eMedicine Specialties > Hematology > Immune System and Disorders
Granulocytopenia
Updated: Apr 8, 2009
Introduction
Background
Granulocytopenia is defined as a reduced number of blood granulocytes, namely neutrophils, eosinophils, and basophils. The term granulocytopenia is often used synonymously with neutropenia. Agranulocytosis refers to a complete absence of neutrophils in peripheral blood. Neutropenia is the primary focus of this article.
Granulocytopenia (neutropenia) is defined specifically as a decrease in the number of circulating neutrophils in the nonmarginal pool, which constitutes 4-5% of total body neutrophil stores. Most of the neutrophils are contained in the bone marrow, either as mitotically active (one third) or postmitotic mature cells (two thirds).1,2,3
Age, race, genetic background, environment, and other factors can influence the neutrophil count. The lower limit of the absolute neutrophil count (ANC) in adults is 1800/mm3, but for practical purposes, a value of less than 1500/mm3 is used to define neutropenia.
Neutropenia is classified as mild, moderate, or severe, based on the ANC, which is calculated by multiplying the total white blood cell (WBC) count by the percentage of neutrophils plus the band forms of neutrophils in the differential. Mild neutropenia is present when the ANC is 1000-1500/mm3, moderate neutropenia is present with an ANC of 500-1000/mm3, and severe neutropenia refers to an ANC of less than 500/mm3.
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.
Pathophysiology
Neutropenia can be caused by insufficient or injured bone marrow stem cells, shifts in neutrophils from the circulating pool to the marginal blood or tissue pools, increased destruction in the circulation, or a combination of these mechanisms. Intravascular stimulation of neutrophils by plasma-activated complement 5 (C5a) and endotoxin may cause increased margination along the vascular endothelium, decreasing the number of circulating neutrophils. The term pseudoneutropenia refers to neutropenia caused by increased margination.1,2,4,5,6
Disorders of the pluripotent myeloid stem cells and committed myeloid progenitor cells, which cause decreased neutrophil production, include some congenital forms of neutropenia, aplastic anemia, acute leukemia, and myelodysplastic syndrome. Other examples include bone marrow tumor infiltration, radiation, infection (especially viral), and bone marrow fibrosis. Cancer chemotherapy, other drugs, and toxins may damage hematopoietic precursors by directly affecting bone marrow.
Peripheral loss of neutrophils can occur during infection and by immunologic destruction triggered by autoimmune diseases (eg, Felty syndrome) and by drugs acting as haptens.
The risk of serious infection increases as the ANC falls to the severely neutropenic range (<500/mm3). The duration of severe neutropenia directly correlates with the total incidence of all infections and those infections that are life threatening.
Bacterial organisms most often cause fever and infection in neutropenic patients. Historically, gram-negative aerobic bacteria (eg, Escherichia coli, Klebsiella species, Pseudomonas aeruginosa) have been most common in these patients. However, gram-positive cocci, especially Staphylococcus species and Streptococcus viridans, have emerged as the most common pathogens in fever and sepsis because of the increasing use of indwelling right atrial catheters.
After treating neutropenic patients with broad-spectrum antibiotics for several days, superinfection with fungi is common. Candida species are the most frequently encountered organisms in this setting.
Frequency
United States
The incidence rate of neutropenia was studied in New York City in 2008 in 261 healthy women aged 20-70 years of varying ethnicity.7 The incidence rate was 10.5% among US blacks. American and European white individuals and those from the Dominican Republic had a 0% incidence rate. Other ethnic groups included those from Haiti, 8.2% incidence rate; Barbados/Trinidad-Tobago, 6.4%; and Jamaica, 2.7%.7
Race
Race and genetic background can influence the neutrophil count. Blacks, Ethiopians, Yemenite Jews, and certain populations in the world could have lower ANCs due to lower WBC counts. Data from US National Health and Nutritional examination 1999 to 2004 survey showed the prevalence of neutropenia was 4.5% among black participants relative to 0.79% in white individuals and 0.38% in Mexican-Americans participants.8
Blacks have a lower neutrophil count either due to defective granulocyte release from normal bone marrow, or they may have a compromised bone marrow reserve.
Age
Age can influence the neutrophil count.
Clinical
History
Hallmarks of significant neutropenia are fever and recurrent infection, primarily of the oropharynx and skin. Obtaining a careful drug history is important.
- Common presenting symptoms of neutropenia
- Low-grade fever
- Sore mouth
- Odynophagia
- Gingival pain and swelling
- Skin abscesses
- Recurrent sinusitis and otitis
- Symptoms of pneumonia (eg, cough, dyspnea)
- Perirectal pain and irritation
- Congenital neutropenia – This condition is suggested by a personal history of lifelong infections, family history of recurrent infections, and limited survival.
- Chronic, benign familial neutropenia – This condition is suggested by a history of long-standing neutropenia without an increased risk of infection. These patients do not generate increased leukocyte counts with infection, but they have fevers and other symptoms, such as tachycardia, when infected.
Physical
Physical findings on examination of a patient with neutropenia may include the following:
- Fever
- Stomatitis
- Periodontal infection
- Cervical lymphadenopathy
- Skin infection
- Splenomegaly (see image below)
The margins of this massive spleen were palpated easily preoperatively. Medially, the 3.18-kg (7-lb) spleen crosses the midline. Inferiorly, it extends into the pelvis.
- Associated petechial bleeding
- Perirectal infection
- Growth retardation in children
Causes
The causes of neutropenia can be classified as either acquired (most common) or congenital.
- Acquired neutropenia (disorder of neutrophil production)
- Intrinsic bone marrow diseases
- Aplastic anemia
- Hematologic malignancy (eg, leukemia, lymphoma, myelodysplasia, myeloma)
- Ionizing radiation
- Tumor infiltration
- Granulomatous infection
- Myelofibrosis
- Drugs, including, but not limited to, the following:
- Acetaminophen
- Aminoglutethemide
- Antithyroid drugs: propylthiouracil, carbimazole, methimazole
- Cytotoxic chemotherapeutic agents
- Gold salts
- Chloramphenicol
- Indomethacin
- Phenylbutazone
- Phenothiazines
- Semi-synthetic penicillins
- Cephalosporins
- Antituberculosis drugs
- Trimethoprim/sulfamethoxazole
- Anticonvulsants
- Cimetidine
- Clonazepam
- Ranitidine
- Ibuprofen
- Hydralazine
- Captopril, enalapril
- Tocainide
- Chlorpropamide
- Benzodiazepines
- Ticlopidine
- Zidovudine
- Sulfasalazine
- Propranolol
- Digoxin
- Ticlopidine
- Infection, including, but not limited to, the following:
- Bacterial sepsis
- Viral infections (eg, influenza, measles, Epstein Barr virus [EBV], cytomegalovirus [CMV], viral hepatitis, human immunodeficiency virus [HIV]-1) (see image below)
Bilateral interstitial infiltrates in a 31-year-old patient with influenza pneumonia.
- Toxoplasmosis
- Brucellosis
- Typhoid
- Tuberculosis (see images below)
Anteroposterior chest radiograph in a young ED patient presenting with cough and malaise. The radiograph shows a classic posterior segment right upper lobe density consistent with active tuberculosis. This woman was admitted to isolation and started empirically on a 4-drug regimen in the ED. Tuberculosis was confirmed on sputum testing. Image courtesy of Remote Medicine, remotemedicine.org.
Lateral chest radiograph in a 31-year-old patient with influenza pneumonia. Image courtesy of Remote Medicine, remotemedicine.org.
- Malaria
- Dengue fever
- Rickettsial infection
- Babesiosis
- Intrinsic bone marrow diseases
- Idiopathic
- Nutritional deficiency (eg, vitamin B-12, folate, copper, cachexia and debilitated states)
- Acquired neutropenia (peripheral destruction of neutrophils is usually immune mediated)
- Alloimmune neutropenia in the neonate usually reflects a transplacental transfer of maternal alloantibodies to neutrophil antigens present on the neutrophils of the fetus.
- Drug immune-mediated neutropenia
- Aminopyrine
- Quinidine
- Cephalosporins
- Penicillins
- Sulfonamides
- Phenothiazines
- Phenylbutazone
- Hydralazine
- Other medications have been implicated.
- Autoimmune neutropenia may be associated with the following:
- Crohn disease
- Rheumatoid arthritis (with or without Felty syndrome)
- Sjogren syndrome
- Chronic, autoimmune hepatitis
- Hodgkin lymphoma
- Systemic lupus erythematosus
- Thymoma
- Goodpasture disease
- Wegener granulomatosis
- Pure red blood cell (RBC) aplasia – In this disorder, there is complete disappearance of granulocyte tissue from the bone marrow. Pure RBC dysplasia is a rare disorder due to the presence of antibody-mediated, granulocyte-macrophage colony forming unit (GM-CFU) inhibitory activity, and it is often associated with thymoma.
- Transfusion reactions – The surface antigens of neutophilia can cause transfusion reactions. Recipients of repeated granulocyte transfusions could become alloimmunized (see image below).
Rapid test to distinguish hematuria from hemoglobinuria. The onset of red urine during or shortly after a blood transfusion may represent hemoglobinuria (indicating an acute hemolytic reaction) or hematuria (indicating bleeding in the lower urinary tract). If freshly collected urine from a patient with hematuria is centrifuged, red blood cells settle at the bottom of the tube, leaving a clear yellow urine supernatant. If the red color is due to hemoglobinuria, the urine sample remains clear red after centrifugation.
- Large granular lymphocyte proliferation or leukemia
- Acquired neutropenia (shifts of neutrophils from the circulating to the marginated pool of neutrophils)
- Bacterial infection
- Cardiopulmonary bypass
- Hemodialysis
- Splenic sequestration
- Sepsis
- Congenital neutropenia
- Cyclic neutropenia
- Cartilage-hair hypoplasia syndrome
- Chediak-Higashi syndrome
- Dyskeratosis congenita
- Infantile genetic agranulocytosis (Kostmann syndrome)
- Lazy leukocyte syndrome
- Myelokathexis
- Shwachman-Diamond syndrome
- Reticular dysgenesis
- Eosinopenia may be associated with the following:
- Acute bacterial infection
- Glucocorticoid administration
- Hypogammaglobulinemia
- Physical stress
- Thymoma
- Decreased circulating basophils may be associated with the following:
- Anaphylaxis
- Acute infection
- Drug-induced hypersensitivity
- Congenital absence of basophils
- Hemorrhage
- Hyperthyroidism
- Ionizing radiation
- Neoplasia
- Ovulation
- Urticaria
- Drugs (eg, corticosteroid, adrenocorticotropic hormone [ACTH] therapy, chemotherapeutic agents, thyroid hormones)
More on Granulocytopenia |
 Overview: Granulocytopenia |
| Differential Diagnoses & Workup: Granulocytopenia |
| Treatment & Medication: Granulocytopenia |
| Follow-up: Granulocytopenia |
| Multimedia: Granulocytopenia |
| References |
| Further Reading |
| Next Page » |
References
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[Best Evidence] Massey E, Paulus U, Doree C, Stanworth S. Granulocyte transfusions for preventing infections in patients with neutropenia or neutrophil dysfunction. Cochrane Database Syst Rev. Jan 21 2009;CD005341. [Medline]. [Full Text].
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Further Reading
Related eMedicine Topics
Best Evidence
- Massey E, Paulus U, Doree C, Stanworth S. Granulocyte transfusions for preventing infections in patients with neutropenia or neutrophil dysfunction. Cochrane Database Syst Rev. Jan 21 2009;CD005341. [Medline]. [Full Text].
Clinical Trials
- FDG-PET/CT In the Evaluation of Persistent Febrile Neutropenia in Cancer Patients
- Fatigue and Symptom Burden in Febrile Neutropenia
- A Pilot Study to Evaluate the Safety and Activities of EW02 in Reducing Neutropenia Caused by Chemotherapy
- Safety and Effectiveness of Granulocyte Transfusions in Resolving Infection in People With Neutropenia (The RING Study)
National Guidelines Clearinghouse
- 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. American Society of Clinical Oncology - Medical Specialty Society. 1994 Nov (revised 2006 Jul 1). 19 pages. NGC:005040
- Clinical guideline on dental management of pediatric patients receiving chemotherapy, hematopoietic cell transplantation, and/or radiation. American Academy of Pediatric Dentistry - Professional Association. 2004. 6 pages. [NGC Update Pending] NGC:004039
Keywords
granulocytopenia, neutropenia, agranulocytosis, granulopenia, leukopenia, hypogranulocytosis, neutrophils, eosinophils, basophils, granulocytes, granulocyte colony-stimulating factor, GCSF, granulocyte-macrophage colony-stimulating factor, GM-CSF
