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CHAPTER 64 The two compartments of neutrophils in the blood (cells marginated
along vascular beds as distinct from cells circulating and counted in the
CLASSIFICATION AND blood neutrophil count [Chap. 65]), the random disappearance of neu-
trophils from the circulation, the short circulation time of neutrophils,
CLINICAL MANIFESTATIONS the absence of practical techniques for measuring the size of the tis-
sue neutrophil compartment, and the disappearance of neutrophils by
apoptosis or excretion from the tissue compartment also make multi-
OF NEUTROPHIL DISORDERS compartmental kinetic analysis difficult. Also, neutropenic disorders
are uncommon, and few laboratories are able, or prepared, to undertake
the studies necessary to define the mechanisms of their development
in sporadic cases. Therefore, efforts to understand the pathophysiology
Marshall A. Lichtman and kinetics of neutropenia have been of more limited success than that
of red cells or platelets. Hence, the classification of neutrophil disor-
ders is partly pathophysiologic and partly descriptive (see Table 64–1).
SUMMARY Classification, although imperfect, does provide a language for com-
munication and a basis for rectification as knowledge of the cause and
Neutrophil disorders can be grouped into deficiencies, or neutropenia, mechanism of each entity advances.
excesses, or neutrophilia, and qualitative abnormalities. Neutropenia can have The classification is self-explanatory except in two areas. First,
the severe consequence of predisposing to infection, whereas neutrophilia certain childhood (congenital or hereditary) syndromes listed under
decreased neutrophilic granulopoiesis could have been listed under
usually is a manifestation of an underlying inflammatory or neoplastic disease: chronic hypoplastic neutropenia or chronic idiopathic neutropenia;
the neutrophilia, per se, having no specific consequences. Qualitative disorders however, they seem to hold a special interest. Their unique status and
of neutrophils may lead to infection as a result of defective cell translocation their pathogenesis have become further clarified as the mutations linked
to an inflammatory site or defective microbial killing. Neutropenia may reflect to each are identified. Three childhood syndromes that are associated
an inherited disease that is evident in childhood (such as congenital [heredi- with neutropenia are omitted because the neutropenia is part of a more
1,2
tary] severe neutropenia), but more often it is acquired. A common cause of global suppression of hematopoiesis: Pearson syndrome, Fanconi ane-
3,4
neutropenia is the adverse effect of a drug. Some cases of neutropenia have mia, and dyskeratosis congenita (Chap. 35). 5,6
no evident cause. The health consequence of neutropenia is a function of the A second area requiring explanation is the chronic idiopathic neu-
mechanism of the neutropenia, the abruptness and severity of the decrease tropenias. This group includes (1) cases with normocellular marrows
in the blood neutrophil count, and the duration of the decrease. Neutrophils but an inadequate compensatory increase in granulopoiesis for the
have also been identified as mediators of vascular or tissue injury. Table 64–1 degree of neutropenia and (2) cases with hyperplastic granulopoiesis
that apparently is ineffective as a result of apoptosis of marrow neu-
provides a comprehensive categorization of quantitative and qualitative neu- trophils and late precursors. Unlike hypoplastic neutropenia in which
trophil disorders. the granulocyte precursors are markedly reduced or absent, precursors
are present in the marrow in the idiopathic neutropenias, but the extent
of effective granulopoiesis probably is low. A variety of mutations have
CLASSIFICATION been discovered that are causal for inherited or sporadic neutropenia
syndromes. For example, mutation of the serine protease neutrophil
Table 64–1 lists disorders that result from a primary deficiency in neu- elastase 2 gene (ELANE) is found in 70 percent of cases of the autoso-
trophil numbers or function. Neutropenia or neutrophilia also occurs mal dominant form of severe congenital neutropenia and in most cases
7
as part of a disorder that affects multiple blood cell lineages, as in infil- of cyclic neutropenia. Kostmann syndrome is the autosomal recessive
trative diseases of the marrow, or intrinsic disorders of multipotential form of severe congenital neutropenia and is caused by mutations in the
8
marrow hematopoietic cells, or removal of several blood cell types in HAX1 gene. Some cases of severe congenital neutropenia have been
the circulation. These diseases are not included in this classification and related to mutations in GPI1, G6PC3, and others. 9–11 There is evidence
are discussed in other chapters of this text. This classification and chap- that these mutations result in apoptotic loss of marrow neutrophil pre-
ter considers disorders in which the neutrophil either is the only cell cursors as a result of downregulation of the BCL-2 family of antiap-
type affected or the dominant cell type affected. optotic proteins, the upregulation of the proapoptotic FAS receptor, or
A pathophysiologic classification of neutrophil disorders has other apoptosis-enhancing pathways, described more fully in Chap. 65.
proved elusive. Techniques for measuring mechanisms of (1) impaired A comprehensive listing of the genetic mutations found in monogenic
production resulting from hypoplasia or exaggerated apoptosis of mar- congenital neutropenia and the extra hematopoietic manifestations of
row precursors (ineffective neutropoiesis) or (2) accelerated destruc- those disorders can be found in a publication of the Service d’Hémato
tion of neutrophils are more difficult and complex than the techniques Oncologie Pédiatrique Registre des neutropénies. 12
used to measure decreases in red cells or platelet concentrations. The Qualitative disorders of neutrophils affect their ability to enter the
low concentration of blood neutrophils, accentuated in neutropenic circulation, to leave the circulation, enter inflammatory exudates, or to
states, makes radioactive-labeling techniques for studying the kinetics ingest or kill microorganisms. Chapter 66 describes these abnormalities
of autologous cells in neutropenic subjects difficult, if not impossible. in more detail.
CLINICAL MANIFESTATIONS

Acronyms and Abbreviations: CD, cluster of differentiation; G-CSF, granulo- The clinical manifestations of decreased concentrations or abnormal
cyte colony-stimulating factor; HLA-DR, human leukocyte antigen-D related. function of neutrophils principally result from infection. The combined
deficit of neutrophils and monocytes characteristic of aplastic anemia,

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