INTRODUCTION — Neutropenia refers to a decrease in circulating neutrophils, which for adults corresponds to <1500 cells/microL in most clinical laboratories.
This topic discusses evaluation of the adult patient with unexplained neutropenia.
The following topics are discussed separately:
●Approach to the patient with pancytopenia (see "Approach to the adult with pancytopenia")
●Evaluation of neutropenia in children (see "Overview of neutropenia in children and adolescents")
●Management of neutropenia and fever (see "Overview of neutropenic fever syndromes")
●Management of non-chemotherapy-induced neutropenia (see "Management of the adult with non-chemotherapy-induced neutropenia")
●Management of drug-induced neutropenia (see "Drug-induced neutropenia and agranulocytosis")
DEFINITIONS AND NORMAL VALUES — The normal range (ie, two standard deviations above and below the mean) for the white blood cell (WBC) count in adults is 4400 to 11,000 cells/microL (4.4 to 11 x 109 cells/L) in most clinical laboratories. (See 'Epidemiology' below.)
●Neutrophils – Neutrophils are the most abundant WBCs in peripheral blood (typically 40 to 70 percent). The term neutrophil refers to the staining characteristics of the cytoplasmic granules; mature neutrophils are also called polymorphonuclear cells (PMNs) based on the characteristic segmentation of the nucleus (picture 1).
●Absolute neutrophil count – The absolute neutrophil count (ANC) is the number of neutrophils plus bands, but does not include metamyelocytes and less mature forms.
ANC = WBC (cells/microL) x percent (PMNs + bands) ÷ 100 (calculator 1)
●Neutropenia – Neutropenia is usually defined as an ANC <1500 cells/microL in an adult. Some institutions use different values (eg, the World Health Organization uses ≤1800 cells/microL) .
Neutropenia can be categorized as :
•Mild – ANC ≥1000 and <1500 cells/microL
•Moderate – ANC ≥500 and <1000 cells/microL
•Severe – ANC <500 cells/microL
●Agranulocytosis – ANC <200 cells/microL
●Chronic neutropenia – Neutropenia for >3 months 
●Constitutional neutropenia – Longstanding neutropenia, typically since childhood
●Granulocytopenia – Reduced number of neutrophils, eosinophils, and basophils
●Isolated neutropenia – Neutropenia without associated anemia and/or thrombocytopenia
●Leukopenia – Reduced total WBC count (<4400 cells/microL in most clinical laboratories)
Normal values for WBC and ANC count in children vary by age and are discussed separately. (See "Overview of neutropenia in children and adolescents".)
EPIDEMIOLOGY — The prevalence of neutropenia in normal adults varies by the population studied due, in part, to different normal values for white blood cell/absolute neutrophil count in certain ethnic groups.
The prevalence of neutropenia is reported from 0 to 10 percent in healthy, asymptomatic individuals, but is higher in individuals with certain medical conditions (eg, autoimmune/connective tissue diseases), as follows:
●Neutropenia was reported in 1 percent of >370,000 routine complete blood counts (CBCs) in Denmark . Chronic neutropenia (from repeat CBCs >3 months apart) was reported in 0.1 percent.
●A United States study that included >25,000 individuals reported the following rates of prevalence :
•Black Americans – 4.5 percent
•White Americans – 0.79 percent
•Mexican Americans – 0.38 percent
●Among 261 healthy women in New York City, prevalence varied by country of origin (self-identified) :
•United States (Black participants) – 10.5 percent
•Haiti – 8.2 percent
•Barbados/Trinidad and Tobago – 6.4 percent
•Jamaica – 2.7 percent
•Dominican Republic – 0 percent
•United States or European (White participants) – 0 percent
●Neutropenia is more common in certain rheumatologic disorders (eg, rheumatoid arthritis, systemic lupus erythematosus), as discussed separately. (See "Hematologic complications of rheumatoid arthritis", section on 'Neutropenia' and "Hematologic manifestations of systemic lupus erythematosus", section on 'Neutropenia'.)
The prevalence of neutropenia in children is discussed separately. (See "Overview of neutropenia in children and adolescents", section on 'Normal variants'.)
MECHANISMS — Neutrophils are produced in the bone marrow and migrate to the circulation, vascular endothelium, spleen, and sites of infection/inflammation. The normal processes of neutrophil production and differentiation are described separately. (See "Regulation of myelopoiesis", section on 'Neutrophil production and maturation'.)
Neutropenia can result from three basic mechanisms:
●Decreased neutrophil production/differentiation in bone marrow (eg, drug-associated, infection, nutritional deficiency)
●Redistribution of circulating neutrophils to the vascular endothelium or to the spleen (termed "margination")
●Immune destruction (eg, drug reaction, autoimmunity)
CAUSES OF NEUTROPENIA — Neutropenia in adults can be caused by inherited/congenital disorders or acquired conditions.
The causes of neutropenia vary with the population and clinical setting. As an example, the causes of neutropenia in hospitalized patients differ from those of ambulatory adults. (See 'Other scenarios' below.)
●Duffy-null associated neutrophil count – Duffy-null associated neutrophil count (DANC; formerly called benign ethnic neutropenia) is an inherited cause of mild/moderate neutropenia in individuals of African descent and certain other ethnic groups that is not associated with increased infections. There is an effort to move away from the designation "benign ethnic neutropenia" because it implies an abnormality when it is in fact a normal variant. The clinical presentation, pathophysiology, and diagnosis of DANC are discussed below. (See 'Normal variants <1500/microL' below.)
●Familial neutropenia – Familial neutropenia refers to unexplained mild neutropenia in families from ethnic groups that are not typically associated with DANC. (See 'Normal variants <1500/microL' below.)
●Congenital neutropenia – Congenital neutropenia syndromes are occasionally first detected in adults, but they are usually recognized during childhood because of associated infections or somatic findings (eg, premature graying of the hair, abnormalities of fingernails or skeleton), as discussed separately. (See "Congenital neutropenia".)
●Infection – Neutropenia can be seen with viral (eg, hepatitis, human immunodeficiency virus [HIV], Epstein-Barr virus [EBV]), bacterial, parasitic, and rickettsial infections. Infectious causes of neutropenia are discussed separately. (See "Infectious causes of neutropenia".)
●Medications – Predictable, dose-dependent effects of cytotoxic or immunosuppressive agents are the most common reason for medication-associated neutropenia. Such neutropenia is usually associated with thrombocytopenia and/or anemia, and these effects are generally reversible if the suspected agent is reduced or stopped. (See "Approach to the adult with pancytopenia", section on 'Suspected medications'.)
Some other anti-cancer agents (eg, rituximab, tyrosine kinase inhibitors) that are not considered myelosuppressive are occasionally associated with isolated neutropenia, as described separately. (See "Drug-induced neutropenia and agranulocytosis", section on 'Rituximab' and "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Myelosuppression'.)
Many medications have been associated with severe idiosyncratic isolated neutropenia (table 1), which typically occurs within three months of starting a new drug. Drug-induced neutropenia is discussed in detail separately. (See "Drug-induced neutropenia and agranulocytosis", section on 'Drug-induced neutropenia'.)
●Nutritional – Deficiencies of dietary vitamins and minerals (eg, vitamin B12, folate, copper) typically cause neutropenia in association with other cytopenias, but isolated or predominant neutropenia is possible, as discussed separately (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency" and "Overview of dietary trace elements", section on 'Copper'.)
●Hematologic malignancies – Large granular lymphocyte (LGL) leukemia, hairy cell leukemia, other lymphoproliferative disorders, myelodysplastic syndromes, or other hematologic malignancies occasionally present with isolated neutropenia, but they are more typically manifest as pancytopenia, as discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia", section on 'Clinical features' and "Clinical features and diagnosis of hairy cell leukemia", section on 'Peripheral blood' and "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)", section on 'Complete blood count'.)
●Rheumatologic disorders – Rheumatoid arthritis, systemic lupus erythematosus, and other rheumatologic disorders may be associated with neutropenia, as discussed separately. (See "Hematologic complications of rheumatoid arthritis", section on 'Neutropenia' and "Hematologic manifestations of systemic lupus erythematosus", section on 'Neutropenia'.)
●Autoimmune neutropenia – Autoimmune neutropenia may occur alone (primary autoimmune neutropenia) or in association with other conditions, as discussed separately. (See "Immune neutropenia".)
●Aplastic anemia – Neutropenia may be the initial or predominant manifestation, but aplastic anemia is typically manifest as pancytopenia, as discussed separately. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)
●Chronic idiopathic neutropenia – Chronic idiopathic neutropenia (CIN) is characterized by longstanding neutropenia without an obvious cause. The clinical presentation of CIN in adulthood is variable, ranging from an asymptomatic, incidental finding to aphthous ulcers, gingivitis, and frequent infections. Diagnosis and management of CIN are described separately. (See "Immune neutropenia", section on 'Chronic idiopathic neutropenia'.)
Causes of neutropenia in the setting of pancytopenia are discussed separately. (See "Approach to the adult with pancytopenia".)
INITIAL EVALUATION — Neutropenia may be encountered in the course of evaluating other clinical findings or as an incidental abnormality on a complete blood count (CBC) and differential.
Evaluation of neutropenia should include prompt assessment for potential medical emergencies and determination of the cause of neutropenia, as described in the sections below.
Initial evaluation includes CBC and differential, history and physical examination, and review of the blood smear. In some circumstances, other laboratory tests may be performed as part of the initial evaluation, as described below. (See 'Other initial laboratory testing' below.)
Urgency of evaluation — The urgency of evaluation of neutropenia is guided by the patient's clinical condition, severity of neutropenia, and the presence of worrisome findings on the blood smear.
Management of infections and other emergency conditions should not be delayed by evaluation of the cause of neutropenia.
Our approach follows:
●All patients, regardless of the level of absolute neutrophil count (ANC), with findings of sepsis, hemodynamic instability, respiratory compromise, or other clinical emergencies require immediate hospitalization and urgent evaluation. (See "Approach to the adult with pancytopenia", section on 'Emergencies'.)
●Patients with ANC <500 cells/microL or worrisome findings on blood smear (eg, leukemic blasts, schistocytes) should be evaluated immediately and often require hospitalization. (See "Evaluation of the peripheral blood smear", section on 'Worrisome findings'.)
●Asymptomatic patients with moderate neutropenia (ie, ≥500 to <1000 neutrophils/microL) and no worrisome findings on blood smear should have a repeat CBC and differential count within one to two weeks, followed by outpatient evaluation if neutropenia persists.
●Asymptomatic patients with ANC >1000 cells/microL and no worrisome findings on blood smear should have repeat CBC/differential within two to six weeks, followed by outpatient evaluation if neutropenia persists.
Complete blood count (CBC) — CBC with differential count should be repeated to confirm the level of ANC, with the urgency of repeat testing informed by the criteria described above. (See 'Urgency of evaluation' above.)
When available, prior CBCs (both normal and abnormal) can provide important information about the duration and trajectory of neutropenia.
Isolated severe neutropenia (ie, <500 cells/microL) is most commonly due to medications; sepsis and viral infections may also cause isolated neutropenia, but it is seldom severe. Rarely, severe neutropenia is caused by a congenital neutropenia syndrome that was not identified in childhood. (See 'Causes of neutropenia' above.)
The most common causes of isolated mild neutropenia in adults are Duffy-null associated neutrophil count (DANC), dose-dependent drug-induced neutropenia (eg, cytotoxic agents), and infections (usually viral). Other common causes of mild neutropenia include nutritional deficiencies, rheumatologic disorders, and hematologic conditions (eg, myelodysplasia).
Neutropenia may be the only hematologic abnormality or it may be accompanied by other findings including:
●Eosinophilia and/or basophilia that may be associated with drug reaction/allergy, infection (especially parasitic), or cancer (eg, eosinophilic leukemia, other acute leukemia, solid tumor) (table 2). (See "Approach to the patient with unexplained eosinophilia".)
●Lymphocytes (see "Approach to the adult with lymphocytosis or lymphocytopenia"):
•Lymphocytosis (eg, large granular lymphocyte [LGL] leukemia, chronic lymphocytic leukemia [CLL], acute lymphoblastic leukemia, lymphomas)
•Lymphopenia (eg, immunodeficiency)
●Anemia: Anemia associated with neutropenia can have varied causes. Examples include:
•Hemolytic anemia (eg, disseminated intravascular coagulation [DIC], thrombotic thrombocytopenic purpura [TTP], paroxysmal nocturnal hemoglobinuria [PNH]) (see "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria")
•Anemia of chronic disease (eg, rheumatologic disorders, cancers, chronic infections) (see "Anemia of chronic disease/anemia of inflammation")
•Macrocytic anemia may be due to megaloblastic disorders (eg, deficiency of vitamin B12 or folate) or reticulocytosis (eg, hemolytic anemia, recovery from bone marrow suppression) (see "Macrocytosis/Macrocytic anemia", section on 'Causes of macrocytosis/macrocytic anemia')
•Aplastic anemia (see "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis")
•Myelophthisic disorders (bone marrow infiltration by fibrosis, malignancy, or infection) (see "Evaluation of the peripheral blood smear", section on 'Leukoerythroblastic smear')
•Thrombocytopenia (eg, DIC, autoimmunity) (see "Diagnostic approach to the adult with unexplained thrombocytopenia")
•Thrombocytosis (eg, infection, inflammatory conditions) (see "Approach to the patient with thrombocytosis")
●Pancytopenia – Evaluation of pancytopenia (ie, neutropenia accompanied by both anemia and thrombocytopenia) is discussed separately. (See "Approach to the adult with pancytopenia".)
History — The history should seek evidence of disorders that might account for neutropenia. (See 'Causes of neutropenia' above.)
Important aspects of the history include evidence of:
●Active or prior infection or inflammatory processes (eg, trauma, rheumatologic disorders)
●Episodic aphthous ulcers and/or infections (eg, a periodicity of two to three weeks may suggest cyclic neutropenia) (see "Cyclic neutropenia")
●Previously diagnosed hematologic malignancy (eg, lymphoma, leukemia), other cancers, or related clinical findings (eg, unexplained lymphadenopathy, fevers, sweats, weight loss)
●Gastrointestinal disorders (eg, inflammatory bowel disease or bariatric surgery may impair absorption of vitamin B12, folate, or copper) or liver disease (eg, associated with infections, rheumatologic conditions, or hematologic malignancies)
●Infections (eg, hepatitis, human immunodeficiency virus [HIV], Epstein-Barr virus [EBV], intestinal parasites)
●Medications – The relationship between the onset of neutropenia and administration of medications should be determined (table 1) (see 'Causes of neutropenia' above)
●Personal and occupational exposures – Diet (eg, long-standing veganism may be associated with dietary deficiency of vitamin B12), excessive alcohol consumption (which may be associated with folate deficiency), exposure to toxic agents at work or home (eg, organic solvents), and travel history (eg, exposure to malaria, leishmania)
●Family history of neutropenia, bone marrow failure syndromes, other hematologic disorders, skeletal abnormalities, or early childhood deaths may suggest a congenital neutropenia syndrome (see "Congenital neutropenia")
●Ethnicity – Ethnicity/national origin from a region associated with Duffy-associated neutrophil count (DANC) (see 'Normal variants <1500/microL' below)
Physical examination — Classic findings of infection may be less apparent in a patient with severe neutropenia, due to the lack of pus and/or signs of inflammation, both of which require adequate neutrophils.
Physical examination may reveal:
●Evidence of infection:
•Skin erythema, ulcerations, fissures, and tenderness, especially at sites of indwelling catheters and the perirectal/genital areas
•Gingivitis, swelling, oral ulceration, or dental pain
•Abnormal respiratory exam
●Findings that may help to determine the cause of the neutropenia:
•Jaundice or other stigmata of liver disease
•Joint swelling or bone pain may suggest a rheumatologic disorder, infection, or malignancy
•Rash may suggest a rheumatologic disorder or drug allergy
•Lymphadenopathy (table 3) or splenomegaly (table 4) may suggest hematologic malignancy or other cancer, rheumatologic disorders, or infection (see "Evaluation of peripheral lymphadenopathy in adults")
•Neuro/psychiatric abnormalities may suggest a nutritional deficiency (eg, vitamin B12, copper), alcoholism, or HIV infection
Peripheral blood smear — The peripheral blood smear should assess neutrophil morphology and detect other hematologic findings.
●Neutrophils (see "Evaluation of the peripheral blood smear", section on 'Neutrophil series'):
•Toxic granulations or Dohle bodies (picture 2) associated with sepsis
•Bilobed (picture 3) or dysplastic neutrophils (picture 4) due to myelodysplastic syndromes (MDS) or congenital disorders
•Hypersegmented neutrophils (picture 5) due to megaloblastic disorders (eg, vitamin B12 or folate deficiency)
•Immature myeloid cells without mature neutrophils due to acute myeloid leukemia (picture 6)
●Lymphocytes (see "Approach to the adult with lymphocytosis or lymphocytopenia", section on 'Peripheral blood smear'):
•Atypical lymphocytes (picture 7) suggest a viral cause (eg, EBV, cytomegalovirus [CMV])
•"Smudge" lymphocytes (picture 8) are characteristic of CLL
•"Hair-like" projections on lymphocytes (picture 9) are seen in hairy cell leukemia
•Lymphocytes with azurophilic granules (picture 10) may be seen in LGL leukemia
●Red blood cells (see "Evaluation of the peripheral blood smear", section on 'Red blood cells'):
•Macro-ovalocytes (picture 11) associated with megaloblastic anemias
•Fragmented cells from microangiopathy (eg, DIC)
•Tear drop-shaped cells (picture 12) associated with myelophthisic processes (eg, primary myelofibrosis)
•Spiculated (picture 13) or target cells (picture 14) that may be due to liver disease
Other initial laboratory testing — Other laboratory studies may provide important data for defining the cause or assessing complications of neutropenia.
●The following tests should be performed for incidentally discovered neutropenia, clinical evidence of liver disease, or blood smears that demonstrate macrocytosis, spiculated or target red blood cells, hypersegmented neutrophils, and/or atypical lymphocytes (see 'Peripheral blood smear' above):
•Vitamin B12, folate, and copper levels
•Liver function tests and screening for viral hepatitis and HIV infection (if not recently evaluated) (see "Approach to the patient with abnormal liver biochemical and function tests" and "Initial evaluation of adults with HIV", section on 'Initial laboratory testing')
●Coagulation testing (eg, prothrombin time, partial thromboplastin time, D-dimer), lactate dehydrogenase (LDH), and serum creatinine should be performed for febrile or hemodynamically unstable patients who may have sepsis and/or DIC, or fragmented red blood cells on the blood smear. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)
●Evaluation and management of fever or suspected infection with neutropenia are discussed separately. (See "Overview of neutropenic fever syndromes", section on 'Management'.)
For patients with suspected infections, we suggest not performing routine serologic screening for infectious causes of neutropenia, other than hepatitis, EBV, and HIV, as described above, unless it is otherwise clinically important (eg, CMV, toxoplasma infections in a pregnant woman). (See "Overview of TORCH infections".)
●Erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) may be useful in a patient with moderate/severe neutropenia (eg, <1000 cells/microL), since classic findings of infection or inflammation may be subtle or inapparent. (See "Management of the adult with non-chemotherapy-induced neutropenia", section on 'Monitoring response to treatment'.)
●Blood typing for Duffy antigen is suggested by some experts to support a diagnosis of Duffy-null associated neutrophil count. (See 'Normal variants <1500/microL' below.)
●We suggest not performing screening studies for rheumatologic disorders (eg, anti-nuclear antibody, anti-DNA antibody, complement levels) in the absence of clinical findings associated with such disorders (eg, arthritis, serositis). (See 'Rheumatologic/Autoimmune disorders' below.)
SUBSEQUENT EVALUATION AND MANAGEMENT — Our approach is guided by whether findings from the initial evaluation lead to identification of a clear cause for neutropenia, as described below.
Often, more than one possible cause of neutropenia is identified by the initial evaluation. As examples, repletion of vitamin deficiencies or discontinuing/reducing other contributing factors (eg, medications, alcohol) may lessen the degree of neutropenia and clarify the diagnostic possibilities.
Evaluation of specific causes of neutropenia is described in the sections below.
Management of medical emergencies must take place even as the diagnostic evaluation is proceeding. As examples, treatment of sepsis or the complications of acute leukemia must be addressed immediately. (See "Approach to the adult with pancytopenia", section on 'Emergencies'.)
The urgency of evaluation and, in some cases, the need for hospitalization is described above. (See 'Urgency of evaluation' above.)
Diagnosis established by initial evaluation — For the following diagnoses that may be defined by the initial evaluation, no further testing or follow up is required if one or two subsequent complete blood counts (CBCs) reveal that the absolute neutrophil count (ANC) responded as expected.
If the ANC does not reveal the expected response or if the ANC declines, further evaluation is appropriate, as described in the sections below.
Nutritional deficiency — Repletion of vitamin B12, folate, or copper should cause a predictable improvement in hematologic parameters; evaluation and management of an inadequate response is described separately. Neutropenia should improve within days but may take two to four weeks to resolve; hypersegmented neutrophils may persist for up to four weeks. (See "Treatment of vitamin B12 and folate deficiencies" and "Copper deficiency myeloneuropathy", section on 'Diagnosis and evaluation'.)
Viral infection — Acute viral infections may cause transient, mild neutropenia that should improve within one to two weeks. Recovery of ANC may be slower with human immunodeficiency virus (HIV) and hepatitis infections, as described separately. (See "Approach to the patient with abnormal liver biochemical and function tests" and "HIV-associated cytopenias", section on 'Neutropenia'.)
If recovery from an apparent viral infection is significantly delayed or incomplete, other causes of neutropenia (eg, medications, inherited/congenital disorders) should be considered and referral to hematology may be helpful. (See 'Hematology referral' below.)
Medications — Management of medications that may contribute to neutropenia is guided by the ANC:
●If the ANC is <1000 cells/microL, all drugs that are associated with idiosyncratic reactions (table 1) should be discontinued immediately, if clinically feasible, and cytotoxic/immunosuppressive drugs should be withheld. Critical medications (eg, some psychotropic or antiseizure medications) for which no suitable alternative is available, may be continued unless the ANC falls <500 cells/microL.
●Mild neutropenia (ie, ≥1000 cells/microL) is less likely to represent an idiosyncratic drug reaction. Cytotoxic/immunosuppressive drugs should be withheld until the neutropenia improves, but it is not necessary to discontinue all other suspect critical medications (eg, psychotropic or antiseizure medications).
Neutropenia caused by bone marrow suppression due to cytotoxic or immunosuppressive drugs should improve within two to three weeks of the last treatment. Delayed recovery or worsening of neutropenia may suggest other contributing causes (eg, concurrent viral suppression, treatment-associated hematologic disorder) and may benefit from referral to a hematologist for bone marrow evaluation. (See 'Hematology referral' below.)
Other scenarios — For conditions that are not explained by the initial evaluation, further testing is guided by the clinical setting, as described below.
Hospitalized patient — The hospitalized patient with neutropenia should be promptly assessed for potential medical emergencies and managed accordingly. (See "Approach to the adult with pancytopenia", section on 'Emergencies'.)
Evaluation of neutropenia in the hospitalized patient should determine, when possible, whether neutropenia developed during the hospitalization or was present previously. Results of CBCs/differential counts from prior hospitalizations and the ambulatory setting are important for making this distinction.
For neutropenia that developed while hospitalized, the ANC should be correlated with all medications, including drugs that have predictable marrow suppressive activity and those associated with idiosyncratic neutropenia (table 1). Management of medications that may contribute to neutropenia is described above. (See 'Medications' above.)
For patients whose ANC does not improve in the face of the medication adjustments described above, and for neutropenia that remains otherwise unexplained, referral to hematology and/or bone marrow evaluation may be useful, especially if there is suspicion for an underlying hematologic malignancy (eg, lymphadenopathy, splenomegaly, leukoerythroblastic blood smear) or chronic infection (eg, fungal or mycobacterial). (See 'Hematology referral' below.)
Other aspects of management of drug-associated neutropenia are discussed separately. (See "Drug-induced neutropenia and agranulocytosis", section on 'Treatment'.)
Asymptomatic incidental neutropenia — Laboratory testing and management of medications for the patient with incidentally detected, asymptomatic neutropenia is described above. (See 'Other initial laboratory testing' above and 'Medications' above.)
Our approach is informed by the level and trajectory of the ANC, as follows:
●For an asymptomatic patient with ANC ≥1000 cells/microL, the initial evaluation can be performed as an outpatient.
If the ANC improves over days to weeks, the most likely diagnoses are transient neutropenia from a viral syndrome or myelosuppressive medication. No further testing is required and suggestions for monitoring are described below. (See 'Monitoring' below.)
For a stable pattern of mild neutropenia, the most likely diagnoses are Duffy-null associated neutrophil count, familial neutropenia, autoimmune neutropenia, rheumatologic conditions, hematologic malignancies (eg, low grade lymphoma), or nutritional deficiencies, as described above. (See 'Causes of neutropenia' above and 'Normal variants <1500/microL' below.)
●For patients with ANC <1000 cells/microL, worsening neutropenia, or those who become symptomatic, the urgency and setting of evaluation and management (ie, outpatient versus hospital) is described above. (See 'Urgency of evaluation' above.)
Abnormal blood smear/CBC — Further evaluation is informed by the nature of abnormalities on the blood smear:
●Findings that suggest acute leukemia or other aggressive hematologic malignancy (eg, leukemic blasts, maturation arrest, myelophthisic changes) should be evaluated immediately with hospitalization and urgent referral to hematology, as described separately. (See "Evaluation of the peripheral blood smear", section on 'Worrisome findings' and "Approach to the adult with pancytopenia", section on 'Emergencies'.)
●Schistocytes or other findings that suggest disseminated intravascular coagulation (DIC) warrant immediate hospitalization and emergency management, as described separately. (See "Approach to the adult with pancytopenia", section on 'Emergencies'.)
●Neutrophils with toxic granulations and/or Dohle bodies suggest acute infection and/or sepsis, and should be evaluated urgently, as described below. (See 'Infection/Fever' below.)
●Dysplastic granulocytes, aberrant lymphoid cells (eg, hairy cells, smudge cells, large granular lymphocytes), and other findings that suggest an underlying hematologic malignancy should lead to prompt hematology referral and further evaluation, as described separately. (See "Evaluation of the peripheral blood smear", section on 'Worrisome findings' and 'Hematology referral' below.)
Infection/Fever — Patients with neutropenia and findings of sepsis, hemodynamic instability, respiratory compromise, or other clinical emergencies require immediate hospitalization and urgent evaluation. (See "Approach to the adult with pancytopenia", section on 'Emergencies' and "Management of the adult with non-chemotherapy-induced neutropenia", section on 'Treatment of infection'.)
Oral temperature ≥38.0°C (>100.4°F) should be assumed to be due to infection and requires prompt antibiotic therapy, whether the fever/infection is thought to be the cause of neutropenia (eg, viral infection) or a result of neutropenia (especially bacterial infections). Urgent evaluation and management of fever with neutropenia is described separately. (See "Overview of neutropenic fever syndromes", section on 'Management'.)
Rheumatologic/Autoimmune disorders — Neutropenia is often encountered in the setting of rheumatologic disorders (eg, systemic lupus erythematosus, rheumatoid arthritis) and establishing a clear cause for neutropenia may be challenging.
Evaluation of hematologic manifestations of rheumatologic conditions is discussed separately. (See "Hematologic complications of rheumatoid arthritis" and "Clinical manifestations and diagnosis of Felty syndrome", section on 'Diagnosis' and "Hematologic manifestations of systemic lupus erythematosus", section on 'Neutropenia'.)
Suspected congenital neutropenia — Congenital neutropenia should be considered in adults with unexplained, severe neutropenia (<500 cells/microL) in the setting of somatic findings (eg, pancreatic dysfunction, premature graying of the hair, abnormalities of fingernails or skeleton), or a family history of neutropenia, unexplained childhood deaths, or somatic syndromes. Examples of congenital syndromes that may present with neutropenia in adulthood are cyclic neutropenia, Shwachman-Diamond syndrome, Fanconi anemia, dyskeratosis congenita, and others . The patient with a suspected congenital neutropenia syndrome should be referred to a hematologist who has expertise in these disorders, and the diagnosis is established by a bone marrow biopsy with genetic testing, as described separately. (See "Congenital neutropenia".)
Cyclic neutropenia should also be considered in patients with an episodic pattern of recurrent aphthous ulcers or infections with a two- to four-week periodicity. To demonstrate a pattern of cyclic neutropenia, CBCs/differentials should be obtained two times per week for six weeks, as described separately. (See "Cyclic neutropenia".)
Normal variants <1500/microL — Some individuals have an ANC <1500/microL with no recurrent or severe infections, other cytopenias, or associated illnesses . Most commonly, this inherited condition is associated with the Duffy null [Fy(a-b-)] red blood cell phenotype (which is protective against malaria), but other causes have been identified.
These variants are most often encountered in individuals of African descent and in Sephardic Jews, West Indians, Yemenites, Greeks, and Arabs. This condition may also be called constitutional neutropenia and was formerly described as "benign ethnic neutropenia," but the preferred designation is "Duffy-null associated neutrophil count (DANC)."
●Clinical presentation – Constitutional neutropenia is not associated with recurrent or unusual infections, other cytopenias, physical findings, or other causes of cytopenias (eg, medications, excessive alcohol consumption, liver disease, autoimmune conditions).
•Duffy null [Fy(a-b-)] phenotype – Homozygosity for rs2814778, a single nucleotide polymorphism (SNP) of the ACKR1 gene, is most commonly associated; this SNP is the predominant ACKR1 allele in Black individuals, yet neutropenia is manifest in only a subset of individuals who are homozygous for rs2814778 .
•CXCL2/CXCR2 – The rs9131 SNP of the chemokine, CXCL2, has been associated with lower levels of ANC ; rare variants of the receptor, CXCR2, are also associated with lower neutrophil counts .
•TCIRG1 – Rare variants of TCIRG1 (eg, rs587779413) may be associated with low ANC; homozygous or compound mutations of TCIRG1 may cause osteopetrosis [11,12].
●Evaluation and diagnosis – The ANC is typically >1200 cells/microL, but it may occasionally be <1000 cells/microL. The blood smear is normal.
The diagnosis is based on persistent ANC <1500/microL in an individual with no history of abnormal infections and no findings from the history, physical examination, or laboratory studies that suggest an alternative explanation for neutropenia. In practice, we generally repeat the CBC two or three times, separated by intervals of at one month. Detection of homozygosity for ACKR1 rs2814778 or the Duffy null [Fy(a-b-)] phenotype supports, but is not required for the diagnosis of constitutional neutropenia. Bone marrow examination is not required for diagnosis, but it should be performed if there is substantial concern for an alternative diagnosis (eg, inherited and acquired causes for neutropenia).
FURTHER EVALUATION — Referral to hematology and/or specialized testing may be useful for patients in whom the cause for neutropenia has not been established by the initial evaluation.
Hematology referral — Most patients with neutropenia do not require referral to a hematologist. For patients with mild, asymptomatic neutropenia that is explained by the initial evaluation, the diagnosis, management, and monitoring can be performed by the primary clinician. (See 'Diagnosis established by initial evaluation' above.)
Examples of situations that warrant referral to hematology include:
●Immediate referral (within hours):
•Leukemic blasts or other worrisome findings on the blood smear that suggest acute leukemia (see 'Abnormal blood smear/CBC' above)
•Agranulocytosis (ANC <200 cells/microL)
●Prompt referral (within days):
•Other abnormalities on blood smear that suggest a hematologic malignancy (eg, dysplastic granulocytes, tear drop red blood cells, "hairy" lymphocytes, "smudge" cells, large granular lymphocytes), or related clinical findings (eg, unexplained lymphadenopathy, splenomegaly) (see 'Peripheral blood smear' above)
•Presence of or progression to pancytopenia (see "Approach to the adult with pancytopenia", section on 'Subsequent evaluation')
•Characteristic physical findings or family history of congenital neutropenia syndrome (see 'Suspected congenital neutropenia' above)
●Timely referral (days to weeks):
•Worsening of neutropenia or persistence of ANC <1000 cells/microL that is not due to Duffy-null associated neutrophil count, rheumatologic disorder, or hypersplenism (eg, due to liver cirrhosis) (see 'Diagnosis established by initial evaluation' above)
•Inadequate response to treatment of a nutritional deficiency that is not accounted for by poor compliance or malabsorption, as described separately (see "Treatment of vitamin B12 and folate deficiencies", section on 'Approach to lack of response')
•Pattern of episodic infections and/or aphthous ulcers that is consistent with cyclic neutropenia (see "Cyclic neutropenia")
Bone marrow examination — Bone marrow aspirate and biopsy is useful in a minority of patients with neutropenia. (See "Bone marrow aspiration and biopsy: Indications and technique", section on 'Indications'.)
The urgency for performing a bone marrow biopsy is influenced by the likely cause(s) of neutropenia, severity and trajectory of ANC, clinical stability, medical complications, and the urgency for evaluation and management. (See 'Urgency of evaluation' above.)
Bone marrow specimens provide information regarding abundance, maturation, and morphology of neutrophils; and other normal cellular elements; infiltrative disorders (eg, fibrosis, lymphoma, leukemia, metastatic cancer, fungal or mycobacterial infection); and provides material for microbiology culture, flow cytometry, and cytogenetic/molecular studies. (See "Bone marrow aspiration and biopsy: Indications and technique", section on 'Indications'.)
In general, bone marrow examination for evaluation of neutropenia is:
●Essential when a primary hematologic disorder (eg, acute leukemia, myelodysplastic syndrome, aplastic anemia) or congenital neutropenia syndrome is suspected. (See 'Abnormal blood smear/CBC' above and 'Suspected congenital neutropenia' above.)
●May be useful when a diagnosis of fungal infection or tuberculosis is suspected. (See "Infectious causes of neutropenia".)
●May be useful when neutropenia responds inadequately after appropriate management (eg, after exclusion of noncompliance of malabsorption after repletion of vitamin B12 or folate). (See "Treatment of vitamin B12 and folate deficiencies", section on 'Approach to lack of response'.)
Bone marrow evaluation is usually uninformative for Duffy-null associated neutrophil count, drug-induced or autoimmune destruction, and viral or bacterial infections.
In some circumstances a bone marrow biopsy may be unhelpful or even distracting and confounding. As an example, a bone marrow biopsy performed just days after discontinuation of a suspect medication may show a "maturation arrest" (ie, recovery of bone marrow cells only up to an immature stage of differentiation) that may be morphologically indistinguishable from acute leukemia. Similarly, recent treatment with recombinant hematopoietic growth factors may induce a bone marrow morphology that is indistinguishable from certain myeloproliferative neoplasms or inflammatory conditions. In such situations it may be preferable to delay the biopsy by days to weeks.
RISK OF INFECTION — The risk of infection is influenced by the severity and trajectory of the absolute neutrophil count (ANC). Stratification for infectious risk is discussed separately. (See "Management of the adult with non-chemotherapy-induced neutropenia", section on 'Infectious risk stratification'.)
The underlying cause of neutropenia also affects the risk of infection. Conditions that are associated with impaired neutrophil production (eg, congenital neutropenia syndromes, nutritional deficiencies, aplastic anemia, myelodysplastic syndromes) are more likely to be associated with infections than those caused by other mechanisms (eg, Duffy-null associated neutrophil count, immune neutropenia), which generally have adequate bone marrow neutrophil reserves. (See 'Mechanisms' above.)
Patients who are neutropenic without fever or other evidence of infection are probably safer outside of a hospital than in a hospital. In contrast, most patients with fever and neutropenia require urgent hospital admission, as discussed separately. (See "Management of the adult with non-chemotherapy-induced neutropenia", section on 'Overview of treatment'.)
Counseling the patient and family regarding risk and management of infections is discussed separately. (See "Management of the adult with non-chemotherapy-induced neutropenia", section on 'Overview of treatment' and "Management of the adult with non-chemotherapy-induced neutropenia", section on 'Counseling regarding infectious risk'.)
MONITORING — The frequency and nature of follow-up for neutropenia is guided by the severity and trajectory of the absolute neutrophil count (ANC), the underlying diagnosis, response to interventions, the presence of associated symptoms and/or complications, and concern of the clinician and patient.
It is important to balance the need for periodic re-evaluation with the avoidance of unnecessary worry in an otherwise healthy individual. The cause of neutropenia should be explained to the patient to avoid exposure to inciting agents and to limit risks associated with future events of neutropenia.
Examples of monitoring schedules follow:
●For patients with uncomplicated, mild or moderate neutropenia, the ANC should be documented by serial complete blood counts (CBC). As an example, CBCs can be repeated weekly for the first two to four weeks, and again at three months:
•If neutropenia resolves and the patient remains asymptomatic, there is no need for further follow-up. However, the patient should be re-evaluated urgently if fever or other infectious symptoms arise in the first year.
•If mild neutropenia (>1000 cells/ microL) persists, a CBC should be repeated every three to four months for the first year, and if stable, further evaluated only if the patient becomes symptomatic with fever, mouth sores, or other signs of a hematological disorder. The patient should be evaluated for fever or other infectious symptoms, but no other routine follow-up is required.
●For a patient with Duffy-null associated neutrophil count, no further monitoring is required, as described separately. (See 'Normal variants <1500/microL' above.)
●Follow-up of patients with other defined causes of neutropenia (eg, hematologic malignancy, rheumatologic disorder, splenomegaly) is guided by needs related to the underlying disease.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bone marrow failure syndromes".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Neutropenia (The Basics)")
●Definition – Neutropenia is defined as an absolute neutrophil count (ANC) <1500 cells/microL (calculator 1). (See 'Definitions and normal values' above.)
When neutropenia is accompanied by anemia and/or thrombocytopenia, it is considered aplastic anemia (AA). Evaluation and diagnosis of AA are discussed separately. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)
●Initial evaluation – Initial evaluation of neutropenia includes:
•Clinical – History of infections, prior neutropenia, other cytopenias, medications (table 1), diet, alcohol use, and examination for liver disease, acute or chronic infection, or a rheumatologic disorder.
•Complete blood count (CBC) – CBC with differential count and red blood cell (RBC) indices. (See 'Complete blood count (CBC)' above.)
•Blood smear – Assessment of neutrophil morphology and other lineages. (See 'Peripheral blood smear' above.)
●Further evaluation – Further testing is guided by the duration, severity, and trajectory of neutropenia and findings from the initial evaluation.
•Nutritional disorder – Patients with macrocytic RBC indices, hypersegmented neutrophils (picture 5), macro-ovalocytes (picture 11), history of gastrointestinal surgery, poor diet, alcohol use, or long-term veganism should be tested for RBC folate, vitamin B12, copper deficiency, and liver disease. (See 'Nutritional deficiency' above.)
•Suspected medications – Urgency of evaluation and management vary with the ANC:
-Severe neutropenia (ANC <1000 cells/microL) – Drugs associated with idiosyncratic reactions (table 1) should be discontinued immediately, if clinically feasible, and cytotoxic/immunosuppressive drugs should be withheld.
-Moderate/mild neutropenia (ie, ≥1000 cells/microL) – Cytotoxic/immunosuppressive drugs should be withheld until the neutropenia improves, but it is not necessary to discontinue all suspected medications (eg, psychotropic or antiseizure medications).
•Infectious causes – Neutropenia can occur with viral hepatitis, HIV, or Epstein-Barr virus (EBV); bacterial, parasitic, and rickettsial infections. Observation and/or treatment with antimicrobials are appropriate. (See 'Viral infection' above.)
•Rheumatologic condition – Evaluation of hematologic manifestations of rheumatologic conditions is discussed separately. (See "Hematologic complications of rheumatoid arthritis" and "Hematologic manifestations of systemic lupus erythematosus", section on 'Neutropenia'.)
•Suspected hematologic malignancy – Bone marrow examination and/or flow cytometry should be performed for patients with unexplained splenomegaly, abnormal blood smear (eg, dysplastic features (picture 4 and picture 3), blasts (picture 6), abnormal lymphoid cells (picture 7 and picture 8 and picture 9 and picture 10)), or other findings that suggest a leukemia or other hematologic malignancy, as described separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)
•Normal variant – Moderate neutropenia (eg, >1000/microL) is more common in individuals of African descent, Sephardic Jews, West Indians, Yemenites, Greeks, and Arabs; this condition, formerly called "benign ethnic neutropenia", is not associated with increased risk for infections. Duffy null phenotype (Fy(a-b-)) supports the diagnosis. (See 'Normal variants <1500/microL' above.)
•Suspected familial disorder – Patients with a family history of unexplained neutropenia or characteristic skeletal, skin, or other characteristic somatic findings should be evaluated for an inherited disorder, as described separately. (See 'Suspected congenital neutropenia' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge the late Laurence A Boxer, MD, for his previous role as a section editor for this topic.
3 : Prevalence and clinical significance of neutropenia discovered in routine complete blood cell counts: a longitudinal study.
4 : Prevalence of neutropenia in the U.S. population: age, sex, smoking status, and ethnic differences.
8 : Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene.
9 : Genome-wide association study of white blood cell count in 16,388 African Americans: the continental origins and genetic epidemiology network (COGENT).
10 : Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits.
11 : Association Between Absolute Neutrophil Count and Variation at TCIRG1: The NHLBI Exome Sequencing Project.
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