Updated: Nov 21, 2023
  • Author: Carly DeFaria, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Practice Essentials

Neutropenia is a decrease in circulating (ie, nonmarginal) neutrophils in the blood. [1] The nonmarginal pool constitutes only 4-5% of total body neutrophil stores; most of the neutrophils in the body are contained in the bone marrow, either as mitotically active (one third) or postmitotic mature cells (two thirds). [2] Granulocytopenia is defined as a reduced number of blood granulocytes, namely neutrophils, eosinophils, and basophils. However, the term granulocytopenia is often used synonymously with neutropenia and, in that sense, is again confined to the neutrophil lineage alone.

A common reference range for the absolute neutrophil count (ANC), which is calculated on the basis of the percentage of neutrophils in the white blood cell count (see the Absolute Neutrophil Count calculator) is 2500-8000/µL. Neutrophils play a vital role in protecting against infection, so the duration and severity of neutropenia directly correlate with the total incidence of all infections, including those that are life threatening.

The risk of opportunistic infection increases as the ANC falls below 1500/μL, and the risk of serious infection increases as the ANC falls to the severely neutropenic range (< 500/µL). Vulnerability to infection is extremely high in patients with agranulocytosis, which is the virtual absence of neutrophils in peripheral blood, with ANC typically lower than 100/μL.

Neutropenia has a wide range of causes, both hereditary and acquired (see Etiology). [3] Major causes of acquired neutropenia are infection, drugs (through direct toxicity or immune effects), and autoimmunity. 

Signs and symptoms

Common presenting symptoms of neutropenia include the following:

  • 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

Patients with severe agranulocytosis usually present with the following:

  • Sudden onset of malaise
  • Sudden onset of fever, possibly with chills and prostration
  • Stomatitis and periodontitis accompanied by pain
  • Pharyngitis, with difficulty swallowing

Physical findings on examination of a patient with neutropenia may include the following:

  • Fever
  • Stomatitis
  • Periodontal infection
  • Cervical lymphadenopathy
  • Skin infection: The skin examination focuses on rashes, ulcers, or abscesses
  • Splenomegaly
  • Associated petechial bleeding
  • Perirectal infection
  • Growth retardation in children

In agranulocytosis, the following may be present:

  • Fever (often 40°C or higher)
  • Rapid pulse and respiration
  • Hypotension and signs of septic shock
  • Painful aphthous ulcers in the oral cavity
  • Swollen and tender gums

See Presentation for more detail.


Before undertaking a major workup, rule out infectious and drug-induced causes of neutropenia; then, obtain the following laboratory studies:

  • Complete blood count, including a manual differential in cases of agranulocytosis
  • Differential white blood cell count
  • Peripheral smear, with review by a pathologist
  • Blood cultures (at least two sets with a set collected simultaneously from each lumen of an existing central venous catheter (CVC), if present, and from a peripheral vein site)
  • Serum creatinine and blood urea nitrogen
  • Electrolytes
  • Hepatic transaminase enzymes and total bilirubin

The following studies are applicable in some patients with neutropenia:

  • Antinuclear antibody
  • Rheumatoid factor
  • Serum immunoglobulin studies [4]
  • Peripheral blood flow cytometry
  • T-cell gene rearrangement for T-cell clonality
  • Paroxysmal nocturnal hemoglobinuria testing: By high-sensitivity or fluorescent aerolysin (FLAER)–based flow cytometry
  • Antineutrophil antibodies: Tests for antineutrophil antibodies should be performed in patients with a history suggestive of autoimmune neutropenia and in those with no other obvious explanation for agranulocytosis

Concurrent anemia, thrombocytopenia, and/or an abnormal result on a peripheral blood smear from a patient with neutropenia suggest an underlying hematologic disorder. In this setting, immediately perform a bone marrow aspiration and obtain a biopsy from the posterior iliac crest. Cytogenetic analysis and cell-flow analysis of the aspirate may be indicated.

See Workup for more detail.


General measures to be taken in patients with neutropenia include the following:

  • Remove any offending drugs or agents; if the identity of the causative agent is not known, stop administration of all drugs until the etiology is established

  • Use careful oral hygiene to prevent infections of the mucosa and teeth
  • Avoid rectal temperature measurements and rectal examinations

  • Administer stool softeners for constipation

  • Use proper skin care for wounds and abrasions; skin infections should be managed by personnel with experience in the treatment of infection in neutropenic patients


Start specific antibiotic therapy to combat infections. Options are as follows [5, 6, 7, 8, 9, 10] :

  • Cefepime, meropenem, imipenem-cilastatin, or piperacillin-tazobactam can be used empirically as a single agent
  • Gentamicin or another aminoglycoside should be added in patients whose condition is unstable or who appear septic

  • Vancomycin should be added if infection with methicillin-resistant Staphylococcus aureus (MRSA) or a Corynebacterium species is suspected

A joint guideline from the American Society of Clinical Oncology (ASCO) and Infectious Diseases Society of America (ISDA) recommends antibacterial and antifungal prophylaxis for patients who are at high risk of infection, including patients who are expected to have profound, protracted neutropenia, which is defined as less than 100 neutrophils/µL for more than 7 days. The guideline states that the preferable agent for antibacterial prophylaxis is an oral fluoroquinolone, while that for antifungal prophylaxis is an oral triazole or parenteral echinocandin. [11]

A companion ASCO/IDSA guideline contains recommendations on outpatient management of fever and neutropenia in patients with cancer. The guideline recommends using clinical judgment and the Multinational Association for Supportive Care in Cancer (MASCC) scoring system or Talcott's rules to identify patients who may be candidates for outpatient management. In patients with solid tumors who have undergone mild- to moderate-intensity chemotherapy, who appear to be clinically stable, and who are in close proximity to an appropriate medical facility that can provide 24-hour access, the Clinical Index of Stable Febrile Neutropenia (CISNE) may be used as an additional tool to determine the risk of major complications. [5]

Colony-stimulating factors

Hematopoietic growth factors can be given to accelerate neutrophil recovery and shorten the duration of neutropenic fever; they are also used in the treatment of chronic neutropenia. Such agents include the following:

  • Filgrastim
  • Sargramostim
  • Pegfilgrastim
  • Eflapegrastim
  • Efbemalenograstim


In individuals with neutropenia and Felty syndrome who have recurrent, life-threatening bacterial infections, splenectomy is the treatment of choice, though the response is often short-lived. Systemic lupus associated with autoimmune agranulocytosis may also respond to splenectomy or to immunosuppressive therapy. [12]

See Treatment and Medication for more detail.



Neutrophils are myeloid leukocytes that play an important role in innate immunity. These cells are the initial host defense against numerous pathogens, including bacteria, fungi, and protozoa.

Neutrophils are multi-functional cells, utilizing several mechanisms to combat invading organisms. They act as robust phagocytes, engulfing microbes following opsonization. They also contain several types of cytoplasmic granules that aid them in killing pathogens. Finally, neutrophils can destroy pathogens by creating neutrophil extracellular traps (NETs). Neutrophils form NETS by expelling their DNA into a weblike configuration covered with antimicrobial molecules, neutrophil proteases, and other toxic molecules. These NETs trap invading microorganisms and destroy them. [13]

Neutropenia is defined as a decrease in circulating neutrophils. Only about 4-5% of total body neutrophil stores are contained in the central pool; most neutrophils are in the bone marrow. [12, 14]

Neutropenia is defined in terms of the absolute neutrophil count (ANC). The ANC is calculated by multiplying the total white blood cell (WBC) count by the percentage of neutrophils (segmented neutrophils or granulocytes) plus the immature (band) forms of neutrophils in the complete blood cell count (CBC) differential. See the Absolute Neutrophil Count calculator.

Note that many modern automated instruments actually calculate and provide the ANC in their reports. These instruments do not analyze bands separately from more mature segmented neutrophils, so the combined number represents both bands and segmented neutrophils. If a band number is reported separately, usually by smear review, then one can divide the ANC into bands and segmented neutrophils by subtracting the absolute band number from the total ANC.

The lower limit of the reference value for ANC in adults varies in different laboratories from 1.5-1.8 109/L or 1500-1800/µL (mm3). For practical purposes, a value lower than 1500 cells/µL is generally used to define neutropenia. Age, race, genetic background, environment, and other factors can influence the neutrophil count. For example, people of African descent may have a lower but normal ANC value of 1000 cells/µL, with a normal total WBC count.

Neutropenia is classified as mild, moderate, or severe, based on the ANC, as follows:

  • Mild neutropenia: ANC 1000-1500 cells/µL
  • Moderate neutropenia: ANC 500-1000/µL
  • Severe neutropenia: ANC < 500 cells/µL

The risk of bacterial infection rises not only with the severity of neutropenia but also its duration.

The term agranulocytosis is used to describe a more severe subset of neutropenia. Agranulocytosis refers to a virtual absence of neutrophils in peripheral blood. In these cases the ANC is typically lower than 100/μL. [14, 15, 16, 17] The reduced number of neutrophils makes patients extremely vulnerable to infection. [14, 18] Cardinal signs include fever, sepsis, and other manifestations of infection. Causes can include drugs, chemicals, infective agents, ionizing radiation, immune mechanisms, primary bone marrow failure syndromes, and heritable genetic aberrations.

Some cases, including benign familial neutropenia (see Pediatric Autoimmune Neutropenia), are characterized by only mild neutropenia and are of no obvious significance for health. [14] This article is limited to discussing neutropenia (ANC < 1500/µL) and agranulocytosis (ANC < 100/µL). It does not address the transient neutropenia associated with cancer chemotherapy (for that, see Antimicrobial Agents in Neutropenic Cancer Patients), nor does it consider agranulocytosis occurring as part of primary marrow-failure syndromes (eg, aplastic anemia, pancytopenia, acute leukemia, myelodysplastic syndromes).



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

Mature neutrophils leave the marrow storage compartment and enter the blood without reentry into the marrow. In the blood, two compartments are also present, the marginal compartment and the circulating compartment. Approximately half of the total neutrophils in the blood compartment belong in the marginal compartment, these neutrophils do not circulate freely but are adherent to the vascular surface.

Neutrophils leave the blood pool in a random manner and enter the tissues, where they are destined for cellular action or death. Typically, neutrophils have a life-span of about 6-8 hours. However, during acute infection the longevity of these cells can increase significantly. [19]

Neutropenia can involve any of the three compartments or their subcomponents: bone marrow (mitotic or mature storage pools); blood (circulating and marginal pools); or tissues (sequestration). For example, in benign congenital neutropenias, only the pool of circulating neutrophils is decreased; affected individuals have entirely normal marrow pools, marginal blood pools, and tissue neutrophils.

Neutropenia can be caused by any of the following, alone or in combination:

  • 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

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. Pseudoneutropenia refers to neutropenia caused by such increased margination. [1, 2, 20, 21, 22]

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 syndromes. 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.

The clinical sequelae of neutropenia usually manifests 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. However, the usual clinical signs of infection, including local warmth and swelling, may be absent, as these require the presence of significant numbers of neutrophils. Fever, however, is often present, and requires urgent attention in the setting of severe neutropenia.

The risk of serious infection increases as the ANC falls to the severely neutropenic range (< 500/µL). The duration and severity of neutropenia directly correlate with the total incidence of infection. When the ANC is persistently lower than 100 cells/µL for longer than 3-4 weeks, the incidence of infection approaches 100%. 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, as these are defended by innate and lymphocyte-mediated immune mechanisms.

Bacterial organisms most often cause fever and infection in neutropenic patients. 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 neutropenic patients receive treatment with broad-spectrum antibiotics for several days, superinfection with fungi is common. Candida species are the most frequently encountered organisms in this setting.



The list for all the potential causes of neutropenia is extensive. The etiology of neutropenia can conceptually be viewed in two broad ways, by mechanism or etiologic category.

The mechanisms that cause neutropenia are varied and not completely understood. In many cases, neutropenia occurs after prolonged exposure to a drug or other substance, resulting in decreased neutrophil production by hypoplastic bone marrow. This suggests a direct stem cell toxic effect. In other cases, repeated but intermittent drug or other exposure is needed. This suggests an immune mechanism, although this idea has not been proven. In many clinical situations, the exact exposure and its duration in relation to the onset of neutropenia are not known.

In view of this incomplete understanding of the mechanisms for neutropenia, classification by broad etiologic category is simpler to retain. In this schema, the etiology of neutropenia can be classified as either congenital (hereditary) or acquired.

Hereditary neutropenias

The Table below lists some of the genetic conditions that can lead to neutropenia. Of note, these syndromes are all rare.

Table 1. Genetic (Hereditary) Conditions in Neutropenia (Open Table in a new window)




Clinical Features

Cyclic neutropenia

Autosomal dominant


Alternate 21-day cycling of neutrophils and monocytes

Kostmann syndrome

Autosomal recessive


Stable neutropenia, no MDS or AML

Severe congenital neutropenia

Autosomal dominant

ELA2 (35-84%)

Stable neutropenia, MDS or AML

Autosomal dominant


Stable neutropenia, circulating myeloid progenitors, lymphopenia

Sex linked


Neutropenic variant of Wiskott-Aldrich syndrome

Autosomal dominant


G-CSF–refractory neutropenia, no AML or MDS

Hermansky-Pudlak syndrome type 2

Autosomal recessive


Severe congenital neutropenia, platelet dense-body defect, oculocutaneous albinism

Chediak-Higashi syndrome

Autosomal recessive


Neutropenia, oculocutaneous albinism, giant lysosomes, impaired platelet function

Barth syndrome

Sex linked


Neutropenia, often cyclic; cardiomyopathy, methylglutaconic aciduria

Cohen syndrome

Autosomal recessive


Neutropenia, mental retardation, dysmorphism

Thrombocytopenia with absent radii (TAR)

Autosomal recessive


Thrombocytopenia, MDS, absent radii, abnormal ulna

Diamond-Blackfan anemia

Autosomal dominant, X-linked recessive

RPS19, RPL5, RPS26

Macrocytic anemia, other cytopenias, solid tumors, short stature, abnormal thumbs, cardiac septal defect

Fanconi syndrome

Autosomal recessive (rarely, X-linked recessive or autosomal dominant)


Pancytopenia, solid tumors, skin hyperpigmentation and café au lait spots, abnormal thumbs

Dyskeratosis congenita

X-linked recessive, autosomal dominant, autosomal recessive



Pancytopenia, MDS, nail dystrophy, leukoplakia, solid tumors

Source: Modified from Berliner et al, 2004. [23]

AML = acute myeloid leukemia; G-CSF = granulocyte colony-stimulating factor; MDS = myelodysplastic syndrome.

Congenital neutropenia with associated immune defects

Neutropenia with abnormal immunoglobulins is observed in individuals with X-linked agammaglobulinemia, isolated immunoglobulin A (IgA) deficiency, X-linked hyperimmunoglobulin M (XHIGM) syndrome, and dysgammaglobulinemia type I. [24] 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).

Patients with reticular dysgenesis demonstrate severe neutropenia, no cell-mediated immunity, agammaglobulinemia, and lymphopenia. [24] Life-threatening infections occur that are refractory to granulocyte colony-stimulating factor (G-CSF). [25, 26, 27] Bone marrow transplantation is the treatment of choice.

Congenital or chronic neutropenias

Severe congenital neutropenia (SCN), or Kostmann syndrome, is most often caused by a recessive inheritance and found in remote, isolated populations with a high degree of consanguinity. [28] Autosomal dominant and sporadic cases have also been reported, most often due to mutations in the G-CSF receptor. No uniform genetic defect exists in this syndrome. Mutations in ELA2, which are causative for cyclic neutropenia (see below) are not sufficient to explain the phenotype of Kostmann-like SCN.

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. 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.

Some patients with other forms of SCN appear to have mutations in GFI1, a zinc-finger transcriptional repressor gene involved in hematopoietic stem cell function and lineage commitment decisions.

Cyclic neutropenia (CN) is characterized by periodic bouts of neutropenia associated with infection, followed by peripheral neutrophil count recovery. Its periodicity is about 21 days (range, 12-35 d). Granulocyte precursors disappear from the marrow before each neutrophil nadir in the cycle because of accelerated apoptosis of myeloid progenitor cells. [1] Some cases may be genetically determined with an autosomal recessive inheritance. Other cases may be due to an autosomal dominant inheritance. In some sporadic cases of CN, patients have mutations in ELA2.

People with CN typically present as infants or children, though acquired forms of CN 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

Familial chronic benign neutropenia, or benign ethnic neutropenia, is a disorder with an autosomal dominant pattern of inheritance observed in African, Yemenite Jewish, Ethiopian Jewish, Arab, Caribbean, and West Indian descent. In populations of African and Yemenite Jewish ancestry, genetic studies show a strong association with a single-nucleotide polymorphism in the DARC gene. Patients are typically asymptomatic, and the infections are mild. Affected individuals with chronic benign neutropenia have an overall low risk of infection and no specific therapy is required. [29]

In 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

Idiopathic chronic severe neutropenia is a diagnosis of exclusion. Affected patients exhibit infections and severe neutropenia.

Neutropenia associated with phenotypic abnormalities

Shwachman syndrome (Shwachman-Diamond) 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. [30] 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.

In CHH, the inheritance pattern is autosomal recessive on chromosome 9, and it is observed in Amish and Finnish families. CHH is caused by mutations in the RMRP gene, which encodes the RNA component of the ribonuclease mitochondrial RNA processing (RNase MRP) complex. The neutropenia is moderate to severe. CHH presents with cell-mediated immunity defects, macrocytic anemia, gastrointestinal disease, and dwarfism. It also shows a predisposition to cancer, especially lymphoma. The treatment is bone marrow transplantation.

Dyskeratosis congenita (Zinsser-Cole-Engman syndrome) 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, which encodes dyskerin, a nucleolar protein associated with ribonucleoprotein particles. The autosomal dominant form 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 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 is an X-linked recessive disorder presenting with cardiomyopathy in infancy, skeletal myopathy, recurrent infections, dwarfism, and moderate to severe neutropenia.

Chediak-Higashi syndrome 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.

Thrombocytopenia with absent radii syndrome (TAR) is an autosomal recessive disorder characterized by bilateral radial dysplasia and hypermegakaryocytic thrombocytopenia


Myelokathexis presents in infancy as moderate neutropenia and is associated with recurrent infections. The condition is due to accelerated apoptosis and decreased expression of bcl-x in neutrophil precursors. Neutrophils have an abnormal nuclear appearance, with hypersegmentation with nuclear strands, pyknosis, and cytoplasmic vacuolization. The treatment is G-CSF and GM-CSF.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a severe congenital neutropenia caused by an autosomal dominant gain-of-function mutation in the CXCR4 gene encoding chemokine receptor type 4.  Management includes treatment of infections and warts, correction of neutropenia with G-CSF, and supplementing immunoglobulin deficiency when present. Allogeneic hematopoietic stem cell transplantation has provided cures. CXCR4 blocking agents are undergoing clinical trials. [31]

Lazy leukocyte syndrome

Lazy leukocyte syndrome is a severe neutropenia with associated abnormal neutrophil motility. The etiology is unknown, and the treatment is supportive in nature.

Metabolic disorders

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.

Acquired neutropenias

Intrinsic bone marrow diseases that may cause neutropenia include the following:

  • Aplastic anemia
  • Hematologic malignancy (eg, leukemia, lymphoma, myelodysplasia, myeloma)
  • Ionizing radiation
  • Tumor infiltration
  • Granulomatous infection
  • Myelofibrosis

Immune-mediated neutropenia

A drug may act as a hapten and induce antibody formation. This mechanism operates in cases due to gold, aminopyrine, and antithyroid drugs. The antibodies destroy the granulocytes and may not require the continued presence of the drug for their action. Alternatively, the drug may form immune complexes that attach to the neutrophils. This mechanism operates with quinidine.

Drug immune-mediated neutropenia may be caused by the following:

  • Aminopyrine
  • Quinidine
  • Cephalosporins
  • Penicillins
  • Sulfonamides
  • Phenothiazines
  • Hydralazine

Autoimmune neutropenia is the neutrophil analogue of autoimmune hemolytic anemia and of idiopathic thrombocytopenic neutropenia. It should be considered in the absence of any of the common causes. Antineutrophil antibodies have been demonstrated in these patients. Autoimmune neutropenia may be associated with the following:

  • Rheumatoid arthritis (with or without Felty syndrome)
  • Sjögren syndrome
  • Chronic, autoimmune hepatitis
  • Systemic lupus erythematosus
  • Thymoma
  • Goodpasture disease
  • Granulomatosis with polyangiitis (Wegener granulomatosis)
  • Pure red blood cell (RBC) aplasia, in which 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, which can be caused by the surface antigens of neutrophilia; recipients of repeated granulocyte transfusions could become alloimmunized
  • Large granular lymphocyte proliferation or leukemia

In 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 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, or lymphoproliferative disorder, is a clonal disease of CD3+ T lymphocytes or CD3- natural killer (NK) cells that infiltrate the bone marrow and tissues. Also known as leukemia of large granular lymphocytes (LGL-leukemia), 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 often supportive in nature, but it is also directed at eliminating the clonal population.


Infections are the most common form of acquired neutropenia. Infections that may cause neutropenia include, but are 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 first image below)
  • Toxoplasmosis
  • Brucellosis
  • Typhoid
  • Tuberculosis (see second and third images below)
  • Malaria
  • Dengue fever
  • Rickettsial infection
  • Babesiosis

The most commonly involved organisms are from endogenous flora, such as Staphylococcus aureus in cases of skin infections. Gram-negative organisms are observed in infections of the urinary and gastrointestinal tracts, particularly Escherichia coli and Pseudomonas species. Candida albicans infections may also occur. Mixed flora may be found in the oral cavity.

Viral infections often lead to mild or moderate neutropenia. Agranulocytosis is uncommon but may occur. The most common organisms are Epstein-Barr virus, hepatitis B virus, yellow fever virus, cytomegalovirus, and influenza. Many overwhelming infections, both viral and bacterial, may cause severe neutropenia.

Nutritional deficiency

Nutritional deficiencies that can cause neutropenia include vitamin B-12, folate, and copper deficiency.

Drugs and chemicals, excluding cytotoxic chemotherapy

Numerous drugs have been associated with neutropenia. Drug-induced neutropenia usually occurs within 6 months of starting the offending drug. Once the offending agent is stopped, neutrophil counts tend to recover within 1 week. Some drugs with significantly high risk of neutropenia require weekly blood counts for monitoring (eg, clozapine, sulfasalazine). Other highest-risk categories include antithyroid medications, macrolides, and procainamides.

As stated above, many drugs act by an immune-mediated mechanism. However, some drugs appear to have direct toxic effects on marrow stem cells or neutrophil precursors in the mitotic compartment. For example, drugs such as the antipsychotics, antidepressants, and chloramphenicol may act as direct toxins in some individuals, based on metabolism and sensitivity in this manner. Other drugs may have a combination of immune and nonimmune mechanisms or may have unknown mechanisms of action.

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. [32]

Analgesics and anti-inflammatory agents include indomethacin, ibuprofen, acetylsalicylic acid, diflunisal, sulindac, tolmetin, benoxaprofen, barbiturates, mesalazine, and quinine. Aminopyrine and dipyrone have been withdrawn from the market in many countries due to risk of agranulocytosis.

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.

Diuretics include acetazolamide, bumetanide, chlorothiazide, hydrochlorothiazide, chlorthalidone, methazolamide, and spironolactone.

Hypoglycemic agents include chlorpropamide and tolbutamide.

Antimalarial drugs include amodiaquine, dapsone, hydroxychloroquine, pyrimethamine, and quinine.

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.

Exposure to drugs or chemicals is the most common cause of agranulocytosis: about one half of patients have a history of medication or chemical exposure. Any chemical or drug that can depress the bone marrow and cause hypoplasia or aplasia is capable of causing agranulocytosis. Some drugs do this to everyone if they are administered in large enough doses. Other agents seem to cause idiosyncratic reactions that affect only certain susceptible individuals.

Some agents (eg, valproic acid, carbamazepine, and beta-lactam antibiotics) act by direct inhibition of myelopoiesis. In bone marrow cultures, these agents inhibit granulocyte colony formation in a dose-related fashion. Direct damage to the bone-marrow microenvironment or myeloid precursors plays a role in most other cases.

Many drugs associated with agranulocytosis have been reported to the US Food and Drug Administration (FDA) under its adverse reactions reporting requirement. Many agents are also reported to a registry maintained by the American Medical Association (AMA). The reported drugs were used alone, in combination with another drug known to be potentially toxic, or with another drug without known toxicity. Several drugs are particularly salient because of their high frequency of association with agranulocytosis. They include the following:

  • Phenothiazine
  • Antithyroid drugs (thiouracil and propylthiouracil)
  • Aminopyrine
  • Chloramphenicol
  • Sulfonamides

Miscellaneous immunologic neutropenias

Immunologic neutropenias may occur after bone marrow transplantation and blood product transfusions.

Felty syndrome is a syndrome of rheumatoid arthritis, splenomegaly, and neutropenia. Splenectomy produces an initial response, but neutropenia may recur in 10-20% of patients. Treatment is directed toward rheumatoid arthritis.

In 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.

In 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.

Eosinopenia and basophilopenia

Eosinopenia may be associated with the following:

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)

Go to Pediatric Autoimmune Neutropenia for complete information on this topic.



The incidence of drug-induced neutropenia is one case per million persons per year. The exact frequency of agranulocytosis is unknown; the estimated frequency is 1.0-3.4 cases per million population per year.

In a Danish study that comprised more than 370,000 primary care patients, neutropenia was found on approximately 1% of routine complete blood cell counts. Neutropenia was particularly associated with HIV infection, acute leukemias, and myelodysplastic syndromes. [33]

A United States study found that in 2012, children with cancer accounted for 1.8% of pediatric hospital discharges and of those, 12.2% (n = 13,456) met the criteria for fever and neutropenia. Two fifths of children with fever and neutropenia had a short length of stay; the majority had no serious infections, with viral infection or upper respiratory infection being the most common. [34]

Age distribution for neutropenia

Age can influence the neutrophil count. Elderly individuals have a higher incidence rate of neutropenia than younger individuals.

Agranulocytosis occurs in all age groups. The congenital forms are most common in childhood; acquired agranulocytosis is most common in the elderly population. [23] Go to Pediatric Autoimmune and Chronic Benign Neutropenia for complete information on this topic.

Sex distribution for neutropenia

Neutropenia occurs more commonly in females than in males. Agranulocytosis occurs slightly more frequently in women than in men, possibly because of their increased rate of medication usage. Whether this higher frequency is related to the increased incidence of autoimmune disease in women is unknown.

Incidence of neutropenia by race or ethnicity

Race and genetic background can influence ANC. 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 found the prevalence of neutropenia to be 4.5% among black participants, 0.79% in white individuals, and 0.38% in Mexican-Americans. [35] 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.

The incidence rate of neutropenia was studied in New York City in 2008 in 261 healthy women aged 20-70 years of varying ethnicity. [36] 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%. [36]

Agranulocytosis has no racial predilection.



The prognosis of a patient with neutropenia depends on the primary etiology, duration, and severity of the neutropenia. Improved broad-spectrum antibiotic agents, combined with improved supportive care, have improved the prognosis for most patients with severe neutropenia. Ultimately, patient survival depends on the recovery of adequate neutrophil numbers.

Morbidity in those with neutropenia usually involves infections during severe, prolonged episodes of neutropenia. The infections may be superficial, involving mainly the oral mucosa, gums, skin, and sinuses, or they may be systemic, with life-threatening septicemia.

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. [27, 37, 38] Neutropenic fever in cancer patients typically carries an overall mortality rate of 4-30%. A study of febrile neutropenia-related hospitalizations in patients with breast cancer reported an average in-hospital mortality rate during 2009-2011 of 2.6%, but a rate of 4.4% in patients 65 years of age and older. Mean length of hospital stay was 5.7 days. [39]

The three identified high-risk groups among cancer patients with neutropenic fever (many of whom have received aggressive chemotherapy) are as follows:

  • Inpatients with fever while developing neutropenia
  • Outpatients requiring acute hospital care for problems beyond neutropenia and fever
  • Stable outpatients with uncontrolled cancer

However, a post-hoc analysis of the TROPIC trial in men with metastatic castration-resistant prostate cancer found that occurrence of grade ≥3 neutropenia during cabazitaxel therapy was associated with a prolonged overall survival (median 16.3 versus 14.0 months), a twice-longer progression-free survival (median 5.3 versus 2.6 months) and a higher confirmed prostate-specific antigen response ≥50% (49.8% versus 24.4%), as compared with patients who did not develop grade ≥3 neutropenia. These authors concluded that the inferior outcome in patients who failed to experience grade ≥3 neutropenia during therapy may suggest insufficient drug exposure or a limited impact on the tumor-associated immune response. [40]

If agranulocytosis is untreated, the risk of dying is high. Death results from uncontrolled sepsis. If the condition can be reversed with treatment, the risk of dying is low. Antibiotic and antifungal medications can cure the infection if the ANC rises. Agranulocytosis secondary to viral infections is usually self-limited, and patients with such conditions have a good prognosis.

Drug-induced agranulocytosis carries a mortality rate of 6-10%. If treated promptly and vigorously, patients with drug-induced agranulocytosis have a good prognosis.


Patient Education

Patients with neutropenia should be instructed to avoid exposure to people with respiratory tract infections. [41] They should avoid overcrowded areas, and if their ANC is less than 1000/µL, they should wear a facemask in public places.

Patients should be instructed to avoid any drug that was previously implicated in causing them neutropenia. They should be educated about the importance of frequent CBC testing in the initial period when a new drug with a high propensity to cause neutropenia is introduced. The exact frequency of testing depends on the specific drug and the time course of neutropenia association. At the first sign of a drop in the ANC, the drug should be discontinued.

The Centers for Disease Control and Prevention offers patient education information on neutropenia and infection risk for cancer patients receiving chemotherapy and preventing infections during cancer therapy. In the workplace, people must be educated to follow regulations from the Occupational Safety and Health Administration (OSHA) that cover safety precautions when they deal with toxic substances.

For patient education information, see Neutropenia.