Chapter 29: Classification and Clinical Manifestations of Neutrophil Disorders

One should use appropriate normal neutrophil concentration values for certain ethnic groups in which neutrophil counts are significantly lower than persons of European ancestry (eg, African ancestry, Yemeni Jewish ancestry).

In this classification, diseases resulting from neutrophil abnormalities in which the neutrophil is either the only cell type affected or is the dominant cell type affected are considered (Table 29–1).

Neutropenia or neutrophilia occurs as part of disorders that affect multiple blood cell lineages (eg, aplastic anemia [see Chap. 3], myelodysplastic syndrome [see Chap. 44], acute and chronic myelogenous leukemias [see Chaps. 45 and 46], chronic myeloproliferative diseases [see Chaps. 41, 42, and 47]).

A strict pathophysiologic classification of neutrophil disorders has proved elusive because:

— The low concentration of blood neutrophils in neutropenic states makes measuring the circulatory kinetics of autologous cells technically difficult.

— The two compartments of neutrophils in the blood, the random disappearance of neutrophils from the circulation, the extremely short circulation time of neutrophils (t_1/2 = ~6 hours), the absence of facile techniques to measure the size of the tissue neutrophil compartment, and the disappearance of neutrophils by apoptosis or gastrointestinal excretion from the tissue compartment make multicompartment kinetic analysis difficult.

Thus, the classification of neutrophil disorders is partly pathophysiologic and partly descriptive (see Table 29–1).

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 as pediatric conditions and the causative gene mutations are known in many cases.

Three childhood syndromes, although associated with neutropenia, are omitted because the neutropenia is part of a more global suppression of hematopoiesis: Pearson syndrome, Fanconi syndrome, and dyskeratosis congenita (see Chap. 3).

Chronic idiopathic neutropenias include:

— Cases with normocellular marrows but an inadequate compensatory increase in granulopoiesis for the degree of neutropenia (~1/3 of cases)

— Cases with hyperplastic marrow granulopoiesis that is apparently ineffective (~1/2 of cases)

— Cases with hypoplastic marrow granulopoiesis (~1/6 of cases)

The clinical manifestations of decreased concentrations or abnormal function of neutrophils are the result of infection.

— 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 persons not otherwise compromised are most likely to result, initially, from gram-positive cocci and usually are superficial, involving the skin, oropharynx, bronchi, anal canal, or vagina. However, any site may become infected, and gram-negative organisms, viruses, or opportunistic organisms may be involved.

— There is a decrease in the formation of pus in patients with severe neutropenia. This failure to suppurate can mislead the clinician and delay identification of the site of infection because minimal physical or radiographic findings develop.

— Exudate, swelling, and regional adenopathy are much less prevalent in severely neutropenic patients. Fever is common, and local pain, tenderness, and erythema are nearly always present despite a marked reduction in neutrophils.

Some individuals may have apparent neutropenia because a larger fraction of their blood neutrophils is in the marginal rather than the circulating blood pool. In this type of neutropenia, the total blood neutrophil pool is normal, the neutrophil’s ability to enter tissues is normal, and infections do not result from this atypical circulatory distribution of neutrophils. This type of alteration has been called pseudoneutropenia.

Neutrophil function depends on the ability of neutrophils to adhere to vascular endothelium, penetrate endothelium, migrate along chemotactic gradients, and ingest and kill microorganisms on contact. Loss of any of these functions can predispose to infection (see Chap. 31).

Defects in 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 and Chédiak-Higashi disease are two examples of inherited disorders (see Chap. 31).

Among the acquired disorders are those extrinsic to the cell, such as in the movement, chemotactic, or phagocytic defects of diabetes mellitus, alcohol abuse, and glucocorticoid excess.

Acquired intrinsic disorders are usually manifestations of clonal myeloid diseases (eg, deficient granules in leukemic neutrophils) (see Chap. 44).

Severe functional abnormalities in neutrophils can result in Staphylococcus aureus, Klebsiella aerobacter, Escherichia coli, and other catalase-positive microorganism infections (see Chap. 31).

An overabundance of neutrophils has not been shown to result in specific clinical manifestations.

Impairment of postischemic reperfusion of the coronary microcirculation has been thought to be dependent, in part, on neutrophil plugging of myocardial capillaries.

Neutrophil products may contribute to the pathogenesis of inflammatory skin, bowel, synovial, glomerular, bronchial, retinal, and interstitial pulmonary diseases.

Highly reactive oxygen products of neutrophils may be mutagens that increase the risk of neoplasia.

— Development of carcinoma of the bowel in patients with chronic ulcerative colitis

— Relationship between chronically 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 neutrophils are extremely short-lived but may inactivate protease inhibitors in tissue fluids, permitting elastase, collagenase, gelatinase, and other proteases or cationic proteins to cause tissue injury.

Expression of neutrophil selectins and integrin molecules (eg, intracellular adhesion molecule-1, endothelial-leukocyte adhesion molecule-1) contribute to neutrophils as pathogens. They contribute to microvascular damage by adherent neutrophils (eg, diabetic retinopathy; sickle cell vasculopathy [see Chap. 16]; transfusion-related acute lung injury [see Chap. 91]; specific types of renal, cerebral, retinal, and coronary vasculopathies; and other situations).

Thrombogenesis has also been ascribed to leukocyte products, especially tissue factor.