CHAPTER 70 CLASSIFICATION AND CLINICAL MANIFESTATIONS OF NEUTROPHIL DISORDERS
CHAPTER 70 CLASSIFICATION AND CLINICAL MANIFESTATIONS OF NEUTROPHIL DISORDERS
MARSHALL A. LICHTMAN
Qualitative Neutrophil Abnormalities
Neutrophil-Induced Vascular or Tissue Damage
Neutrophil disorders can be grouped into deficiencies, or neutropenia, and excesses, or neutrophilia. The former can have the severe consequence of predisposing to infection, whereas the latter is usually a manifestation of an underlying inflammatory or neoplastic disease: the neutrophilia, per se, having no specific consequences. Neutropenia may reflect an inherited disease that is usually evident in childhood (such as congenital neutropenia), but it is more often acquired. The most common cause for neutropenia is the adverse effect of the use of a drug. Some cases of neutropenia have no evident cause. The health consequence of neutropenia is a function of the severity of the decrease in the blood neutrophil count and the abruptness and duration of the decrease. Qualitative disorders of neutrophils may lead to infection as a result of defective chemotaxis to an inflammatory site or defective microbial killing. Table 70-1 provides a comprehensive categorization of neutrophil disorders.
TABLE 70-1 CLASSIFICATION OF NEUTROPHIL DISORDERS
Table 70-1 lists disorders that result from a primary deficiency in neutrophil numbers or function. Neutropenia or neutrophilia may also occur as part of a disorder that affects multiple blood cell lineages, such as occurs in infiltrative diseases of the marrow or after cytotoxic drug therapy, but these are not included in this classification and are discussed in other parts of this text. In this classification, and in this section of the text, we consider diseases resulting from neutrophil deficiencies in which the neutrophil is either the only cell type affected or is the dominant cell type affected.
A pathophysiologic classification of neutrophil disorders has proved elusive. Techniques to measure mechanisms of impaired production or accelerated destruction of neutrophils are more difficult and complex than those used for red cells or platelets. The low concentration of blood neutrophils, accentuated in neutropenic states, makes radioactive labeling techniques to study the kinetics of autologous cells in neutropenic subjects technically difficult or not possible. The two compartments of neutrophils in the blood, the random disappearance of neutrophils from the circulation, the extremely short circulation time of neutrophils, the absence of techniques to measure the size of the tissue neutrophil compartment, and the disappearance of neutrophils by death or excretion from the tissue compartment also make multicompartment kinetic analysis exceedingly 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 of neutropenia have had limited success. Hence, the classification of neutrophil disorders is partly pathophysiologic and partly descriptive (see Table 70-1). Although imperfect, classification does provide a language for communication and a basis for rectification as knowledge of the cause and mechanism of disease advances.
The classification is self-explanatory except in two areas. First, certain childhood syndromes have been listed under decreased neutrophilic granulopoiesis. They could have been listed under chronic hypoplastic or chronic idiopathic neutropenia; however, they seem to hold a special interest, and their pathogenesis is still disputed. Three childhood syndromes, although associated with neutropenia, are omitted because the neutropenia is part of a more global suppression of hemopoiesis: Pearson syndrome,1,2 Fanconi syndrome,3,4 and dyskeratosis congenita.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 is apparently ineffective. Unlike hypoplastic neutropenias 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 is probably low.
Qualitative disorders of neutrophils affect their ability to enter inflammatory exudates, to ingest microorganisms, or to kill ingested microorganisms (see Chap. 72).
The clinical manifestations of decreased concentrations or abnormal function of neutrophils are principally the result of 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 have not been associated with clinical manifestations, although increased concentrations of leukemic neutrophil precursors can produce clinical manifestations of microcirculatory leukostasis (see Chap. 91).
The lower limit of the normal neutrophil count is about 1800/µl (1.8 × 109/liter) in subjects of European descent and 1400/µl (1.4 × 109/liter) in subjects of African descent.148,149,150,151,152,153 and 154 This finding is especially striking in Yemenite Jews, another ethnic group with very low “normal” neutrophil counts.155 A decrement in neutrophil concentration to 1000/µl (1.0 × 109/liter) usually poses little threat in the otherwise healthy individual. If the neutrophil count drops further, the risk of infection increases, and subjects chronically neutropenic as a result of a production abnormality with counts less than 500 neutrophils/µl (0.5 × 109/liter) are at risk of developing recurrent infections.156
The relationship of frequency or type of infection to neutrophil concentration is an imperfect one. The cause of the neutropenia, the coincidence of monocytopenia or lymphopenia, concurrent use of alcohol or glucocorticoids, and other factors can influence the likelihood of infection.
Infections in neutropenic subjects, not otherwise compromised, are most likely to result from gram-positive cocci and usually are superficial, involving skin, oropharynx, bronchi, anal canal, or vagina. However, any site may become infected, and gram-negative organisms, viruses, or opportunistic organisms may be involved.
A decrease in neutrophil count can occur abruptly or gradually (see Chap. 71). One type of drug-induced neutropenia is distinguished by the rapidity of onset. This abrupt-onset neutropenia is more likely to be severe and lead 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.157,158 and 159 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.
There is a decrease in the formation of pus in patients with severe neutropenia.160,161 This failure to suppurate can mislead the clinician and delay identification of the site of infection because minimal physical or radiographic findings develop. For example, lack of pneumonic consolidation is characteristic of pneumonia in granulocytopenic subjects. Exudate, swelling, heat, and regional adenopathy are much less prevalent in granulocytopenic patients. Fever is common, and local pain, tenderness, and erythema are nearly always present despite a marked reduction in neutrophils.162,163 and 164
The mechanism of neutropenia, as well as the severity of the deficiency of cells, plays a role in clinical manifestations. Chronic idiopathic (benign) neutropenia is associated with normal granulopoiesis in the marrow and is asymptomatic even when present for prolonged periods, sometimes in the face of neutrophil counts approaching zero.49 Presumably the delivery of neutrophils from marrow to tissues is sufficient to prevent infection despite the low blood pool size.50,51 Monocyte counts are normal, and this may also aid in host defenses, since these cells are effective phagocytes.
Chronic idiopathic (symptomatic) neutropenia is often associated with pyoderma and otitis media in children.55 The former is usually caused by Staphylococcus aureus, Escherichia coli, and Pseudomonas spp., and the latter is usually the result of infection by pneumococci or Pseudomonas aeruginosa. Unexplained chronic gingivitis also may be a manifestation of chronic neutropenia.165 Pneumonia, lung abscesses, stomatitis, hepatic abscesses, or infections in other sites may occur.56
Chronic cyclic neutropenia is characterized by periodic oscillations in the number of neutrophils, with the nadir occurring at about 3-week intervals.36,166 During neutropenia, patients develop malaise, fever, and buccal, labial, or lingual ulcers, and cervical adenopathy. Furuncles, carbuncles, cellulitis, infected cuts with lymphangitis, chronic gingivitis, and abscesses of the axilla or groin also may occur. Although severe infections may lead to fatality, life-threatening complications are uncommon (see Chap. 71).
Some individuals may have neutropenia because a larger proportion of their blood neutrophils is in the marginal rather than in the circulating pool. The total blood neutrophil pool is normal, and infections do not result from this atypical distribution of neutrophils.167 This type of alteration has been called pseudoneutropenia.
QUALITATIVE NEUTROPHIL ABNORMALITIES
Neutrophil function depends on the ability of neutrophils to adhere to endothelium, move, respond to chemotactic gradients, ingest microorganisms, and kill ingested pathogens. Loss of any of these functions can predispose to infection (see Chap. 72). Defects in each step of the neutrophil’s participation in the inflammatory response have been identified.168,169 Defects in cytoplasmic contractile proteins, granule synthesis or contents, or intracellular enzymes may underlie a movement, ingestion, or killing defect. These defects may be congenital or acquired. Chronic granulomatous disease102,103 and Chédiak-Higashi disease121 are two examples of the former. Among the acquired disorders are those extrinsic to the cell, such as in the movement, chemotactic, or phagocytic defects of diabetes mellitus,168,169,170 and 171 alcohol abuse,172,173 or glucocorticoid excess.174 Acquired intrinsic disorders are usually manifestations of stem cell disorders like preleukemia175 (see Chap. 91).
Severe defects in bacterial killing, such 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 are relatively infrequent and that 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.
An overabundance of neutrophils has not been shown to result in specific clinical manifestations. Neutrophils 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.124 Impairment of reperfusion of the coronary microcirculation has been thought to be dependent, in part, on neutrophil plugging of myocardial capillaries.123
NEUTROPHIL-INDUCED VASCULAR OR TISSUE DAMAGE
Neutrophil products may contribute to the pathogenesis of inflammatory skin, bowel, synovial, glomerular, and bronchial and interstitial pulmonary diseases.124,125,126,127,128,129,130,131,132,133,134,135,136,137 and 138 In addition, these products may act as mediators of tissue injury in myocardial infarction.139,140,141 and 142 Also, highly reactive oxygen products of neutrophils may be mutagens that increase the risk of neoplasia.144,145 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.146 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.129 Thrombogenesis has also been ascribed to leukocyte products.143
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn