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Chapter 32 Acquired Disorders of Red Cell, White Cell, and Platelet Production 431

TABLE Classification of Neutropenia TABLE Human Neutrophil Alloantigens and Autoantigens
32.4 32.5
Congenital Nomenclature
Primary Autoimmune neutropenia Integrin α M chain CD11b HNA-4a (MART)
Pure white cell aplasia
Idiopathic Integrin α L chain CD11a HNA-4a (OND)
Thymoma Gp50-64 CD177 HNA-2a (NB1) PRV-1
Hematologic malignancies (e.g., T-LGL leukemia) Gp70-95 HNA-3a/5b
Infections/postinfectious Integrin β2 chain CD18
Viral
Measles, 128 mumps, roseola, 129,130 rubella, 131 FcγIII CD16
RSV, influenza 132 FCGR3B-01 HNA-1a (NA1)
Hepatitis A, 133 B, 133,134 and C 35 FCGR3B-02 HNA-1b (NA2)
CMV, 135–137 EBV, 138–140 HIV 141,142
Parvovirus 143–145 FCGR3B-03 HNA-1c (SH/NA3)
Bacterial
Tuberculosis 146,147
Brucellosis 148–150 antibodies have been implicated. Neutrophil-specific antibodies can
Tularemia 151 be detected using many assays, including specific enzyme-linked
Typhoid fever 152 immunosorbent assay, opsonization, leukoagglutination, and direct
Rickettsial antibody binding. There are several proposed effector mechanisms as
Rocky Mountain spotted fever 153 to how ANAs can result in neutropenia or affect neutrophil integrity.
Ehrlichiosis. 154,155 For example, ANAs may act as opsonins and directly enhance neu-
Fungal trophil destruction. Alternatively, ANAs can indirectly activate,
Histoplasmosis 156,157 complement, and facilitate opsonization. Immune complexes may
Parasitic also bind to the neutrophil Fc portion, leading to increased neutrophil
Malaria, 158 leishmaniasis 36,159 clearance by the reticuloendothelial system, and finally, ANAs may
Autoimmune conditions, (e.g., SLE, 160,161 RA 162 ) recognize and damage myeloid precursors. The currently available
Drugs and chemicals diagnostic assays used to detect ANAs are generally based on immu-
Neutropenia associated with immunodeficiency 163,164 nofluorescence and agglutination assays. The former allows for the
Severe nutritional deficiencies 165,166 detection of IgM and IgG antibodies from a suspected patient that
Neutropenia caused by increased margination are attached to normal donor neutrophils detected by flow cytometry
Iatrogenic (e.g., hemodialysis 167,168 ) performed with the patient’s serum and antihuman IgG. The second
CMV, Cytomegalovirus; EBV, Epstein-Barr virus; HIV, human immunodeficiency technique, called agglutination assay, uses serum that leads to agglu-
virus; RA, refractory anemia; RSV, respiratory syncytial virus; SLE, systemic tination of normal neutrophils into either small or large clumps.
lupus erythematosus; T-LGL, T-cell large granular lymphocyte. These tests suggest an underlying immunologic process but cannot
establish the definite cause. If there is a high index of suspicion that
ANAs are the causative factor, some authors suggest that a minimum
bone marrow biopsy may show evidence of an arrest in myeloid of two methods be used to detect ANAs.
maturation and mild hypercellularity. ANAs may be seen in 36% of In addition to antibodies, T-cell responses may be associated with
patients, suggesting an immunologic pathogenesis. An altered TCR neutropenia. The most extreme example of such responses is T-LGL
Vβ repertoire, telomere shortening, and activation of Toll-like recep- leukemia associated with neutropenia and polarized proliferation of
tor 4 have been reported to play a role in pathogenesis of chronic CTLs (see later). In AIN, CTL responses are polyclonal and are often
idiopathic neutropenia. accompanied by the simultaneous presence of antibodies. It is likely
Idiopathic neutropenias may be chronic and benign in nature or that specialized CTL clones are capable of recognizing and killing
may be associated with significant morbidity. In certain instances, myeloid precursors, interrupting granulocyte production. Conse-
immune neutropenia may be associated with hemolytic anemia or quently, some cases of AIN may be amenable to therapy with
with immune thrombocytopenia, but these forms likely represent a immunosuppressive agents directed against T cells.
distinct nosologic entity. Idiopathic neutropenia can occur at any age
with a median age at diagnosis being 28.3 years and affects predomi-
nantly females (85%). AIN may be associated with moderate and Chronic Benign Neutropenia of Infancy and Childhood
severe depression of neutrophil counts. Monocytosis is frequently
present. Some cases present with splenomegaly, which is to be distin- Chronic benign neutropenia of infancy and childhood is considered
guished from cytopenias associated with hypersplenism in Felty the most common cause of chronic neutropenia in the pediatric age
syndrome. The frequency of infectious complications rarely correlates group. The majority of cases are autoimmune in nature and show
with the severity of neutropenia, and patients with severe neutropenia clinical overlap with childhood idiopathic thrombocytopenic purpura
may remain asymptomatic for long periods. and autoimmune hemolytic anemia. It is therefore considered a type
Conceptually, AIN may be caused by peripheral autoimmune of AIN. This form of neutropenia typically presents in children less
destruction of neutrophils caused by lineage-specific inhibition of than 3 years of age, with a median age of 8–11 months and with a
myeloid precursors, with its extreme form being pure white cell predominance of girls. The ANC is usually less than 250 cells/µL
aplasia (PWCA) (see Fig. 32.3). Consequently, increased peripheral with normal morphologic characteristics and normal Hb and platelet
destruction is associated with marrow hypercellularity and an count. Occasionally monocytosis, eosinophilia, and mild thrombo-
increased number of myeloid precursors or, if myeloid progenitors cytopenia may be present. In this condition, neutropenia is caused
are the targets, decreased myeloid precursors and a myeloid matura- by chronic depletion of mature granulocytes and is accompanied by
tion arrest. Autoimmune processes have been implicated in the a compensatory myeloid left shift in the marrow. Most frequent
pathogenesis of AIN and could be mediated by both peripheral clinical signs and symptoms are oral infections, including bothersome
destruction of neutrophils and inhibition of myelopoiesis. The anti- ulcers, but these are often associated with additional functional
gens involved in these processes include neutrophil antigens NA1, defects of neutrophils and cellulitis of the labia majora. Of importance
NA2, ND1, ND2, and NB1 (Table 32.5). Both IgG and IgM is the normal neutrophil count at birth and absence of a history of