Quantitative Granulocyte Disorders



Quantitative Granulocyte Disorders


Donald H. Mahoney Jr.



NEUTROPENIAS

Neutropenia is defined as an absolute decrease in the number of circulatory neutrophils in the blood. The age and race of the child are important variables for the definition of normal values. In the normal newborn, the neutrophil accounts for approximately 60% of the differential count. However, by 2 weeks of age, lymphocytes assume predominance and retain this predominance until approximately 4 years of age. For normal white infants between 2 weeks and 1 year of age, the lower limit of normal for the absolute neutrophil count (ANC) including neutrophils and bands is 1,000 cells/μL. After infancy, an ANC of 1,500 cells/μL is the lower limit. For African American children, the lower limits of normal are 200 to 400 cells/μL less than those for white children. Technical factors such as excessive leukocyte clumping or lengthy delays in performance of leukocyte counts may cause falsely low values.


Classification

The classification of the neutropenias on a pathophysiologic basis has been problematic. Kinetic, biochemical, and functional studies are difficult to perform because of an insufficiency of circulating neutrophils. Most neutropenia states are transient, and some discretion in the choice of investigations is indicated. Chronic neutropenia is defined as having an ANC of less than 500 for more than 6 months. Chronic neutropenia syndromes are rare and are largely characterized on the basis of their clinical features.

As a first step, individual cases may be characterized by the severity of neutropenia. Mild neutropenia may be defined as an ANC of 1,000 to 1,500 cells/μL, moderate neutropenia as an ANC of 500 to 1,000 cells/μL, and severe neutropenia as an ANC of less than 500 cells/μL. This is a functional classification based on a recognized susceptibility for life-threatening infections, especially in children with persistent, severe neutropenia. For the neutropenic child, infection with Staphylococcus or with a gram-negative enteric organism is the greatest danger. However, any organism may become a pathogen. Stomatitis, gingivitis, perirectal inflammation, recurrent otitis media, cellulitis, pneumonia, and septicemia are potential clinical complications. On the other hand, these patients do not have an increased susceptibility to viral or parasitic infections.

Using a functional classification scheme, neutropenia of childhood may be categorized as either intrinsic disorders of myeloid production and proliferation or acquired disorders resulting from extrinsic factors, such as infections, drugs, or immune-mediated mechanisms.


Disorders of Production and Proliferation

Reticular dysgenesis is a rare defect of the committed stem cell compartment and is characterized by thymic agenesis, severe neutropenia and lymphopenia, and agammaglobulinemia. Early in life, infants are vulnerable to fatal bacterial and viral infections.

Cyclic neutropenia is a sporadic or autosomal dominant disorder characterized by regular, periodic oscillations in the numbers of circulating neutrophils and is associated with cyclic clinical manifestations. The disease affects both genders. The underlying defect has been shown to be due to a mutation in the neutrophil elastase gene, mapped to chromosome 19p13.3. The mutation appears to increase apoptosis of neutrophil precursors. Cyclic oscillations in bone marrow function result in neutropenia with nadirs at intervals of 19 to 21 days. The specific periodicity is regular and constant for each patient and may be as short as 14 days or as long as 28 to 36 days. A 21-day cycle has been observed in more than 70% of patients. The neutropenia is severe with an ANC of less than 200 cells/μL and may persist for 3 to 10 days, followed by increasing neutrophil counts and normal physical findings. For some patients, neutrophil oscillations may not exceed 1,000 cells/μL and the patient may have the appearance of chronic neutropenia. Oscillations of monocytes, platelets, and reticulocytes also may occur. During the neutropenic phase, patients may suffer with fever, malaise, oral ulcers, stomatitis, pharyngitis, and lymphadenopathy. More serious infections such as mastoiditis, pneumonia, and sepsis have occurred, and an estimated 10% of patients have died from complications of infectious diseases.

The diagnosis is established by serial neutrophil counts obtained over a 6- to 8-week period to establish the periodicity. Bone marrow examinations during periods of neutropenia may show granulocytic hypoplasia or an apparent arrest of maturation. Treatment is symptomatic. Recombinant human granulocyte colony-stimulating factor (G-CSF) produces marked benefits for patients by reducing the duration of neutropenia and substantially decreasing the risk of infection. However, some patients may still experience neutropenic cycles, but of shorter duration.

Severe congenital neutropenia (i.e., infantile genetic agranulocytosis of Kostmann) is a rare autosomal recessive disorder
characterized by a failure of terminal differentiation of the myeloid precursor. The ANC is usually less than 200 cells/μL. Monocytosis and eosinophilia are commonly observed. The bone marrow morphology reveals a developmental arrest at the promyelocyte or myelocyte stage. Studies of bone marrow in vitro colony-forming units reveal a capacity to produce neutrophilic colonies, but with aberrant cells exhibiting bizarre nuclei, excessive cytoplasm, and decreased granules. Mutations in the neutrophil elastase gene (ELA-2) have been observed in more than two-thirds of studied patients, but are more diverse than those observed with cyclic neutropenia.

The clinical presentation is usually one of an acute, life-threatening infection occurring within the first few months of life. Fever, cellulitis, omphalitis, pneumonia, perianal and urinary tract infections, and sepsis have been associated with this disease. Common pathogens include Staphylococcus aureus, Escherichia coli, and Pseudomonas. Recombinant G-CSF is effective treatment, leading to increased numbers of neutrophils and decreased infectious complications. However, with continued follow-up, the cumulative risk for myelodysplasia and acute myeloid leukemia is 13% at 8 years of G-CSF treatment. Bone marrow transplantation has resulted in partial or complete correction of this disorder.

The Shwachman-Diamond-Oski Syndrome is a rare autosomal recessive disorder characterized by multiorgan dysfunction. The gene locus has been mapped to the centromeric region of chromosome 7. Onset is during infancy with failure to thrive, pancreatic exocrine insufficiency, metaphyseal dysostosis, and eczema. Neutropenia is seen in all patients, but may be intermittent in two-thirds of patients. Anemia, thrombocytopenia, and progressive bone marrow failure are common, and transformation to leukemia has been reported in 12% to 25%.

Several additional clinical syndromes have evidence of ineffective granulopoiesis as a common pathophysiologic characteristic. Nutritional deficiencies of vitamin B12 or folic acid, in addition to causing megaloblastic anemia, may be associated with neutropenia. Advanced states of malnutrition, such as anorexia nervosa, marasmus in infants, and copper deficiency, may be complicated by neutropenia. Ineffective myelopoiesis is an important element in the Chédiak-Higashi syndrome and in a rare condition described as myelokathexis. Increased intramedullary destruction of neutrophils with elevated serum lysozyme levels is part of the clinical spectrum.

Dyskeratosis congenita is an X-linked recessive disease characterized by hyperpigmentation, leukoplakia, nail dystrophy, and, in approximately 35% of the cases, mild neutropenia. Cartilage-hair hypoplasia is an autosomal recessive condition associated with short-limbed dwarfism, fine hair, and moderate neutropenia. This condition has been identified frequently in Asian populations. Increased infections and impaired immunologic functions are common complications.

Disorders of immunoglobulin production have been associated with neutropenia syndromes. Patients with X-linked agammaglobulinemia may experience neutropenia during the course of their illness. Dysgammaglobulinemia type I (i.e., no IgA and IgG, normal to elevated IgM) may be associated with periodic or persistent neutropenia. Bacterial infections, failure to thrive, and hepatosplenomegaly may complicate this condition. A syndrome of neutropenia, eczema, polyarthralgia, eosinophilia, and increased IgA levels has been reported. Depressed cellular immunity and an increased risk for infection, including devastating varicella, have been observed with this disease.

Neutropenia may complicate a number of metabolic disorders. Children with hyperglycinemia, isovaleric academia, and methylmalonic academia may have significant neutropenia. High concentrations of these metabolites have been proposed as the causative mechanism for impaired myeloid proliferation. Myelofibrosis may be associated with Gaucher disease. Glycogenesis Ib is an inherited disorder of glycogen metabolism associated with variable neutropenia, abnormal neutrophil motility, and recurrent life-threatening infections. Supportive medical care is the only available therapy for these patients.








TABLE 294.1. FREQUENTLY RECOGNIZED CAUSES OF ACQUIRED NEUTROPENIA








  1. Infection

    1. Viral: hepatitis A and B, varicella, influenza A, measles, rubella, herpes simplex virus, respiratory syncytial virus, cytomegalovirus, infectious mononucleosis, human immunodeficiency virus, parvovirus
    2. Bacterial: overwhelming sepsis, especially group B streptococci, typhoid, paratyphoid, tularemia, brucellosis, tuberculosis
    3. Rickettsial: rickettsialpox, epidemic typhus, scrub typhus, Rocky Mountain spotted fever
    4. Protozoan: malaria, toxoplasmosis

  2. Drugs

    1. Antibiotics: penicillins, aminoglycosides, sulfa, trimethoprim-sulfamethoxazole, cephalosporins, amphotericin, dapsone, griseofulvin, streptomycin, nitrofurantoins, chloroquine
    2. Anticonvulsants: trimethadione, phenytoin, barbiturates, valproic acid, clonazepam, carbamazepine, ethosuximide
    3. Antiinflammatory agents: gold, indomethacin, phenylbutazone, ibuprofen, naproxen, aspirin, penicillamine
    4. Miscellaneous: imipramine, thiazides, acetazolamide, quinidine, procaine amide, propranolol, antithyroid agents, phenothiazines

  3. Chemical or environmental toxins
    Benzol, benzene, arsenic, thiocyanate, carbon tetrachloride, insecticides (e.g., DDT, chlordane)
    Radiation exposure
  4. Anticancer chemotherapy
  5. Bone marrow infiltration
    Leukemia, lymphoma, neuroblastoma, rhabdomyosarcoma, retinoblastoma, primitiveneuroectodermal tumor, myelofibrosis, storage disease
DDT, dichlorodiphenyltrichlorothane.

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Jul 24, 2016 | Posted by in ORTHOPEDIC | Comments Off on Quantitative Granulocyte Disorders
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