Chapter 32: Neutropenia and Neutrophilia

• Leukopenia refers to a reduced total leukocyte count.

• Granulocytopenia refers to a reduced granulocyte (neutrophils, eosinophils, and basophils) count.

• Neutropenia refers to a reduced neutrophil count: less than 1.5 × 10⁹/L in patients from age 1 month to 10 years, and less than 1.8 × 10⁹/L in patients older than age 10 years. Table 31–1 outlines the classification of neutrophil disorders.

• Agranulocytosis literally means a complete absence of blood granulocytes but is used to indicate very severe neutropenia, usually a neutrophil count < 0.5 × 10⁹/L.

• Americans of African descent (as do some other ethnic groups) have lower mean neutrophil counts than do Americans of European descent.

• The risk of infections is inversely related to the severity of the neutropenia: patients with qualitatively normal neutrophils and neutrophil counts of 1.0 to 1.8 × 10⁹/L are at little risk; patients with counts of 0.5 to 1.0 × 10⁹/L are at low or slight risk; and patients with counts less than 0.5 × 10⁹/L are at higher risk.

• Patients with severe, prolonged neutropenia are at particular risk for bacterial and fungal infections.

• The risk is calculated not only by the neutrophil count but by complicating factors as follows:

  — The longer the duration of severe neutropenia, the greater the risk of infection.

  — The risk of infection is greater when the count is falling rapidly or when there is associated monocytopenia, lymphocytopenia, or hypogammaglobulinemia.

  — Neutropenia caused by disorders of hematopoietic progenitor cells (e.g., chemotherapy-induced marrow suppression, severe inherited neutropenia) generally results in a greater susceptibility to infections compared with neutropenia resulting from accelerated turnover (e.g., immune neutropenia).

  — Integrity of the skin and mucous membranes, blood supply to tissues, presence of an indwelling catheter, and nutritional status are also important in considering infection risk.

• Neutropenia can be classified as: (1) disorders of production; (2) disorders of distribution and turnover; (3) drug-induced neutropenia; and (4) neutropenia with infectious diseases.

Inherited Neutropenia Syndromes

Kostmann Syndrome

• Can be an autosomal dominant (mutation in gene for neutrophil elastase, ELA-2), recessive (mutation in gene encoding mitochondrial protein, HAX-1)), or a sporadic (mutation in ELA-2) disease. Mutation in the gene for the glucose-6-phosphate catalytic subunit (G6PC3) also can cause severe neutropenia.

• Mutations in the receptor for granulocyte colony-stimulating factor (G-CSF) and in RAS may be present but are not the cause of the neutropenia but may predispose to evolution to acute myelogenous leukemia.

• Otitis, gingivitis, pneumonia, enteritis, peritonitis, and bacteremia usually occur in the first month of life.

• Neutrophil count is often less than 0.2 × 10⁹/L. Eosinophilia, monocytosis, and mild splenomegaly may be present.

• Marrow usually shows some early neutrophil precursors but few myelocytes or mature neutrophils.

• Immunoglobulin levels are usually normal or increased and chromosome analyses are normal.

• Treatment with G-CSF is usually effective in all types of hereditary neutropenia. It decreases recurrent fevers and infections. About 5 percent of patients do not respond.

• Risk of development of acute myelogenous leukemia.

• Allogeneic hematopoietic stem cell transplantation may be curative.

Neutropenia Associated with Congenital Immunodeficiency Diseases

• X-linked agammaglobulinemia, common variable immunodeficiency, and X-linked hyper-IgM syndrome are each accompanied by neutropenia in a proportion of patients.

• G-CSF may correct the neutropenia.

• Allogeneic hematopoietic stem cell transplantation may correct the primary immune disorder.

• Neutropenia is usually a production disorder based on marrow examinations showing decreased granulopoiesis.

• In X-linked agammaglobulinemia of Bruton (mutation in BTK gene), severe neutropenia is present in about 25 percent of patients.

• Children with common variable immunodeficiency commonly have neutropenia (and thrombocytopenia and hemolytic anemia).

• In X-linked hyperimmunoglobulin-M syndrome (mutation in gene encoding CD40 ligand), neutropenia is present in approximately 50 percent of patients.

• In severe combined immunodeficiency, neutropenia is a constant feature.

• Reticular dysgenesis results from thymic aplasia and inability to produce neutrophils or thymus- or marrow-derived lymphocytes. Neutropenia is severe, and patients have extreme susceptibility to bacterial and viral infections and often die at an early age.

• Allogeneic hematopoietic stem cell transplantation should be considered.

Cartilage-Hair Hypoplasia Syndrome

• Rare autosomal recessive disorder.

• Short-limbed dwarfism with hyperextensible digits, fine hair.

• Neutropenia, lymphopenia, and frequent infections.

• The marrow shows granulocytic hypoplasia.

• A defect in cellular immunity is present, also.

• Allogeneic hematopoietic stem cell transplantation can correct the hematopoietic and immune abnormality.

Shwachman-Diamond Syndrome

• Autosomal recessive inheritance. Mutation in SBDS gene results in proliferative defect in and exaggerated apoptosis of hematopoietic precursors.

• Characterized by short stature, pancreatic exocrine deficiency, steatorrhea, skeletal abnormalities, developmental retardation.

• Neutropenia beginning in the neonatal period. May be intermittent or cyclic and may be as low as 0.2 × 10⁹/L. Anemia and thrombocytopenia occur in about one-third of patients.

• May develop aplastic anemia, oligoblastic or acute myelogenous leukemia (> 20 percent of patients who do not have successful allogeneic hematopoietic stem cell transplantation).

• Some patients may have an increase in neutrophil count with G-CSF.

• Allogeneic hematopoietic stem cell transplantation can correct the hematopoietic abnormality and markedly decrease the risk of transformation to acute myelogenous leukemia.

Chédiak-Higashi Syndrome

• Autosomal recessive disorder with oculocutaneous albinism. Mutation in LYST gene regulating lysosomal trafficking.

• Neutropenia is usually mild.

• Giant granules in granulocytes, monocytes, and lymphocytes.

• Recurrent infections result from moderate neutropenia and ineffective killing of microorganisms.

Failure of Neutrophil Marrow Egress

• Myelokathexis is a rare disorder associated with neutrophil counts of less than 0.5 × 10⁹/L.

  — Marrow contains abundant myeloid precursors and mature neutrophils.

  — Marrow neutrophils show hypersegmentation, cytoplasmic vacuoles, and abnormal nuclei.

  — Neutrophil count does not rise with infection, suggesting that the primary disorder is neutrophil release from the marrow.

• Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM syndrome).

  — Caused by mutation in CXCR-4 gene (encodes the receptor for the stromal cell-derived factor 1) resulting in abnormal trafficking of cells out of marrow.

  — May improve after G-CSF administration.

  — Can evolve into myelodysplastic syndrome or acute myelogenous leukemia.

• Lazy leukocyte syndrome

  — Has ample marrow precursors and neutrophils, but few circulating cells. The neutrophils have a defect in intrinsic motility and do not migrate out of the marrow efficiently.

Glycogen Storage Disease Ib

• Characterized by hypoglycemia, hepatosplenomegaly, seizures, and failure to thrive in infants. Attributable to mutation in gene for intracellular transport protein for glucose.

• Severe neutropenia gradually develops despite normal-appearing marrow.

• Neutrophils have reduced oxidative burst and chemotaxis.

• Neutropenia may improve with G-CSF.

• May evolve into acute myelogenous leukemia.

Cyclic Neutropenia

• Onset is usually in childhood.

• One-third of patients have an autosomal dominant pattern of inheritance. Mutations in ELA-2 gene.

• Recurring episodes of severe neutropenia, every 21 days, lasting 3 to 6 days.

• Malaise, fever, mucous membrane ulcers, and lymphadenopathy.

• The result of a defect in the regulation of hematopoietic stem cells.

• Diagnosis can be made by serial differential counts, at least three times per week for a minimum of 6 weeks.

• Cycling of other white cells, reticulocytes, and platelets may accompany neutrophil cycles.

• Most patients survive to adulthood, and symptoms are often milder after puberty.

• Fatal clostridial bacteremia has been reported.

• Careful observation is warranted with each neutropenic period.

• Treatment with G-CSF is effective. It does not abolish cycling but shortens the neutropenic periods sufficiently to lessen symptoms and infections.

Transcobalamin II Deficiency

• Neutropenia as an early feature of pancytopenia from vitamin B₁₂ deficiency and megaloblastic hematopoiesis as a result of a deficiency in the cobalamin carrier. It is corrected by vitamin B₁₂ treatment.

Neutropenia with Dysgranulopoiesis

• Notable for ineffective granulopoiesis.

• Neutrophil precursors show abnormal granulation, vacuolization, autophagocytosis, and nuclear abnormalities.

Acquired Neutropenia Syndromes

Neutropenia in Neonates of Hypertensive Mothers

• Low birth weight infants with low neutrophil counts common.

• Neutropenia severe and a high risk of infection in first several weeks postpartum.

• G-CSF may increase neutrophil count. Clinical benefit (decreased incidence of infection) has not been documented.

Chronic Idiopathic Neutropenia

• Includes familial, severe or benign neutropenia, chronic benign neutropenia of childhood, and chronic idiopathic neutropenia in adults.

• Some patients with chronic neutropenia may have large granular lymphocyte leukemia (see Chap. 58).

• Patients have selective neutropenia and normal or near-normal red cell, reticulocyte, lymphocyte, monocyte, and platelet counts and immunoglobulin levels.

• The spleen size is normal or minimally enlarged.

• Marrow examination shows normal cellularity or selective neutrophilic hypoplasia; the ratio of immature to mature cells is increased, suggesting ineffective granulocytopoiesis.

• Clinical course can usually be predicted based on the degree of neutropenia, marrow examination, and prior history of fever and infections.

• Treatment with G-CSF will increase neutrophils in most patients, if symptomatic with recurrent infections.

Cytotoxic Drug Therapy

• Causes neutropenia by decreasing cell production; probably the most frequent cause of neutropenia in the United States.

Neutropenia as a Result of Diseases Causing Impaired Production

• Diseases affecting hematopoietic stem and progenitor cells, such as acute leukemia and aplastic anemia.

Neutropenia as a Consequence of Nutritional Deficiencies

• Neutropenia is an early and consistent feature of megaloblastic anemias due to vitamin B₁₂ or folate deficiency.

• Copper deficiency can cause neutropenia in patients receiving total parenteral nutrition with inadequate supplies of trace metals, in patients who have had gastric resection, and in malnourished children.

• Mild neutropenia may occur in patients with anorexia nervosa.

Pure White Cell Aplasia

• Rare disorder exhibiting selective severe neutropenia.

• Marrow devoid of neutrophils and their precursors.

• Counterpart to pure red cell aplasia.

• May be associated with thymoma or agammaglobulinemia.

• Presumptive autoimmune mechanism.

• Treat with antithymocyte globulin, glucocorticoids, and/or cyclosporine.

Alloimmune (Isoimmune) Neonatal Neutropenia

• Neutropenia caused by the transplacental passage of maternal IgG antibodies against neutrophil-specific antigens inherited from the father.

• The disorder occurs in about 1 in 2000 neonates and usually lasts 2 to 4 months.

• Often not recognized until bacterial infections occur in an otherwise healthy infant and may be confused with neonatal sepsis.

• Hematologic picture usually consists of isolated severe neutropenia and marrow with normal cellularity but reduced numbers of mature neutrophils.

• Diagnosis is usually made with antineutrophil agglutination or immunofluorescence tests.

• Antibiotic treatment used only when necessary; glucocorticoids should be avoided.

• Exchange transfusions to decrease antibody titers may be useful.

Autoimmune Neutropenia

Idiopathic Immune Neutropenia

• Neutrophil autoantibodies may accelerate neutrophil turnover and impair production.

• Patients usually have selective neutropenia and one or more positive tests for antineutrophil antibodies.

• Difficult to distinguish cases of autoimmune neutropenia from chronic idiopathic neutropenia.

• Spontaneous remissions sometimes occur; intravenous immunoglobulin is effective for some pediatric patients; response to glucocorticoids is unpredictable.

Systemic Lupus Erythematosus

• Neutropenia occurs in 50 percent of patients, anemia in 75 percent (direct antiglobulin test positive in one-third), thrombocytopenia in 20 percent, and splenomegaly in 15 percent.

• Increased IgG on the surface of neutrophils, and marrow cellularity and maturation are normal.

• Neutropenia usually does not increase susceptibility to infections in the absence of treatment with glucocorticoids or cytotoxic drugs.

Rheumatoid Arthritis

• Less than 3 percent of patients with classic rheumatoid arthritis have leukopenia.

Sjögren Syndrome

• About 30 percent of patients have leukocyte counts of 2.0 to 5.0 × 10⁹/L, with a normal differential count. Severe neutropenia with recurrent infections is rare.

• Treatment of the neutropenia should be reserved for patients with recurrent infections.

Felty Syndrome

• Rheumatoid arthritis, splenomegaly, leukopenia represent classic triad.

• Prominent neutropenia is a constant feature.

• Troublesome infections are common in patients with absolute neutrophil counts below 0.2 × 10⁹/L.

• High levels of circulating immune complexes may play a role in neutropenia.

• Lymphopenia and a very high rheumatoid factor titer. A subset of patients has large granular lymphocytic leukemia (see Chap. 58).

• No clear relationship exists between spleen size and neutrophil count.

• Two-thirds of patients respond to splenectomy with an increase in neutrophil count, but two-third of these responders relapse later.

• Splenectomy should be reserved for patients with severe, recurrent, or intractable infections.

• Improvement has been reported with lithium, gold, and methotrexate. Some clinicians favor weekly methotrexate therapy because of ease of administration, effectiveness, and comparatively lower toxicity.

• Rituximab and tocilizumab have been used but response is unpredictable.

• Treatment with G-CSF or GM-CSF may improve neutropenia but may exacerbate arthritic manifestations.

• Treatment of the neutropenia should be reserved for patients with recurrent infections.

Autoimmune Neutropenia

• Sporadically reported in Hodgkin lymphoma, chronic autoimmune hepatitis, and Crohn disease.

Other Neutropenias Associated with Splenomegaly

• A variety of diseases may cause this type of neutropenia including sarcoidosis, lymphoma, tuberculosis, malaria, kala-azar, and Gaucher disease, usually in association with thrombocytopenia and anemia.

• Neutropenia associated with splenomegaly may be due to immune mechanisms or sluggish blood flow through the spleen with trapping of neutrophils.

• The neutropenia is usually not of clinical significance and splenectomy is rarely indicated to correct neutropenia.

• Drugs may cause neutropenia because of (1) dose-related toxic effects or (2) by immune mechanisms.

• Table 32–1 lists drugs implicated. Information about new drugs can be obtained from the manufacturer, a drug information center, or a poison control center.

• Dose-related toxicity refers to nonselective interference of the drug with protein synthesis or cell replication.

• Phenothiazines, antithyroid drugs, and chloramphenicol cause neutropenia by this mechanism.

• Dose-related toxicity is more likely to occur with multiple drugs, high plasma concentrations, slow metabolism, or renal impairment.

• Cases not dose-related may be allergic (i.e., the immunologic mechanism is poorly understood but appears to be similar to drug-induced hemolytic anemia). Neutropenia tends to occur relatively early in the course of treatment with drugs to which the patient has been previously exposed.

• Women, older persons, persons with history of allergies are more commonly affected with drug-induced neutropenia.

• Patients usually present with fever, myalgia, sore throat, and severe neutropenia.

• A high level of suspicion and careful clinical history are critical to identifying the offending drug.

• Differential diagnosis includes acute viral infections and acute bacterial sepsis.

• If other hematologic abnormalities are also present, hematologic diseases that cause bi- and tricytopenia should be considered.

• Once the offending drug is stopped, patients with sparse marrow neutrophils but normal-appearing precursor cells will have neutrophil recovery in 4 to 7 days. When early precursor cells are severely depleted, recovery may take considerably longer.

• Marrow biopsy soon after recovery may reveal a very large cohort of normal promyelocytes, simulating promyelocytic leukemia. Observation for 2 or 3 days establishes the normal recovery process.

• If febrile, cultures of throat, nasal cavities, blood and urine should be done and broad-spectrum antibiotics used.

• Occurs with acute or chronic bacterial, viral, parasitic, or rickettsial diseases.

• Some agents such as those causing infectious hepatitis, Kawasaki disease, and HIV infection may cause neutropenia and pancytopenia by infecting hematopoietic progenitor cells.

• In severe gram-negative bacterial infections, neutropenia is probably a result of increased adherence to the endothelium, as well as increased utilization of neutrophils at the site of infection. This mechanism may also occur in rickettsial infections and some viral infections.

• Chronic infections causing splenomegaly, such as tuberculosis, brucellosis, typhoid fever, and malaria, probably cause neutropenia by splenic sequestration and marrow suppression.

• Acute onset of severe neutropenia often presents with fever, sore throat, and inflammation of the skin or mucous membranes. This is an urgent clinical situation requiring prompt cultures, intravenous fluids, and broad-spectrum antibiotics.

• In the absence of recent hospitalization and antibiotic exposure, infections are usually caused by organisms found on the skin, nasopharynx, and intestinal flora, and are sensitive to several antibiotics. Immediate evaluation should include a careful history with particular attention to drug use and physical examination with attention to skin; oronasopharynx; sinuses; lungs; lymph nodes; abdomen, including liver and spleen size or bone tenderness.

• Prompt blood counts, microbial cultures, institution of intravenous fluids, and other supportive measures may be critical in an acute and severe situation. The history and physical examination may point to other needs such as chest or abdominal imaging.

• Chronic neutropenia is usually found by chance or during evaluation of recurrent fevers or infections. It is useful to determine whether the neutropenia is chronic or cyclic, and the average neutrophil count when the patient is well.

• The absolute monocyte, lymphocyte, eosinophil, and platelet counts, as well as hemoglobin and immunoglobulin levels, should be determined, and the blood film should be studied carefully for reactive lymphocytes and abnormal cells.

• Marrow examination is useful if multilineage involvement suggests a clonal myeloid disease or another cause of multicytopenia (e.g., aplastic anemia or megaloblastosis).

• It may be useful to measure antinuclear antibodies (ANA) and rheumatoid factor, or to obtain other serologic tests for collagen vascular diseases, especially if skin rashes or articular symptoms or signs are present.

• Examination of the blood and marrow may identify abnormal cells (e.g., Chédiak-Higashi syndrome or large granular lymphocytic leukemia).

• Infectious and nutritional causes for chronic neutropenia are rare and seldom difficult to recognize.

• Measurements of antineutrophil antibodies, in vitro marrow colony-forming activity, and studies of drug-induced neutropenia may require laboratory techniques available only in specialized laboratories.

• Neutrophilia is an increase in the absolute neutrophil count (bands and mature neutrophils) to greater than 7.5 × 10⁹/L.

• For infants younger than 1 month of age, the normal range is as high as 26 × 10⁹/L.

• Extreme neutrophilia is often referred to as a leukemoid reaction because the height of the leukocyte count may simulate leukemia.

• Neutrophilia may occur as a result of:

  — An increase in neutrophil production. Required for sustained neutrophilia.

  — Accelerated release of neutrophil from the marrow "storage pool" into the blood.

  — Shift from the marginal to circulating pool (demargination). (Cannot generate more than a twofold to threefold increase in neutrophil count.)

  — Reduced egress of neutrophils from the blood to tissues.

  — A combination of these mechanisms.

• The time required to develop neutrophilia may be:

  — Minutes (demargination).

  — Hours (accelerated release of neutrophils from marrow).

  — Days (increase in cell production).

• The causes are listed in Table 32–2.

• Pseudoneutrophilia is caused by a shift from the marginated to circulating pool (demargination) induced by vigorous exercise, by acute physical and emotional stress, or by the infusion of epinephrine.

• Marrow storage pool shifts involve the release of segmented neutrophils and bands from the marrow reserve in response to inflammation, infections, or colony-stimulating factors (CSFs).

• Table 32–2 lists the causes of chronic neutrophilia.

• The neutrophil production rate increases up to threefold with chronic infections and even more in clonal myeloid disorders and in response to therapeutic administration of G-CSF or GM-CSF. The maximum response requires at least 7 to 10 days to develop.

• Neutrophilia as a result of decreased egress from the vascular compartment occurs with glucocorticoids, leukocyte adhesion deficiency (CD11/CD18 deficiency) (see Chap. 33), and recovery from infection.

• Chronic neutrophilic leukemia is a rare disorder with a very high blood concentration of neutrophils, often with few immature cells (see Chap. 46).

• Perhaps the most frequent are conditions with elevations of endogenous epinephrine and cortisol, such as exercise or emotional stress (Table 32–2).

• The mean neutrophil count of people who smoke two packs of cigarettes daily is twice normal on average.

• Gram-negative infections, particularly those resulting in bacteremia or septic shock, may cause extreme neutrophilia or neutropenia.

• Some infections characteristically do not cause neutrophilia (e.g., typhoid fever, brucellosis, many viral infections).

• Neutrophilia in association with cancer may be a result of tumor cell secretion of colony-stimulating factors (esp. G-CSF) or because of tumor necrosis and infection.

• In patients with cancer, subarachnoid hemorrhage, or coronary artery disease, neutrophilia may portend a less favorable prognosis.

• In addition to the clonal myeloid diseases, several unusual hematologic conditions may be associated with neutrophilia:

  — Hereditary disorders associated with thrombocytopenia may also be accompanied by leukemoid reactions (e.g., thrombocytopenia with absent radii, see Chap. 74).

  — Benign idiopathic neutrophilic leukocytosis may be acquired or may occur as an autosomal dominant trait.

  — In Down syndrome, neonatal leukemoid reactions may resemble myelogenous leukemia.

Neutrophilia and Drugs

• Catecholamines and glucocorticoids are common causes of neutrophilia.

• Lithium causes neutrophilia, presumably because of G-CSF release.

• Rarely, other drugs will cause neutrophilia (e.g., ranitidine or quinidine).

• In most instances, the finding of neutrophilia, with an increase in bands and with toxic granules in the mature cells, can be related to an infection or inflammatory condition or, less commonly, the release of G-CSF by a neoplasm such as lung cancer.

• The history should make note of smoking, drug usage, or symptoms of occult malignancy.

• If the neutrophilia is accompanied by myelocytes, promyelocytes, increased basophils, and splenomegaly, a clonal myeloid disorder (e.g., chronic myelogenous leukemia, primary myelofibrosis, chronic myelomonocytic leukemia) should be considered.

• There are no direct adverse effects of an elevated neutrophil count in most situations in which the response is to an infection. Sickle cell crisis has been associated with chronic or recurring neutrophilia, as have some vasculopathies (see Chapter 31, Section on Neutrophil-Induced Vascular or Tissue Damage"). In the clonal myeloid diseases in which there are very elevated blast cell counts, adverse effects may occur (see "Hyperleukocytic Syndromes" in Chap. 41). The retinoic acid syndrome in acute promyelocytic leukemia treated with all-trans retinoic acid is a special situation in which morbid effects are often correlated with simultaneous neutrophilia (see Chap. 46).

• In some inflammatory diseases, glucocorticoids and immunosuppressive therapies are used to reduce inflammation in part by reducing production or altering distribution of neutrophils.

• Specific therapy, if indicated, is generally directed at the underlying cause of neutrophilia.