Table 64–1 lists disorders that result from a primary deficiency in neutrophil numbers or function. Neutropenia or neutrophilia also occurs as part of a disorder that affects multiple blood cell lineages, as in infiltrative diseases of the marrow, or intrinsic disorders of multipotential marrow hematopoietic cells, or removal of several blood cell types in the circulation. These diseases are not included in this classification and are discussed in other chapters of this text. This classification and chapter considers disorders in which the neutrophil either is the only cell type affected or the dominant cell type affected.

A pathophysiologic classification of neutrophil disorders has proved elusive. Techniques for measuring mechanisms of (1) impaired production resulting from hypoplasia or exaggerated apoptosis of marrow precursors (ineffective neutropoiesis) or (2) accelerated destruction of neutrophils are more difficult and complex than the techniques used to measure decreases in red cells or platelet concentrations. The low concentration of blood neutrophils, accentuated in neutropenic states, makes radioactive-labeling techniques for studying the kinetics of autologous cells in neutropenic subjects difficult, if not impossible. The two compartments of neutrophils in the blood (cells marginated along vascular beds as distinct from cells circulating and counted in the blood neutrophil count [Chap. 65]), the random disappearance of neutrophils from the circulation, the short circulation time of neutrophils, the absence of practical techniques for measuring the size of the tissue neutrophil compartment, and the disappearance of neutrophils by apoptosis or excretion from the tissue compartment also make multicompartmental 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 and kinetics of neutropenia have been of more limited success than that of red cells or platelets. Hence, the classification of neutrophil disorders is partly pathophysiologic and partly descriptive (see Table 64–1). Classification, although imperfect, does provide a language for communication and a basis for rectification as knowledge of the cause and mechanism of each entity advances.

The classification is self-explanatory except in two areas. First, certain childhood (congenital or hereditary) syndromes listed under decreased neutrophilic granulopoiesis could have been listed under chronic hypoplastic neutropenia or chronic idiopathic neutropenia; however, they seem to hold a special interest. Their unique status and their pathogenesis have become further clarified as the mutations linked to each are identified. Three childhood syndromes that are associated with neutropenia are omitted because the neutropenia is part of a more global suppression of hematopoiesis: Pearson syndrome,^1,2 Fanconi anemia,^3,4 and dyskeratosis congenita (Chap. 35).^5,6

A second area requiring explanation is the chronic idiopathic neutropenias. This group includes (1) cases with normocellular marrows but an inadequate compensatory increase in granulopoiesis for the degree of neutropenia and (2) cases with hyperplastic granulopoiesis that apparently is ineffective as a result of apoptosis of marrow neutrophils and late precursors. Unlike hypoplastic neutropenia in which 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 been discovered that are causal for inherited or sporadic neutropenia syndromes. For example, mutation of the serine protease neutrophil elastase 2 gene (ELANE) is found in 70 percent of cases of the autosomal dominant form of severe congenital neutropenia and in most cases of cyclic neutropenia.⁷ Kostmann syndrome is the autosomal recessive form of severe congenital neutropenia and is caused by mutations in the HAX1 gene.⁸ Some cases of severe congenital neutropenia have been related to mutations in GPI1, G6PC3, and others.^9,10,11 There is evidence that these mutations result in apoptotic loss of marrow neutrophil precursors as a result of downregulation of the BCL-2 family of antiapoptotic proteins, the upregulation of the proapoptotic FAS receptor, or other apoptosis-enhancing pathways, described more fully in Chap. 65. A comprehensive listing of the genetic mutations found in monogenic congenital neutropenia and the extra hematopoietic manifestations of those disorders can be found in a publication of the Service d’Hémato Oncologie Pédiatrique Registre des neutropénies.¹²

Qualitative disorders of neutrophils affect their ability to enter the circulation, to leave the circulation, enter inflammatory exudates, or to ingest or kill microorganisms. Chapter 66 describes these abnormalities in more detail.

The clinical manifestations of decreased concentrations or abnormal function of neutrophils principally result from infection. The combined deficit of neutrophils and monocytes characteristic of aplastic anemia, hairy cell leukemia, and cytotoxic therapy leads to susceptibility to a broader spectrum of infectious agents. Increased concentrations of normal neutrophils per se are usually not associated with clinical manifestations; although, increased concentrations of leukemic neutrophil precursors can produce clinical manifestations of microcirculatory leukostasis (Chap. 83). Neutrophils also play a role in deleterious vascular or tissue effects, as noted in the last entries in Table 64–1 (see “Neutrophilia” below).

NEUTROPENIA

The lower limit of the normal neutrophil count is approximately 1800/μL (1.8 × 10⁹/L) in subjects of European descent and 1400/μL (1.4 × 10⁹/L) in subjects of African descent.^{174,175,176,177} An additional small proportion (~5 percent) of persons of African descent have neutrophil counts between 1000/μL (1.0 × 10⁹/L) and 1400 (1.4 × 10⁹/L) without evidence of associated abnormalities and this finding also may represent “ethnic neutropenia.” These findings have not been explained by exaggerated margination of neutrophils.¹⁷⁶ Neutropenia is especially striking in Yemenite Jews, another ethnic group with very low “normal” neutrophil counts,¹⁷⁸ and has been reported in West Africans, Caribbean inhabitants of African descent, Ethiopians, and some Arab groups.^176,177 Persons of African descent do not have the increase of neutrophil count seen in Europeans who smoke or are administered glucocorticoids; however, they have an appropriate increase of neutrophils in response to infection. Americans of Mexican descent have a slightly elevated neutrophil count.¹⁷⁶ A decrement in neutrophil concentration to 1000/μL (1.0 × 10⁹/L) usually poses little threat in the individual with an intact immune system. If the neutrophil count drops farther, the risk of infection may increase, if the decrease reflects a decrease in flux rate into the tissues. Subjects who are chronically neutropenic, as a result of severe marrow cell production abnormalities, with counts less than 500 neutrophils/μL (0.5 × 10⁹/L) may be at heightened risk for developing recurrent infections.¹⁷⁹