Agranulocytosis, granulocytopenia, leukopenia
Neonatal autoimmune neutropenia
Large granular lymphocytosis
Severe congenital neutropenia (Kostmann syndrome)
Chronic benign neutropenia
Nonfamilial or chronic granulocytopenia of childhood
Idiopathic chronic severe neutropenia
Neutropenias associated with phenotypic abnormalities
1. Description of the problem
What every clinician needs to know
Neutropenia is defined as a reduction in the absolute neutrophil count (ANC) below 1,500 cells/mm3 in the blood. To calculate ANC, multiply the total WBC count by the percentage of segmented neutrophils and band forms.
ANC = WBC x percentage (segmented neutrophils + bands)
Neutrophil counts can vary based upon age, gender and ethnicity, among other factors. African Americans and Yemenite Jews normally have lower neutophil counts compared to other populations and have no known consequences related to the lower neutrophil counts.
Neutropenia can be classified as mild, moderate or severe based upon the ANC.
Mild: ANC between 1,000 cells/mm3 and 1,500 cells/mm3
Moderate: ANC between 500 cells/mm3 and 1,000 cells/mm3
Severe: ANC less than 500 cells/mm3
The classification is useful in predicting the risk of bacterial infections. The risk of developing an infection increases when the ANC is less than 1,000 cells/mm3, rises significantly when the ANC is less than 500 cells/mm3 and is highest when the ANC is less than 100 cells/mm3. In addition, the risk of infection varies depending upon the cause and duration of neutropenia.
Agranulocytosis, granulocytopenia and leukopenia are often used synonymously with neutropenia but in fact have slightly different meanings.
Agranulocytosis refers to a complete absence of blood granulocytes and is commonly used to indicate severe neutropnia (ANC less than 500 cells/mm3).
Granulocytopenia refers to a reduced number of blood granulocytes (neutrophils, eosinophils and basophils).
Leukopenia refers to a reduced total number of white blood cells.
The main clinical feature of neutropenia is recurrent infections. Patients with neutropenia often do not display the classical signs of infection or the signs are less obvious. Swelling, exudate, fluctuation, ulceration or fissure may not be detectable in neutropenic patients. In addition radiographs may fail to demonstrate pneumonia. Fever is often the only sign of infection.
Infections of the oral cavity, mucous membranes, perirectal and genital areas, and skin are the most common sites of infection in neutropenic patients. Bloodstream and pulmonary infections can occur but more commonly in patients with severe neutropenia. The most common pathogens implicated are endogenous bacterial flora.
Staphylococcus aureus from the skin and gram-negative organisms from the gastrointestinal and urinary tracts are the common pathogens.
In patients with neutropenia and cancer, infections with gram-positive organisms have been more common since the 1980s and 1990s, which is likely related to the increased use of indwelling catheters used to deliver chemotherapy.
Key management points
The management of neutropenia relies upon identifying the cause and establishing a diagnosis. In addition it is important to determine if the process is an acute or chronic issue based upon the patient’s history and to determine the severity of neutropenia based upon the patient’s ANC. The degree of neutropenia will alert providers to the patient’s risk of infection. Patients with severe neutropenia of an acute nature are at highest risk of infection. Patients who present with neutropenia should be assessed for the presence of an infection.
Neutropenic patients should be instructed to take preventative steps to limit the number and severity of infections. All patients should maintain good oral hygiene as the mouth and mucous membranes are common sites of infections experienced by neutropenic patients.
Febrile neutropenic patients with or without signs or symptoms of infection require prompt medical care and initiation of antimicrobial therapy.
2. Emergency Management
Stabilizing the patient
Patients presenting with neutropenia need to be immediately assessed for evidence of infection. Neutropenic patients who are febrile, have evidence of infection or are in shock require immediate initiation of broad-spectrum antibiotics and management of shock.
Management points not to be missed
Management of neutropenic patients should include the following:
Particular attention to medications to identify possible causative agent.
ANC values over time to assess for acuity versus chronicity.
Family history of neutropenia in children.
Patient reports of fever, chills, dizziness, or vomiting should cause concern for possible infection.
Inquire about any localizing signs of infection.
Cough, shortness of breath, sore throat, chest pain, dysuria, urinary retention, urgency or frequency, abdominal or rectal pain.
Focus on identifying signs of infection with most attention to oral, lung, skin and perirectal exams.
Complete blood cell count with differential.
Review of ANC value over a period of time is helpful in assessing chronicity.
Blood cultures, urinalysis and urine culture (may only be necessary for patients neutropenic fever or concern for infection).
Chest radiograph (may only be necessary for neutropenic fever or patients with symptoms of pulmonary infection).
Establishing the diagnosis
Patients with neutropenia should have their diagnosis confirmed.Review of a peripheral blood smear can be used to confirm the diagnosisof neutropenia. Pseudoneutropenia can occur if blood is left standingand blood cell counts are performed long after the blood has been drawn.If the differential count making the diagnosis of neutropenia was doneby automated counters, the test should be repeated with a manualdifferential to confirm the automated data. Certain anticoagulants andparaproteinemia can result in neutrophil clumping and low neutrophilcounts.
The differential diagnosis of neutropeniais extensive and includes both congenital and acquired disorders. Inaddition to the list below, neutropenia can result from disorders of thebone marrow such as aplastic anemia, leukemias and myelodysplasticsyndrome. However, these disorders typically result in neutropenia,anemia and thrombocytopenia and not neutropenia alone.
Proposeddiagnostic guidelines for congenital and acquired neutropenia haverecently been published and provide more details (PUBMED:21448998).
Infections are the most common cause of acquired neutropenia. Bacterial, viral, protozoal, rickettsial and fungal infections have been reported as causes of neutropenia. Neutropenia induced by most viral infections is rarely clinically significant. Infection with hepatitis B virus, Epstein-Barr virus and human immunodeficiency virus (HIV) can cause severe and prolonged neutropenia.
Medications are the second most common cause of neutropenia. The majority of chemotherapy agents used in the treatment of cancer can be expected to cause pancytopenia; however, neutropenia may be prominent. Medications known to cause neutropenia are listed table below. In cases where neutropenia is suspected to be caused by a drug, the offending drug should be discontinued. Both the onset and time to neutropenia resolution is widely variable from days to weeks depending upon the agent.
Drugs associated with causing neutropenia
Vitamin B12 and folate deficiencies can lead to megaloblastic anemias in which neutropenia is an early feature. Cooper deficiency has also been reported to cause neutropenia and may be seen in patients receiving total parenteral nutrition.
The development of antineutrophil antibodies can cause destruction of neutrophils via splenic sequestration of opsonized cells or by complement mediated lysis of neutrophils. Immune neutropenia can be an isolated condition impacting only neutrophils or can involve anemia and thrombocytopenia. Immune causes of neutropenia have similar features as other causes of neutropenia and often the presence of antineutrophil antibodies is the only distinguishing feature. However, antineutrophil antibodies are present with other acquired causes of neutropenia, such as drug-induced and infectious causes. Examples of immune causes of neutropenia are:
Neonatal alloimmune neutropenia.
Large granular lymphocytosis and Felty syndrome.
Severe congenital neutropenia (Kostmann syndrome)
The presentation of severe congenital neutropenia is consistent. Infants in the first months of life have recurrent bacterial infections and have neutrophil counts lower than 200 cells/mm3. Typically, granulocytes are absent and monocytosis is a compensatory mechanism. Common bacterial infections are skin and soft tissue abscesses, boils and sores, otitis media, gingivitis, pneumonia and urinary tract infections. Most cases are apparent by the age of 3 months. In the original Swedish population in which the disorder was first described, it was believed to have an autosomal recessive inheritance pattern, but other cases reported internationally are autosomal dominant or have a sporadic pattern of inheritance.
Cyclic neutropenia is sporadic or inherited as autosomal dominant. It is characterized by regular cycles of neutrophil count variation. On average, regular cycles of severe neutropenia occur every 21 days but can vary from 12-36 days. Severe neutropenia lasts for a period of 3-10 days. The diagnosis is often made in the first year of life, especially if there is a positive family history of the disorder.
During the neutropenic cycle, patients can experience fevers, malaise, anorexia, oral infections and adenopathy. Severity of infections depends upon the duration and depth of neutropenia with each cycle. Severe infections are uncommon due to the brief neutropenic episodes, however fatal infections occur in 10% of patients. Clostridium perfringens is a common pathogen in fatal infections due to peritonitis and sepsis.
Chronic benign neutropenia
Chronic benign neutropenia refers to a group of disorders that share characteristics of chronic neutropenia in the absence of increased risk of infection in an otherwise healthy patient. Familial and nonfamilial forms of chronic benign neutropenia have been reported. Familial forms have been described as an autosomal dominant disorder in families of Jewish Yemenite, African and Western Europe backgrounds.
Idiopathic chronic severe neutropenia
Idiopathic chronic severe neutropenia occurs in children or adults, which differentiates it from severe congenital neutropenia. The distinction between chronic severe neutropenia and chronic benign neutropenia is based upon the patient’s history of infection. Other causes of neutropenia should be ruled out before making this diagnosis. Similar to other causes of neutropenia, the risk of infection is related to the degree of neutropenia.
Neutropenias associated with phenotypic abnormalities
Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by neutropenia, dwarfism and pancreatic exocrine deficiency. Other features include anemia, thrombocytopenia, developmental and mental retardation, diarrhea, failure to thrive, and recurrent otitis media and pneumonia. The chromosomal mutation is located at locus 7qll.
Improvement in nutritional status does not improve status. Treatment with granulocyte-colony stimulating factor (GCSF) raises neutrophil levels and hematopoietic stem cell transplant corrects abnormality and prevents progression to acute myelogenous leukemia or myelodysplastic syndrome.
Cartilage-hair hypoplasia is an autosomal recessive disorder found in Amish and Finnish populations. It is characterized by short-limbed dwarfism, fine hair, hyperextensible digits, variable degrees of neutropenia (100-2,000 cells/mm3) and recurrent infections. Varicella zoster virus infections are common due to concomitant cellular immunologic defects.
GCSF increases neutrophil counts and lessen incidence of infections.
Dyskeratosis congenita is a rare multiorgan syndrome reported in males the majority of time. It is characterized by reticulated hyperpigmentation of the skin, nail dystrophy, leukoplakia of the mucous membranes, mental retardation, growth failure, endocrine dysfunction and defects of the eyes, ears and bone. Neutropenia, refractory anemia, thrombocytopenia, marrow failure syndromes and cell mediated immune dysfunction are also part of the syndrome.
Pathophysiology is unknown but hematologic characteristics are very similar to Fanconi anemia.
Barth syndrome is an X-linked recessive cardioskeletal myopathy with associated neutropenia. Male patients have skeletal myopathy, cardiomyopathy, short stature and recurrent bacterial infections. The majority of cases present with dilated cardiomyopathy. Moderate to severe neutropenia (ANC 0 – 500 cells/mm3) and can be intermittent and neutrophil counts increase with age.
Chediak-Higashi syndrome is a rare autosomal recessive disorder characterized by partial oculocutaneous albinism, pathognomonic large lysosomal granules in several types of cells and recurrent infections. Patients may also experience photophobia, nystagmus, gingivitis, immune dysfunction and neutropenia. Neutropenia is reported in 75% of cases and is moderate to severe. A patient’s risk of infection is associated with the presence and degree of neutropenia and coexisting cellular and humoral immunity defects.
Myelokathexis is a rare autosomal dominant or sporadically occurring disorder. It is considered a form of chronic neutropenia with bizzare granulocyte nuclear morphology. Most cases occur during infancy, are congenital, and occur in females. Patients have severe neutropenia and lymphocytopenia, with total white blood cell counts less than 1,000 cells/mm3.
Laboratory diagnosis of neutropenia should be confirmed by review of peripheral blood smear or by a manual differential of the CBC. Once neutropenia is confirmed, an extensive history and physical exam should be taken to elucidate the underlying cause.
A complete blood cell count with manual white blood cell differentiation should be performed. Other tests may be needed to determine the underlying cause of neutropenia; however, some patients will need no further laboratory testing.
Other tests that can be performed to identify the cause are:
Bone marrow aspiration/biopsy.
Cytogenetic studies for monitoring for progression to MDS/AML.
Antineutrophil antibody screens.
HIV, hepatitis B testing.
Metabolic studies: cooper, vitamin B12, folate levels.
Chromosomal fragility/breakage studies.
Pancreatic exocrine function study.
Normal WBC: 4,500 – 11,000 cells/mm.3
Neutrophil count 40-60% of total WBC (ANC > 1,500 cells/mm3).
The development of neutropenia is due to one of four mechanisms:
Decreased neutrophil production.
Shift of circulating PMNs to vascular endothelium or tissue pools.
Increased or enhanced peripheral destruction.
African Americans and Yemenite Jews may have slightly lower WBC and ANC.
Special considerations for nursing and allied health professionals.
What's the evidence?
Boxer, L, Dale, DC. “Neutropenia: causes and consequences”. Semin Hematol. vol. 39. 2002. pp. 75-81. (Reviews background of neutropenia, clinical presentation, types of congenital and acquired neutropenia and evaluation of patients with neutropenia.)
Berliner, N, Horwitz, M, Loughran, TP. “Congenital and acquired neutropenia”. Hematology Am Soc Hematol Educ Program. vol. 63. 2004. pp. 79(Review article on congenital and acquired neutropenia. Provides details on pathophysiology, mutations and management of different types of congenital and acquired neutropenia.)
Bodey, GP, Buckley, M, Sathe, YS. “Quantitative relationships between circulating leukocytes and infection in patients with leukemia”. Ann Intern Med. vol. 64. 1966. pp. 328-430. (Demonstrated infection risk inversely correlated with ANC.)
Sickles, EA, Greene, WH, Wiernik, PH. “Clinical presentation of infection in granulocytopenic patients”. Arch Intern Med. vol. 135. 1975. pp. 715-9. (Describes the clinical presentation of neutropenic patients compared to non-neutropenic patients.)
Zinner, SH. “Changing epidemiology of infections in patients with neutropenia and cancer: emphasis on gram-positive and resistant bacteria”. Clin Infect Dis. vol. 29. 1999. pp. 490494(Describes the incidence and type of infections in neutropenic patients with cancer.)
Wisplinghoff, H, Seifert, H, Wenzel, RP. “Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies and solid neoplasms in hospital in the United States”. Clin Infect Dis. vol. 36. 2004. pp. 1103-10. (Describes the incidence and type of infections in neutropenic patients with cancer.)
Elting, LS, Rubenstein, EB, Rolston, KVI, Bodey, GP. “Outcomes of bacteremia in patients with cancer and neutropenia: observations from two decades of epidemiological and clinical trials”. lin Infect Dis. vol. 25. 1997. pp. 247-59. (Epidemiology study describing the incidence and type of infections that occur in neutropenic patients.)
Freifeld, AG, Bow, EJ, Sepkowitz, KA. “Clinical practice guidelines for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America”. Clin Infect Dis. vol. 52. 2011. pp. e56-93. (Clinical guidelines for the management of febrile neutropenia. Includes background information on infectious risk of neutropenic patients, approach to and management of febrile neutropenia.)
Fioredda, F, Calvillo, M, Bonanomi, S. “Congenital and acquired neutropenia consensus guidelines on diagnosis from the neutropenia committee of the marrow failure syndrome group of the AIEOP (Associazone Italiana Emato-Oncologica Pediatrica)”. Pediatr Blood Cancer. vol. 57. 2011. pp. 10-7. (Proposes diagnostic guidelines for neutropenia to help guide clinicians in making a diagnosis and providing framework for consistency among institutions.)
Watts, RG, Greer, JP, Foerster, J, Rodgers, GM, Paraskevas, F, Glader, B. “Neutropenia”. Wintrobe's Clinical Hematology. 2009. pp. 1528-48. (Textbook chapter with in-depth review of neutropenia.)
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- 1. Description of the problem
- 2. Emergency Management
- 3. Diagnosis
- Acquired neutropenias
- Special considerations for nursing and allied health professionals.
- What's the evidence?