Neutropenia ?>

Neutropenia

Neutropenia


Introduction
Background

Neutropenia is a decrease in circulating neutrophils in the peripheral blood.1 The absolute neutrophil count (ANC) number defines neutropenia. An abnormal ANC value contains fewer than 1500 cells per mm3. Blacks may have a lower but normal ANC value of 1000 cells per mm3, with a normal total white blood cell (WBC) count. The ANC is calculated by multiplying the percentage of bands and neutrophils (segmented neutrophils or granulocytes) on a complete blood cell (CBC) count differential times the total WBC count.

Note that many modern automated instruments actually calculate and provide the ACN number in their reports. These instruments usually do not separate bands from segmented neutrophils, and so the combined number is termed the granulocyte number. Thus, in such an instrument report, the ANC is equivalent to the absolute segmented neutrophil or granulocyte number. If a band number is reported separately, then add it to the granulocyte number.

The severity of neutropenia is categorized as mild when the ANC is 1000-1500 cells per mm3, moderate when the ANC is 500-1000 cells per mm3, and severe when the ANC is less than 500 cells per mm3. The risk of bacterial infection is related to both the severity and duration of the neutropenia.

For excellent patient education resources, visit eMedicine’s Blood and Lymphatic System Center and Immune System Center. Also, see eMedicine’s patient education articles Anemia, Sepsis (Blood Infection), Leukemia, and Lymphoma.

Related eMedicine topics:
Agranulocytosis
Autoimmune and Chronic Benign Neutropenia
Granulocytopenia
Kostmann Disease

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Pathophysiology

Mature neutrophils are produced by precursors in the bone marrow. The total body neutrophil content can be divided conceptually into the following 3 compartments: the bone marrow, the blood, and the tissues. In the marrow, the neutrophils exist in 2 divisions—the proliferative, or mitotic, compartment (myeloblasts, promyelocytes, myelocytes) and the maturation-storage compartment (metamyelocytes, bands, polymorphonuclear leukocytes [“polys”]).

Neutrophils leave the marrow storage compartment and enter the blood without reentry into the marrow. In the blood, 2 compartments are also present, the marginal compartment and the circulating compartment. Some neutrophils do not circulate freely (marginal compartment), but are adherent to the vascular surface, and these constitute approximately half of the total neutrophils in the blood compartment.

Neutrophils leave the blood pool in a random manner after 6-8 hours and enter the tissues, where they are destined for cellular action or death. Thus, if the process producing neutropenia is unknown, measurements of the blood neutrophil number, ANC, must often be supplemented by bone marrow examination to determine whether adequate production of neutrophils or increased destruction of neutrophils exists.

Sites and mechanisms of injury that cause neutropenia can be restricted to the mitotic or mature-storage pools in the marrow or the mature circulating pools (sequestration). Benign congenital neutropenias are associated with a decrease in circulating neutrophils but entirely normal marrow pools, marginal blood pools, and tissue neutrophils. The clinical sequelae of neutropenia manifest as infections, most commonly of the mucous membranes. Skin is the second most common infection site, manifesting as ulcers, abscesses, rashes, and delays in wound healing. The genitalia and perirectum are also affected. Signs of infection, including warmth and swelling, may be absent.

In prolonged severe neutropenia, life-threatening gastrointestinal and pulmonary infections occur, as does sepsis. However, patients with neutropenia are not at increased risk for parasitic and viral infections.
Frequency
International

The incidence of agranulocytosis is 3.4 cases per million persons per year. The incidence of drug-induced neutropenia is 1 case per million persons per year.
Mortality/Morbidity

Morbidity in those with neutropenia usually involves infections during severe, prolonged episodes of neutropenia. Serious medical complications occur in 21% of patients with cancer and neutropenic fever. Mortality correlates with the duration and severity of the neutropenia and the time elapsed until the first dose of antibiotics is administered for neutropenic fever.

The 3 identified high-risk groups among cancer patients with neutropenic fever (many of whom have received aggressive chemotherapy) are inpatients with fever while developing neutropenia, outpatients requiring acute hospital care for problems beyond neutropenia and fever, and stable outpatients with uncontrolled cancer.
Drug-induced agranulocytosis carries a mortality rate of 6-10%. Neutropenic fever in cancer patients carries an overall mortality rate of 4-30%.

Sex

Neutropenia occurs more commonly in females than in males.
Age

Elderly individuals have a higher incidence rate of neutropenia than younger individuals.
Clinical
History

Patients with neutropenia often present with infection. Other sequelae may reflect concurrent pancytopenia (which may increase the patient’s risk for spontaneous bleeding), with anemic symptoms (eg, fatigue, weakness, dyspnea on exertion) and symptoms of thrombocytopenia (eg, petechiae, purpura, epistaxis). This article focuses on neutropenia as the primary disorder. For further information on pancytopenia, refer to the eMedicine article Bone Marrow Failure.

The patient history should focus on the following areas:

Determine if a fever is present, because the physician must be aware of a possible life-threatening infection.
Obtaining a history of infections may aid in the current diagnostic workup.
Obtaining a careful drug history may reveal the offending agent and spare the patient from an extensive diagnostic workup.
A family history of infections or sudden death may be an indication of inherited disorders.
The maternal medical history (in neonatal neutropenia) may indicate inherited disorders or adverse effects of maternal medications.
Records of past CBC counts establish the chronicity of the neutropenia.
Determining the age at onset aids in the differential diagnosis.
Physical

During the physical examination of a patient with neutropenia, focus on finding signs of an infection.

The skin examination focuses on rashes, ulcers, or abscesses.
The oral mucosa examination assesses for aphthous ulcers, thrush, or periodontal disease.
Lymphadenopathy is a possible indication of a disseminated infection or, possibly, malignancy.
For perirectal infections, look for abscesses or mucous membrane abnormalities.
For perineal infections, look for rashes, abscesses, or lymphadenopathy.
Lung infections are usually bacterial or fungal pneumonias.

Causes

The list for all the potential causes of neutropenia is not short. Neutropenia can conceptually be viewed in 2 broad ways, by mechanism or etiologic category. Because the mechanisms for neutropenia are varied and not completely understood, the etiologic category is simplest to retain. Therefore, the etiology of neutropenia can be classified as congenital (hereditary) or acquired. In the setting of hereditary neutropenias, these disorders can be further described as associated with isolated neutropenia or with other defects, whether immune or phenotypic.

Causes of acquired neutropenia are also complex, but most are related to 3 major categories: infection, drugs, or immune. Chronic benign neutropenia, or chronic idiopathic neutropenia, appears to be an overlap disorder with hereditary and acquired forms, and is sometimes indistinguishable. Some patients with neutropenia give a clear history and familial pattern, whereas other patients with neutropenia have no familial history, few blood test determinations, and an unknown duration of neutropenia. This group of patients could have hereditary or acquired neutropenia. The following list briefly summarizes the congenital and acquired forms of neutropenia, as well as various therapies.1, 2, 3, 4, 5
Congenital neutropenia with associated immune defects
Neutropenia with abnormal immunoglobulins: This disorder is observed in individuals with X-linked agammaglobulinemia, isolated immunoglobulin A (IgA) deficiency, X-linked hyperimmunoglobulin M (XHIGM) syndrome, and dysgammaglobulinemia type I. In XHIGM, which is due to mutations in the CD40 ligand, patients can actually have normal or elevated levels of IgM but markedly decreased serum IgG levels. In all these disorders, the infection risk is high, and the treatment is intravenous immunoglobulin (IVIG).
Reticular dysgenesis: Patients demonstrate severe neutropenia, no cell-mediated immunity, agammaglobulinemia, and lymphopenia. Life-threatening infections occur that are refractory to granulocyte colony-stimulating factor (G-CSF). Kostmann syndrome
This disorder was described by Rolf Kostmann in 1956 as an autosomal recessive disorder in a large family from Sweden.6
Patients present by age 3 months with recurrent bacterial infections. The mouth and perirectum are the most common sites of infection. This type of neutropenia is severe, and the treatment is G-CSF.
No uniform genetic defect exists in Kostmann syndrome. Mutations in the neutrophil elastase gene (ELA-2), which are causative for cyclic neutropenia (see below) are not sufficient to explain the phenotype of Kostmann-like severe congenital neutropenia. Some patients with other forms of severe congenital neutropenia appear to have mutations in GFI1, a zinc-finger transcriptional repressor gene. It is involved in hematopoietic stem cell function and lineage commitment decisions. In patients with severe congenital neutropenia, risk of conversion to myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) with monosomy 7 after G-CSF treatments is associated with additional acquired mutations. Most of these cases are caused by a mutation in the G-CSF receptor. Patients whose condition responds clinically to G-CSF are treated for life.
Cyclic neutropenia (CN): Cyclic neutropenia is characterized by a 21-day cycle of oscillating neutrophil numbers. Discoveries have been reported showing autosomal dominant forms of cyclic neutropenia, and some sporadic cases of cyclic neutropenia have mutations in ELA2. People with cyclic neutropenia experience periodic neutropenia with subsequent infections, followed by peripheral neutrophil count recovery. They present as infants or children, but acquired forms of cyclic neutropenia in adulthood exist. The prognosis is good with a benign course; however, 10% of patients will experience life-threatening infections. The treatment for cyclic neutropenia is daily G-CSF.
Chronic benign neutropenia: Affected individuals with chronic benign neutropenia have an overall low risk of infection.
Familial chronic benign neutropenia: This is a disorder with an autosomal dominant pattern of inheritance observed in western Europeans, Africans, and Jewish Yemenites. Patients are typically asymptomatic, and the infections are mild. No specific therapy is required.
Nonfamilial chronic benign neutropenias: Mild infections with a benign course typify this disorder. The ANC, however, does respond to stress, such as infection, corticosteroids, and catecholamines.
Idiopathic chronic severe neutropenia: This disorder is a diagnosis of exclusion. Affected patients exhibit infections and severe neutropenia.
Neutropenia associated with phenotypic abnormalities
Shwachman syndrome (Shwachman-Diamond): This disorder has an autosomal recessive inheritance pattern. The neutropenia is moderate to severe, with a mortality rate of 15-25%, and the syndrome presents in infancy, with recurrent infections, diarrhea, and difficulty in feeding. Dwarfism, chondrodysplasia, and pancreatic exocrine insufficiency can occur. Shwachman-Diamond syndrome and X-linked dyskeratosis congenita (DC), cartilage-hair hypoplasia (CHH), and Diamond-Blackfan anemia (DBA) all appear to share common gene defects involved in ribosome synthesis. Most cases of Shwachman-Diamond syndrome are caused by mutations in the SBDS gene. The precise function of this gene is still being elucidated; however, it is involved in ribosome synthesis and RNA processing reactions. The treatment is G-CSF.
Cartilage-hair hypoplasia: The inheritance pattern is autosomal recessive on chromosome 9, and it is observed in Amish and Finnish families. The neutropenia is moderate to severe. Cartilage-hair hypoplasia presents with cell-mediated immunity defects, macrocytic anemia, gastrointestinal disease, and dwarfism. It also shows a predisposition to cancer, especially lymphoma. Cartilage-hair hypoplasia is caused by mutations in the RMRP gene. This RMRP gene encodes the RNA component of the ribonuclease mitochondrial RNA processing (RNase MRP) complex. The treatment is bone marrow transplantation.
Dyskeratosis congenita (Zinsser-Cole-Engman syndrome): This disorder presents with mental retardation, pancytopenia, and defective cell-mediated immunity. Dyskeratosis congenita is more common in men than in women and is hematologically similar to Fanconi anemia. Dyskeratosis congenita is usually X-linked recessive, although autosomal dominant and autosomal recessive forms of this disorder exist. The X-linked recessive form of the disorder has been linked to mutations in DKC1. DKC1 encodes dyskerin, a nucleolar protein associated with ribonucleoprotein particles. The autosomal dominant form of dyskeratosis congenital is associated with mutations in another gene, TERC, which is part of telomerase. Telomerase has both a protein and RNA component, and TERC codes the telomerase RNA component. Patients with this disorder have shorter telomeres than normal. The treatment is G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF), and bone marrow transplantation.
Barth syndrome: This is an X-linked recessive disorder presenting with cardiomyopathy in infancy, skeletal myopathy, recurrent infections, dwarfism, and moderate to severe neutropenia.
Chediak-Higashi syndrome: This is an autosomal recessive disorder with recurrent infections, mental slowing, photophobia, nystagmus, oculocutaneous albinism, neuropathy, bleeding disorders, gingivitis, and lysosomal granules in various cells. The neutropenia is moderate to severe, and the treatment is bone marrow transplantation.
Myelokathexis: This disorder presents in infancy with moderate neutropenia. An abnormal nuclear appearance is observed, with hypersegmentation with nuclear strands, pyknosis, and cytoplasmic vacuolization. The treatment is G-CSF and GM-CSF.
Lazy leukocyte syndrome: This is a severe neutropenia with associated abnormal neutrophil motility. The etiology is unknown, and the treatment is supportive in nature.
Metabolic diseases: These are chronic neutropenias with variable ANCs. They include glycogen storage disease type 1b and various acidemias, such as isovaleric, propionic, and methylmalonic. In glycogen storage disease type 1b, the treatment is G-CSF and GM-CSF.
Immune-mediated neutropenia
Isoimmune neonatal neutropenia: The mother produces IgG antineutrophil antibodies to fetal neutrophil antigens that are recognized as nonself. This occurs in 3% of live births. The disorder manifests as neonatal fever, urinary tract infection, cellulitis, pneumonia, and sepsis. The duration of the neutropenia is typically 7 weeks.
Chronic autoimmune neutropenia: This disorder is observed in adults and has no age predilection. As many as 36% of patients will exhibit serum antineutrophil antibodies, and the clinical course is usually less severe. Patients can have this disorder in association with systemic lupus erythematosus, rheumatoid arthritis, Wegener granulomatosis, and chronic hepatitis. If chronic autoimmune neutropenia is associated with these diseases, corticosteroids are indicated as treatment. In neonates and children, this disorder is associated with a lower risk of infection and milder infections involving the middle ear, gastrointestinal tract, and skin.
T-gamma lymphocytosis: This is a clonal disorder of T lymphocytes that infiltrate the bone marrow. Also known as leukemia of large granular lymphocytes, T-gamma lymphocytosis can be associated with rheumatoid arthritis and is associated with high-titer antineutrophil antibodies. The neutropenia is persistent and severe. The treatment is supportive in nature, but it is also directed at eliminating the clonal population.
Infections are the most common form of acquired neutropenia.
Nutritional deficiencies include vitamin B-12, folate, and copper deficiency.
Acquired neutropenia caused by drugs and chemicals, excluding cytotoxic chemotherapy
The highest risk categories are antithyroid medications, macrolides, and procainamides.
Antimicrobials include penicillin, cephalosporins, vancomycin, chloramphenicol, gentamicin, clindamycin, doxycycline, flucytosine, nitrofurantoin, novobiocin, minocycline, griseofulvin, lincomycin, metronidazole, rifampin, isoniazid, streptomycin, thiacetazone, mebendazole, pyrimethamine, levamisole, ristocetin, sulfonamides, chloroquine, hydroxychloroquine, quinacrine, ethambutol, dapsone, ciprofloxacin, trimethoprim, imipenem/cilastatin, zidovudine, fludarabine, acyclovir, and terbinafine.
Analgesics and anti-inflammatory agents include aminopyrine, dipyrone, phenylbutazone, indomethacin, ibuprofen, acetylsalicylic acid, diflunisal, sulindac, tolmetin, benoxaprofen, barbiturates, mesalazine, and quinine.
Antipsychotics, antidepressants, and neuropharmacologic agents include phenothiazines (chlorpromazine, methylpromazine, mepazine, promazine, thioridazine, prochlorperazine, trifluoperazine, trimeprazine), clozapine, risperidone, imipramine, desipramine, diazepam, chlordiazepoxide, amoxapine, meprobamate, thiothixene, and haloperidol.
Anticonvulsants include valproic acid, phenytoin, trimethadione, mephenytoin(Mesantoin), ethosuximide, and carbamazepine.
Antithyroid drugs include thiouracil, propylthiouracil, methimazole, carbimazole, potassium perchlorate, and thiocyanate.
Cardiovascular drugs include procainamide, captopril, aprindine, propranolol, hydralazine, methyldopa, quinidine, diazoxide, nifedipine, propafenone, ticlopidine, and vesnarinone.
Antihistamines include cimetidine, ranitidine, tripelennamine (Pyribenzamine), methaphenilene, thenalidine, brompheniramine, and mianserin.
Miscellaneous drugs include allopurinol, colchicine, aminoglutethimide, famotidine, bezafibrate, flutamide, tamoxifen, penicillamine, retinoic acid, metoclopramide, phenindione, dinitrophenol, ethacrynic acid, dichlorodiphenyltrichloroethane (DDT), cinchophen, antimony, pyrithyldione, rauwolfia, ethanol, chlorpropamide, tolbutamide, thiazides, spironolactone, methazolamide, acetazolamide, IVIG, and levodopa.
Heavy metals include gold, arsenic, and mercury.
Miscellaneous immunologic neutropenias
Immunologic neutropenias may occur after bone marrow transplantation and blood product transfusions.
Felty syndrome: This is a syndrome of rheumatoid arthritis, splenomegaly, and neutropenia. Splenectomy shows an initial response, but neutropenia may recur in 10-20% of patients. Treatment is directed toward rheumatoid arthritis.
Complement activation–mediated neutropenia: Hemodialysis, cardiopulmonary bypass, and extracorporeal membrane oxygenation (ECMO) expose blood to artificial membranes and can cause complement activation with subsequent neutropenia.
Splenic sequestration: The degree of neutropenia resulting from this process is proportional to the severity of the splenomegaly and the bone marrow’s ability to compensate for the reduction in circulating bands and neutrophils.

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