Chapter 64: Classification and Clinical Manifestations of Neutrophil Disorders

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

The relationship of frequency or type of infection to neutrophil concentration is imperfect. The cause of the neutropenia, the coincidence of monocytopenia or lymphopenia, concurrent use of alcohol or glucocorticoids, exposure to nosocomial infections, and other factors influence the likelihood of infection. A breakdown in the barrier function of the skin or circumstances such as indwelling catheters, also, increase the risk of infection in severely neutropenic subjects. Lower neutrophil counts in African (Malawian) mothers infected with HIV were associated with an increased risk of HIV in their newborns.¹⁸⁰

Infections in neutropenic subjects who are not otherwise compromised usually result from Gram-positive cocci and usually are superficial, involving skin, oropharynx, bronchi, anal canal, or vagina. However, any site can become infected and Gram-negative organisms, viruses, or opportunistic organisms can be involved.

A decrease in neutrophil count can occur abruptly or gradually (Chap. 65). One type of drug-induced neutropenia is distinguished by the rapidity of onset. Abrupt-onset neutropenia more likely is severe and leads to symptoms. If the neutrophil count approaches zero (agranulocytosis), high fever; chills; necrotizing, painful oral ulcers (agranulocytic angina), and prostration may occur, presumably as a result of sepsis.¹⁸¹ As the disease progresses, headache, stupor, and rash may develop. In the preantibiotic era, persistent agranulocytosis had a fatality rate approaching 100 percent. Even with bactericidal, broad-spectrum antibiotics, severe, sustained neutropenia or agranulocytosis is a serious illness with a high fatality rate.

Pus formation decreases in patients with severe neutropenia.¹⁸² The failure to suppurate can mislead the clinician and delay identification of the infection site because minimal physical or radiographic findings develop. For example, lack of pneumonic consolidation is characteristic of pneumonia in granulocytopenic subjects. An exudate, swelling, heat, and regional adenopathy are much less prevalent in granulocytopenic patients. Fever is common, and local pain, tenderness, and erythema nearly always are present despite a marked reduction in neutrophils.¹⁸¹

The mechanism of neutropenia and the severity of the deficiency of cells play roles in clinical manifestations. Chronic idiopathic (benign) neutropenia is associated with apparent normal granulopoiesis in the marrow and is asymptomatic even when the neutropenia has been present for prolonged periods, sometimes in the face of neutrophil counts approaching zero for prolonged periods.⁵⁰ Presumably the delivery of neutrophils from marrow to tissues is sufficient to prevent infection despite the low blood pool size. Monocyte counts are normal, which may aid in host defenses because monocytes are effective phagocytes.

Chronic idiopathic (symptomatic) neutropenia often is associated with pyoderma and otitis media in children. The former usually is caused by Staphylococcus aureus, Escherichia coli, and Pseudomonas species, and the latter usually results from infection by pneumococci or Pseudomonas aeruginosa. Unexplained chronic gingivitis may be a manifestation of chronic neutropenia. Pneumonia, lung abscesses, stomatitis, hepatic abscesses, or infections in other sites can occur.

Chronic cyclic neutropenia is characterized by periodic oscillations in the number of neutrophils, with the nadir occurring at approximately 3-week intervals.⁴³ During a period of neutropenia, patients develop malaise; fever; buccal, labial, or lingual ulcers; and cervical adenopathy. Furuncles, carbuncles, cellulitis, infected cuts with lymphangitis, chronic gingivitis, and abscesses of the axilla or groin may occur. Although severe infections may be fatal, life-threatening complications are uncommon. The cycling involves other hematopoietic cells as well, but the neutropenia is the most consequential functionally (Chap. 65).

Some individuals have neutropenia because a larger fraction of their blood neutrophils is in the marginal rather than the circulating pool. The total blood neutrophil pool is normal, and infections do not result from this atypical distribution of neutrophils. This alteration has been called pseudoneutropenia.^76,77,78

NEUTROPHILIA

An increased neutrophil count can accompany virtually any cause of inflammation, especially inflammation caused by bacterial or fungal organisms, and a variety of cancers, especially if metastatic. Certain drugs, such as glucocorticoids or hematopoietic growth factors and minocycline, can induce neutrophilia, as can ethylene glycol intoxication (see Table 64–1). Acute hemolysis or acute hemorrhage may also result in neutrophilia. A notable cause of neutrophilia is cancers that elaborate granulocyte-colony stimulating factor (G-CSF). Numerous cancers are associated with neutrophilia and, in many cases, elaboration of very high concentrations of G-CSF has been documented. In these cases, neutrophil counts exceeding 100,000 μL (100 × 10⁹/L) are common. Neutrophilia exceeding 50,000 neutrophils/μL (50 × 10⁹/L) has been designated a “leukemoid reaction” and reflects an underlying inflammatory (e.g., pancreatitis), infectious (e.g., pneumococcal pneumonia), or neoplastic (e.g., carcinoma of the lung) cause. A leukemoid reaction can mimic rare types of chronic myelogenous or chronic neutrophilic leukemia. The leukemoid reaction classically (1) is composed largely of mature neutrophils with a low proportion of bands and myelocytes, (2) has increased leukocyte alkaline phosphatase reaction in neutrophils, (3) has increased granulopoiesis with normal maturation and morphology of cells in the marrow, (4) has normal cytogenetics of marrow cells, (5) has polyclonal-derived cells in women in whom such studies can be conducted (using the human androgen receptor gene assay), and (6) has cytometric analysis of neutrophils indicating a cluster of differentiation (CD) 13 and CD15 phenotype with absent expression of human leukocyte antigen-D related (HLA-DR) and CD34.

Neutrophil function depends on the ability of neutrophils to exit the marrow, adhere to vascular endothelium, move, respond to chemotactic gradients, ingest microorganisms, and kill ingested pathogens. Loss of any of these functions can predispose to infection (Chap. 66). Defects in each step of the neutrophil’s participation in the inflammatory response have been identified. Defects in adhesion molecules, cytoplasmic contractile proteins, granule synthesis or contents, or intracellular enzymes may underlie a movement, ingestion, or killing defect. These defects may be inherited or acquired. Chronic granulomatous disease^113,114 and Chédiak-Higashi disease^145,146 are two examples of inherited defects. Among the acquired disorders are those extrinsic to the cell, as in the movement, chemotactic, or phagocytic defects of diabetes mellitus, the effects of alcohol abuse, or glucocorticoid excess. Acquired intrinsic disorders usually are manifestations of clonal hematopoietic (myeloid) disorders such as acute myelogenous leukemia (Chap. 85).

Severe defects in bacterial killing, as occur in chronic granulomatous disease, result in S. aureus, Klebsiella-Aerobacter, E. coli, and other catalase-positive bacterial infections. Suppurative lymphadenitis, pneumonia, dermatitis, hepatic abscesses, osteomyelitis, and stomatitis occur, and chronic granulomatous reactions in these sites give the disease its name. Fatality rates have been high. Functional disorders may be severe, as in chronic granulomatous disease. Mild functional disorders predispose to infections that occur infrequently and respond readily to antibiotics. Severe functional disorders result in suppurative lesions because neutrophil influx into inflammatory foci is not impaired, whereas agranulocytosis is associated with nonsuppurative lesions.

NEUTROPHIL-INDUCED VASCULAR OR TISSUE DAMAGE

An overabundance of neutrophils does not result in specific clinical manifestations. Neutrophils, however, can transiently occlude capillaries, as determined by supravital microscopy, and such occlusions may reduce local blood flow transiently and contribute to the development of ischemia. Impairment of reperfusion of the coronary microcirculation has been thought to be dependent, in part, on neutrophil plugging of myocardial capillaries, but these effects can occur at normal neutrophil concentrations. An elevated neutrophil count is a feature of sickle cell disease and is a prognostic variable, increasing the likelihood of vasoocclusive events. Neutrophil adhesion to the vascular wall is an intrinsic part of the vasoocclusive events and the salutary effect of hydroxyurea is related to the decrease in neutrophil concentration that accompanies its use.^157,173 In patients with ischemic vascular disease, an increased neutrophil count is associated with an increased probability of acute thrombotic episodes and the severity of chronic atherosclerosis.¹⁸³

Neutrophil products may contribute to the pathogenesis of inflammatory skin, bowel, synovial, glomerular, and bronchial and interstitial pulmonary diseases (see Table 64–1). Diabetic retinopathy has been ascribed in part to the effects of hyperadhesive neutrophils on retinal capillaries.¹⁵⁷ Neutrophils may act as mediators of tissue injury in stroke and myocardial infarction.¹⁵⁷ Highly reactive oxygen products of neutrophils may be mutagens that increase the risk of neoplasia. This action may explain, for example, the development of carcinoma of the bowel in patients with chronic ulcerative colitis and the relationship between elevated leukocyte count and the occurrence of lung cancer, independent of the effect of cigarette usage. The oxidants, especially hypochlorous acid and chloramines, released by the neutrophil are extremely short lived and may play a role in tissue injury by inactivating several protease inhibitors in tissue fluids, permitting proteases, especially elastase, collagenase, and gelatinase, to cause tissue injury. Thrombogenesis also has been ascribed to leukocyte products.