an acquired disorder of myeloid progenitor cells (Table 125-3), which is less common; or, more rarely, as an intrinsic defect affecting proliferation and maturation of myeloid progenitor cells (Table 125-4).

Table 125-2 CAUSES OF NEUTROPENIA EXTRINSIC TO MARROW MYELOID CELLS

CAUSE ETIOLOGIC FACTORS/AGENTS ASSOCIATED FINDINGS
Infection Viruses, bacteria, protozoa, rickettsia, fungi Redistribution from circulating to marginating pools, impaired production, accelerated destruction
Drug-induced Phenothiazines, sulfonamides, anticonvulsants, penicillins, aminopyrine Hypersensitivity reaction (fever, lymphadenopathy, rash, hepatitis, nephritis, pneumonitis, aplastic anemia), antineutrophil antibodies
Immune neutropenia Alloimmune, autoimmune Variable arrest from metamyelocyte to segmented neutrophils in bone marrow
Reticuloendothelial sequestration Hypersplenism Anemia, thrombocytopenia, neutropenia
Bone marrow replacement Malignancy (lymphoma, metastatic solid tumor, etc.) Presence of immature myeloid and erythroid precursors in peripheral blood
Cancer chemotherapy or radiation therapy to bone marrow Suppression of myeloid cell production Bone marrow hypoplasia, anemia, thrombocytosis

Table 125-3 ACQUIRED DISORDERS OF MYELOID CELLS

CAUSE ETIOLOGIC FACTORS/AGENTS ASSOCIATED FINDINGS
Aplastic anemia Stem cell destruction and depletion Pancytopenia
Vitamin B12 or folate deficiency Malnutrition; congenital deficiency of B12 absorption, transport, and storage; vitamin avoidance Megaloblastic anemia, hypersegmented neutrophils
Acute leukemia, chronic myelogenous leukemia Bone marrow replacement with malignant cells Pancytopenia, leukocytosis
Myelodysplasia Dysplastic maturation of stem cells Bone marrow hypoplasia with megaloblastoid red cell precursors, thrombocytopenia
Prematurity with birthweight <2 kg Impaired regulation of myeloid proliferation and reduced size of postmitotic pool Maternal preeclampsia
Chronic idiopathic neutropenia Impaired myeloid proliferation and/or maturation None
Paroxysmal nocturnal hemoglobinuria Acquired stem cell defect secondary to mutation of PIG-A gene Pancytopenia, thrombosis

Table 125-4 INTRINSIC DISORDERS OF MYELOID PRECURSOR CELLS

SYNDROME INHERITANCE (GENE) CLINICAL FEATURES (INCLUDING STATIC NEUTROPENIA UNLESS OTHERWISE NOTED)
PRIMARY DISORDERS OF MYELOPOIESIS
Cyclic neutropenia AD (ELA2) Periodic oscillation (21-day cycles) in ANC
Severe congenital neutropenia AD (ELA2, GFI1, others) Risk of MDS and AML
X-linked (WAS) Neutropenic variant of Wiskott-Aldrich syndrome
Kostmann syndrome AR (HAX1) Neurological abnormalities, risk of MDS and AML
DISORDERS OF RIBOSOMAL FUNCTION
Shwachman-Diamond syndrome AR (SBDS) Pancreatic insufficiency, variable neutropenia, other cytopenias, metaphysical dysostosis
Dyskeratosis congenita Telomerase defects: XL (DKC1), AD (TERC), AR (TERT) Nail dystrophy, leukoplakia, reticulated hyperpigmentation of the skin; 30-60% develop bone marrow failure
DISORDERS OF GRANULE SORTING
Chédiak-Higashi syndrome AR (LYST) Partial albinism, giant granules in myeloid cells, platelet storage pool defect, impaired natural killer cell function, hemophagocytic lymphohistiocytosis
Griscelli syndrome, type II AR (RAB27a) Partial albinism, impaired natural killer cell function, hemophagocytic lymphohistiocytosis
Cohen syndrome AR (COH1) Partial albinism
Hermansky-Pudlak syndrome, type II AR (AP3P1) Cyclic neutropenia, partial albinism
p14 deficiency probable AR (MAPBPIP) Partial albinism, decreased B and T cells
DISORDERS OF METABOLISM
Glycogen storage disease, type 1b AR (G6PT1) Hepatic enlargement, growth retardation, impaired neutrophil motility
G6Pase, catalytic subunit 3, deficiency AR (G6PC3) Structural heart defects, urogenital abnormalities, venous angiectasia
Barth syndrome XL (TAZ1) Episodic neutropenia, dilated cardiomyopathy, methylglutaconic aciduria
Pearson’s syndrome Mitochondrial (DNA deletions) Episodic neutropenia, pancytopenia; defects in exocrine pancreas, liver, and kidneys
NEUTROPENIA IN DISORDERS OF IMMUNE FUNCTION
Common variable immunodeficiency Familial, sporadic (TNFRSF13B) Hypogammaglobulinemia, other immune system defects
IgA deficiency Unknown (Unknown or TNFRSF13B) Decreased IgA
Severe combined immunodeficiency AR, XL (multiple loci) Absent humoral and cellular immune function
Hyper-IgM syndrome XL (HIGM1) Absent IgG, elevated IgM, autoimmune cytopenia
WHIM syndrome AD (CXCR4) Warts, hypogammaglobulinemia, infections, myelokathexis
Cartilage-hair hyperplasia AR (RMKP) Lymphopenia, short-limbed dwarfism, metaphysical chondrodysplasia, fine sparse hair
Schimke immuno-osseous dysplasia probable AR (SMARCAL1) Lymphopenia, pancytopenia, spondyloepiphyseal dysplasia, growth retardation, renal failure

AD, autosomal dominant; AML, acute myelogenous leukemia; ANC, absolute neutrophil count; AR, autosomal recessive; MDS, myelodysplasia; XL, X-linked.