Nonmalignant Disorders of Leukocytes Part 3

Disorders of Neutrophil Function

In patients who have recurrent, severe, or unusual infections but who have a normal number of neutrophils, the presence of a neutrophil function disorder must be considered. Neutrophil function disorders are caused by defects in neutrophil adherence, chemotaxis, degranulation, or oxidative metabolism [see Table 5].

The evaluation of patients with confirmed, recurrent, or un usual infections is first to review the family history and then to examine the patient [see Figure 5 ]. A complete blood count and examination of the granulocytes in a blood smear can show neu-trophilia or neutropenia, specific granule deficiency, or giant granules such as those that occur in Chediak-Higashi syndrome. Evaluation of immunoglobulin levels (IgG, IgM, IgA, and IgE) and complement levels (C3 and CH50) are also potentially helpful, especially if there is a pattern of infection by encapsulated bacteria or unusual organisms. After these considerations, neu-trophil function should be evaluated with the nitroblue tetrazoli-um (NBT) test, superoxide production assays, and chemotactic assays. The NBT test and superoxide assays can determine whether a patient has chronic granulomatous disease (CGD), severe glucose-6-phosphate dehydrogenase (G6PD) deficiency, or a glutathione-pathway disorder14; chemotactic assays can be used to confirm the diagnosis of Chediak-Higashi syndrome and acquired chemotactic defects.12 Leukocyte adhesion deficiency types I and II are diagnosed by flow cytometry.11 If the results of all of these tests are normal, ingestion assays using the patient’s serum and cells and staining for MPO may be helpful. In this manner, all of the known neutrophil function abnormalities can be diagnosed, often with the aid of specialty consultations and a research laboratory.

Monocytes and Macrophage Physiology

Table 4 Guidelines for Management and Prevention of Febrile Neutropenia43


Take careful history and conduct thorough physical examination of the patient

Examine patient carefully for portal for bacterial or fungal infections

Culture blood and other appropriate body fluids

Start antibiotics immediately

Monotherapy (e.g., ceftazidime or imipenem) or duothera-py (e.g., an aminoglycoside, such as gentamicin, with a |-lactam drug that is effective against Pseudomonas, such as piperacillin

Add vancomycin if there is a significant risk of gram-positive sepsis

Adjust antibiotic therapy after 3 days, depending on the

results of cultures and the patient’s clinical status Switch low-risk patients to oral therapy

Continue broad-spectrum therapy for severely ill patients*

Consider antifungal treatments

Consider colony-stimulating factors as an adjunct to antibiotics for febrile neutropenia in severely ill, high-risk patients+


Primary prophylaxis with G-CSF reduces incidence of febrile neutropenia by ~50% when the risk of febrile neutropenia

is ~40%t

Use G-CSF or GM-CSF as a preventive strategy for patients who have had their treatment reduced or experienced a delay in treatment because of an episode of febrile neutro-penia or a prolonged period of neutropenia Consider reducing the intensity of chemotherapy

Note: further information can be found at the following Web sites:,, and *Resolution of illness generally follows resolution of neutropenia. +For most patients with febrile neutropenia, CSF therapy has no proven benefit.

tAdministration of G-CSF or GM-CSF is not routinely indicated in previously untreated patients.

G-CSF—granulocyte colony-stimulating factor

GM-CSF—granulocyte-macrophage colony-stimulating factor phages perform tissue maintenance functions, such as clearance of particles—including bacteria—from the blood and removal of old red blood cells. They process antigens by interacting with T cells and B cells and are essential for containment of mycobacte-rial, parasitic, fungal, and viral infections.

Monocyte-macrophage development

Monocytes develop from hematopoietic progenitor cells in the bone marrow. Once the progenitor cells are committed to a monocyte lineage, they develop morphologically into mono-blasts, then promonocytes, and then monocytes. Monocytes are present in the bone marrow and blood. They are the precursors for the tissue mononuclear phagocyte system (including alveolar, peritoneal, and splenic macrophages), Kupffer cells, osteoclasts, dendritic cells, and Langerhans cells. In addition to having phagocytic capabilities, monocytes and macrophages play a central role in the immune response through the generation of numerous cytokines, including growth factors for white blood cells.

With the exception of the alveolar macrophages, which are uniquely dependent on aerobic metabolism for energy production, monocytes and macrophages are facultative anaerobes. Phagocytosis by monocytes and macrophages is associated with an oxidative burst and stimulation of the hexose monophos-phate shunt. Adhesion, chemotaxis, and activation are similar for monocytes and neutrophils, although macrophages are better than neutrophils at phagocytosis and perform chemotaxis less rapidly and efficiently. Macrophages are also capable of oxygen-independent bactericidal activity that may depend on lytic activity. Stimulated macrophages are capable of producing nitric oxide. Macrophages are capable of secreting many cytokines, growth factors, and acute-phase reactants.

Monocytes and macrophages present antigen to T cells in association with major histocompatibility complex (MHC) class II molecules. This association occurs in the lysosomes of a mononuclear cell before the MHC class II molecules are expressed on the cell surface. Monocytes and macrophages are involved in antibody-dependent and antibody-independent cell-mediated cytotoxicity. The cytotoxicity involves oxidative metabolism, the production of nitric oxide and cytokines, and the secretion of cytotoxic mediators.

Macrophages play a key role in metabolizing high-molecular-weight proteins, glycoproteins, and other material and are intimately involved in the destruction of senescent and killed cells. They also are required for angiogenesis and wound healing and are able to induce neovascularization and endothelial cell proliferation. Given these diverse products and functions, macro-phages are involved in many metabolic, infectious, inflammatory, and degenerative diseases.

Increases in blood monocytes (usually less than two times the normal level or less than 1.0 x 109/L) are a common feature of chronic inflammatory diseases and malignancies. Higher counts should raise concern about a hematologic malignancy (e.g., monocytic or myelomonocytic leukemia) [see 12:XVI Acute Leukemia].

Disorders of Monocytes and Macrophages

Histolytic Syndromes

Histiocytic syndromes are a group of malignant and nonma-lignant disorders in which the macrophages and dendritic (Langerhans) cells are the principal cells of abnormality.49 The malignant disorders include acute monocytic leukemia, mono-cytic sarcoma, and histiocytic sarcoma. The nonmalignant disorders include the Langerhans cell histiocytosis (LCH) syndromes and the hemophagocytic syndromes, such as sinus histiocytosis with massive lymphadenopathy, hemophagocytic lymphohisti-ocytosis (HL), and infection-associated hemophagocytic syndrome (IAHS).

Langerhans Cell Histiocytosis Syndromes

The LCH syndromes include solitary eosinophilic granuloma, multifocal eosinophilic granuloma, Hand-Schuller-Christian disease, and Letterer-Siwe disease.49,50 These disorders predominantly affect children 1 to 15 years of age but also occur in young adults. The LCH syndromes represent a continuum of disease that has been divided on the basis of histologic studies, age at diagnosis, extent of disease, and organ involvement. The signs and symptoms of the LCH syndromes depend on the specific organs involved.51 The bones, skin, teeth, gingival tissue, ears, endocrine organs, lungs, liver, spleen, lymph nodes, and bone marrow can all be involved and become dysfunctional as a result of cellular infiltration.52 For example, diabetes insipidus is caused by histo-cyte infiltration of the pituitary gland,53 and Erdheim-Chester disease is a multisystem disease characterized by histiocyte infiltration of many tissues.54 LCH with solitary and multifocal eosinophilic granuloma is found predominantly in older children and young adults; more infiltrative disease is common in younger patients.55 On presentation, patients with solitary lesions may have an inability to bear weight, or they may have tender swelling caused by tissue infiltrates that overlie a sharply marginated bony lesion. Diagnosis is usually made by demonstration of dendritic cells, eosinophils, and giant cells present in a biopsy specimen; electron microscopy and immunostaining may be helpful for further classification.

Table 5 Selected Disorders of Neutrophil Function



Clinical Features



Leukocyte adhesion deficiency I


Locus: 21q22.3

Neutrophilia with recurrent severe infections; failure of pus formation; delayed umbilical cord separation

Decreased neutrophil adherence and migration; CD11/CD18 deficiency Clinical testing available*

Bone marrow transplantation; antibiotics

Adherence defects

Leukocyte adhesion deficiency II

S, possibly AR

Neutrophilia with recurrent infections

Neutrophils lack surface sLex and have deficient adherence

Bone marrow transplantation; antibiotics

Actin polymerization defect


Recurrent severe infections

Defective neutrophil migration and ingestion of bacteria

Bone marrow transplantation; antibiotics


Chediak-Higashi syndrome


Locus: 1q42

Recurrent infections; partial albinism; lymphoproliferative syndrome; neutropenia; thrombocytopenia

Giant cytoplasmic granules; defective neutrophil migration and bacterial killing Genetic testing: research only*

Antibiotics; vitamin C; bone marrow transplantation


Specific granule deficiency

S, possibly AR

Recurrent infections, especially sinopulmonary and skin infections

Absence of specific (secondary) granules in neutrophils; abnormal neutrophil migration and respiratory burst


Respiratory burst defects

Chronic granuloma-tous disease

AR or X-linked CYBAlocus: 16q24

CYBB locus: Xp21.1 NCF1 locus: 7q11.23 NCF2 locus: 1q25

Recurrent skin, pulmonary, and liver abscesses

Severely defective respiratory burst; NBT test; abnormality in one of four subunits of NADPH oxidase Clinical testing available*

Interferon gamma; antibiotics

Glucose-6-phosphate dehydrogenase deficiency

X-linked Locus: Xq28

Recurrent bacterial infections; hemolytic anemia

Reduced levels of glucose-6-phosphate dehydrogenase Clinical testing available*


Myeloperoxidase deficiency


Mild, if any, susceptibility to infection

Reduced levels of myeloperoxidase

Generally none indicated

AR—autosomal recessive

NADPH—nicotinamide-adenine dinucleotide phosphate

NBT—nitroblue tetrazolium

S—sporadic cases


Treatment of local LCH is sometimes unnecessary; when it is necessary, surgery or local radiation therapy can be cura-tive.50-55 LCH syndromes respond to chemotherapeutic agents, including vinblastine, methotrexate, 6-mercaptopurine, etopo-side, or 2-chlorodeoxyadenosine (cladribine). There is a long-term risk of secondary or treatment-related malignancies in these patients.

Sinus Histiocytosis with Massive Lymphadenopathy

Sinus histiocytosis with massive lymphadenopathy, or Ro-sai-Dorfman disease, is characterized by chronic, painless, massive lymphadenopathy that usually involves the cervical nodes and less frequently involves the axillary, hilar, peritracheal, or inguinal nodes.56 It occurs in both adults and children. Extra-nodal disease in the respiratory tract, bones, orbits, skin, liver,and kidneys is present in almost 30% of patients. The disease is usually benign, but significant morbidity and even death may result if massive tissue invasion of the liver, kidneys, lungs, and other critical structures occurs. Patients are usually of African descent, and the incidence of this disease is highest in Africa and the West Indies.

The affected lymph nodes show marked sinusoidal dilatation and follicular hyperplasia with proliferation of foamy histiocytes and multinucleated giant cells in the sinuses. The etiology of this disorder is unknown and may be related to abnormal immune regulation. Attempts at treatment should be reserved for special circumstances that are potentially life threatening. Surgery, irradiation, corticosteroids, vinblastine, and cyclophosphamide have all been administered with varying degrees of success.

Hemophagocytic Lymphohistiocytosis

HL is a rapidly fatal disorder, occurring as a familial or acquired condition; it is characterized by fever, pancytopenia, hepatic dysfunction, and activated macrophages, which overproduce inflammatory cytokines.57 Family studies suggest that a portion of cases are attributable to mutations in the perforin gene.58,59 The disease is usually diagnosed in young children; however, secondary forms of HL account for numerous cases in adults and occur in association with bacterial, fungal, and parasitic infections and exposure to various drugs. Treatment is difficult. Chemotherapy may be helpful. If the disease is associated with infection, treatment with appropriate antimicrobials may resolve the disorder.

Lysosomal Storage Diseases

Monocytes and macrophages play a role in tissue remodeling and the removal of senescent cellular debris, and lysosomes are the organelles that perform these functions; therefore, enzymatic abnormalities that involve lysosomal constituents result in disorders of storage that are related to macrophage function. These disorders, usually diagnosed in early childhood, include the mu-copolysaccharidoses, the glycoproteinoses, the sphingolipidoses, and the neutral lipid storage diseases [see Table 6]. Enzymatic defects have been described for most of these disorders, and diagnosis depends on demonstrating the enzymatic abnormality in macrophages or histiocytes. Most of these defects result from point mutations or genetic rearrangements at a single locus of the gene that codes for a single lysosomal hydrolase.

Steps in the evaluation of a patient with recurrent infections for a phagocytic cell disorder.

Figure 5 Steps in the evaluation of a patient with recurrent infections for a phagocytic cell disorder.

Table 6 Lysosomal Storage Diseases

Disease (Common Name)


Enzymatic Defect

Organs and Tissues Involved

Stored Material

Mucopolysaccharidoses (MPS)

MPS IH (Hurler syndrome)

AR; locus: 4p16.3


Liver, spleen, brain, heart, cornea, bone (mild and severe variants)

Dermatan sulfate, heparan sulfate

MPS II (Hunter syndrome)

Locus: Xq28


Liver, spleen, brain, heart, bone

Dermatan sulfate, heparan sulfate


(Sanfilippo Asyndrome)

Locus: 17q25.3

Heparan N-sulfatase

Brain, liver, spleen, heart, bone

Heparan sulfate

(Sanfilippo B syndrome)

Locus: 17q21


Brain, liver, spleen, heart, bone

Heparan sulfate

(Sanfilippo C syndrome)

Chromosome 14





(Sanfilippo D syndrome)

Locus: 12q14


(Morquio Asyndrome)

Locus: 16q24.3


Bone, cornea

Keratan sulfate, chondroitin 6-sulfate

(Morquio B syndrome)

Locus: 3p2


Bone, cornea

Keratan sulfate

MPS VI (Maroteaux-Lamy syndrome)

Locus: 5q11-q13


Bone, cornea, liver, spleen, heart (moderate and severe variants)

Dermatan sulfate

MPS VII (Sly syndrome)

Locus: 7q21


Brain, liver, spleen, bone, coro-

Dermatan sulfate, heparan sulfate,

nary arteries

chondroitin 4-sulfate, chondroitin 6-sulfate



AR; locus: 19cen-q12

Lysosomal a-mannosidase

Brain, liver, spleen, bone (several variants)

Mannose-rich oligosaccharides


Locus: 1p34

Glycoprotein a-fucosidase

Brain, liver, spleen, heart, skin

Fucose-containing oligosaccharides

(several variants)


Locus: 4q32-q33


Brain, liver, spleen, bone, heart

Aspartylglucosamine-containing peptides


Locus: 6p21.3

Glycoprotein neuraminidase (sialidase)

Brain, liver, spleen, bone, retina (several variants)

Sialylated glycopeptides


Locus: 20q13

Protector protein deficiency, combined neuraminidase (sialidase) and p-galacto-sidase deficiency

Brain, liver, spleen, bone (several variants)

GM1 ganglioside, sialylated glycopeptides

Mucolipidosis II (I-cell disease)

Locus: 4q21-q23


Brain, bone, connective tissue

Glycoproteins, glycolipids

Mucolipidosis III (Pseudo-Hurler polydystrophy)



Brain, bone, connective tissue

Glycoproteins, glycolipids

Mucolipidosis IV (sialolipidosis)

Locus: 19p13.3-p13.2

Mucolipin 1




(Gaucher disease type I [nonneuronopathic])

AR; locus: 1q21

Acid p-glucosidase, glucocerebrosidase

Liver, spleen, bone, bone marrow (highly variable phenotype)


(Gaucher disease type 2 [acute neuronopathic])

Acid p-glucosidase, glucocerebrosidase

Brain, brain stem, liver, spleen, bone marrow, lungs

Glucosylceramide, glucosylsphingosine

(Gaucher disease type 3 [sub-acute neurono-pathic])

Acid p-glucosidase, glucocerebrosidase

Brain, liver, spleen, bone marrow, lungs (variable phenotype)

Glucosylceramide, glucosylsphingosine

The two types of therapy for lysosomal storage diseases that are currently available are cellular transplantation and enzyme therapy.60 Gaucher disease was formerly treated with bone marrow transplantation, but it is currently treated with alglucerase, an a-mannosyl-terminated glucocerebrosidase. Bone marrow transplantation for the other lysosomal storage diseases is inves-tigational and has yielded mixed results.

Eosinophil Physiology

Eosinophils can enhance or suppress acute inflammatory reactions and mediate responses to helminthic infection, allergy, and certain tumors.61 Like neutrophils, eosinophils are capable of phagocytosis, but eosinophils are primarily secretory cells. Most of the functions they perform require the release of granule contents or reactive oxygen species. The eosinophils respond to unique chemotactic agents and growth factors that permit their accumulation at sites of inflammation.

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