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
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.
