Neutropenia

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Neutropenia is a decrease in circulating neutrophils in the nonmarginal pool, which constitutes 4-5% of total body neutrophil stores. ^[1] Most of the neutrophils 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.

The risk of serious infection increases as the absolute neutrophil count (ANC) falls to the severely neutropenic range (< 500/µL). The duration and severity of neutropenia directly correlate with the total incidence of all infections and of those infections that are life threatening. Tuberculosis (see the image below) is one type of infection that may cause neutropenia.

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 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

Lung infections are usually bacterial or fungal pneumonias. 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 if infection has been present

Painful aphthous ulcers in the oral cavity

Swollen and tender gums

See Presentation for more detail.

Previous to 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 evaluating cases of agranulocytosis

Differential white blood cell count

Peripheral smear review by a pathologist

The following studies are applicable in some patients with neutropenia:

Antinuclear antibody

Rheumatoid factor

Serum immunoglobulin studies ^[3]

Liver function tests

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 in cases involving drug exposure: 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 good skin care for wounds and abrasions: Skin infections should be managed by someone with experience in the treatment of infection in neutropenic patients

Antibiotics

Start specific antibiotic therapy to combat infections. This often involves the use of fourth-generation cephalosporins or equivalents. Fever may be treated as an infection, as follows ^{[4, 5, 6, 7, 8, 9]} :

Cefepime, meropenem, imipenem-cilastatin, or piperacillin-tazobactam can be used empirically as a single agent

Gentamicin or another aminoglycoside should be added if the neutropenic patient’s condition is unstable or the individual appears septic

Vancomycin should be added if infection with methicillin-resistant Staphylococcus aureus 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. ^[10]

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. ^[4]

Splenectomy

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. ^[11]

See Treatment and Medication for more detail.

Neutropenia is a decrease in circulating neutrophils in the nonmarginal pool, which constitutes 4-5% of total body neutrophil stores. ^[1] Most of the neutrophils are contained in the bone marrow, either as mitotically active (one third) or postmitotic mature cells (two thirds). ^{[2, 12]} 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.

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 band forms of neutrophils in the complete blood count (CBC) differential. See the Absolute Neutrophil Count calculator.

Note that many modern automated instruments actually calculate and provide the ANC number in their reports. These instruments do not analyze separately bands from segmented neutrophils, and so the combined number is termed the absolute neutrophil count (ANC), representing both bands and more mature 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, blacks 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. Mild neutropenia is present when the ANC is 1000-1500 cells/µL, moderate neutropenia is present with an ANC of 500-1000/µL, and severe neutropenia refers to an ANC lower than 500 cells/µL. The risk of bacterial infection is related to both the severity and duration of the neutropenia.

The term agranulocytosis is used to describe a more severe subset of neutropenia. Agranulocytosis refers to a virtual absence of neutrophils in peripheral blood. It is usually applied to cases in which the ANC is lower than 100/μL. ^{[12, 13, 14, 15]} The reduced number of neutrophils makes patients extremely vulnerable to infection. ^{[12, 16]} Cardinal symptoms 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, such those from benign familial neutropenia, are characterized by only mild neutropenia and are of no obvious significance for health. ^[12] 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, nor does it consider agranulocytosis occurring as part of primary marrow-failure syndromes (eg, aplastic anemia, pancytopenia, acute leukemia, myelodysplastic syndromes).

For more information, see the Medscape article Pediatric Autoimmune and Chronic Benign Neutropenia.

Mature neutrophils are produced by precursors in the bone marrow. The total body neutrophil content can be divided conceptually into the following 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”]).

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. Some neutrophils do not circulate freely (marginal compartment), but are adherent to the vascular surface, and these constitute approximately half of the total neutrophils in the blood compartment.

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

Sites and mechanisms that cause neutropenia can be restricted to 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, benign congenital neutropenias are associated with a decrease in only the pool of circulating neutrophils; 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, 17, 18, 19]}

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 its presence 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 all infections and those infections that are life threatening. 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. Fungal organisms are also significant pathogens in the setting of neutropenia. Historically, gram-negative aerobic bacteria (eg, Escherichia coli, Klebsiella species, Pseudomonas aeruginosa) have been most common in these patients. However, gram-positive cocci, especially Staphylococcus species and Streptococcus viridans, have emerged as the most common pathogens in fever and sepsis because of the increasing use of indwelling right atrial catheters.

After 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 not short. 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. Though this categorization may have limited clinical diagnostic utility, it can be useful to clearly separate hereditary causes of neutropenia from the panoply of acquired causes. In the setting of hereditary neutropenias, these disorders can be further described as associated with isolated neutropenia or with other defects, whether immune or phenotypic.

Many hereditary disorders are due to mutations in the gene encoding neutrophil elastase, ELA2. Several alleles are involved. The most common mutations are intronic substitutions that inactivate a splice site in intron 4. Genes other than ELA2 are also involved. The Table below lists some of the genetic conditions involved; these are uncommon conditions.

Table 1. Genetic (Hereditary) Conditions in Agranulocytosis ^[20] (Open Table in a new window)

Syndrome

Inheritance

Gene

Clinical Features

Cyclic neutropenia

Autosomal dominant

ELA2

Alternate 21-day cycling of neutrophils and monocytes

Kostmann syndrome

Autosomal recessive

Unknown

Stable neutropenia, no MDS or AML

Severe congenital neutropenia

Autosomal dominant

ELA2 (35-84%)

Stable neutropenia, MDS or AML

Autosomal dominant

GFI1

Stable neutropenia, circulating myeloid progenitors, lymphopenia

Sex linked

Wasp

Neutropenic variant of Wiskott-Aldrich syndrome

Autosomal dominant

G-CSFR

G-CSF–refractory neutropenia, no AML or MDS

Hermansky-Pudlak syndrome type 2

Autosomal recessive

AP3B1

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

Chediak-Higashi syndrome

Autosomal recessive

LYST

Neutropenia, oculocutaneous albinism, giant lysosomes, impaired platelet function

Barth syndrome

Sex linked

TAZ

Neutropenia, often cyclic; cardiomyopathy, methylglutaconic aciduria

Cohen syndrome

Autosomal recessive

COH1

Neutropenia, mental retardation, dysmorphism

Source: Modified from Berliner et al, 2004. ^[20]

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

Causes of acquired neutropenia are complex, but most are related to three major categories: infection, drugs (both direct toxic or immune mediated), and autoimmune. Chronic benign neutropenia, or chronic idiopathic neutropenia, appears to be an overlap disorder with hereditary and acquired forms, and is sometimes indistinguishable. Some neutropenic patients give a clear history and familial pattern, whereas others have no familial history, few blood test determinations, and an unknown duration of neutropenia. This group of patients could have hereditary or acquired neutropenia. ^[1] A brief summary of both congenital and acquired neutropenic disorders follows.

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. ^[21] 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. ^[21] Life-threatening infections occur that are refractory to granulocyte colony-stimulating factor (G-CSF). ^{[22, 23, 24]} Bone marrow transplantation is the treatment of choice.

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. ^[25] 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, but 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.

Affected individuals with chronic benign neutropenia have an overall low risk of infection.

Familial chronic benign neutropenia is a disorder with an autosomal dominant pattern of inheritance observed in western Europeans, Africans, and Jewish Yemenites. Patients are typically asymptomatic, and the infections are mild. No specific therapy is required.

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

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. ^[26] 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.

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

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

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.

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

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

Other medications have been implicated

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:

Crohn disease

Rheumatoid arthritis (with or without Felty syndrome)

Sjögren syndrome

Chronic, autoimmune hepatitis

Hodgkin lymphoma

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. Staphylococcus aureus organisms are found 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 deficiencies that can cause neutropenia include vitamin B-12, folate, and copper deficiency.

Numerous drugs have been associated with neutropenia. The highest risk categories are 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 and 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. ^[27]

Analgesics and anti-inflammatory agents include aminopyrine, dipyrone, indomethacin, ibuprofen, acetylsalicylic acid, diflunisal, sulindac, tolmetin, benoxaprofen, barbiturates, mesalazine, and quinine.

Antipsychotics, antidepressants, and neuropharmacologic agents include phenothiazines (chlorpromazine, methylpromazine, mepazine, promazine, thioridazine, prochlorperazine, trifluoperazine, trimeprazine), clozapine, risperidone, imipramine, desipramine, diazepam, chlordiazepoxide, amoxapine, meprobamate, thiothixene, and haloperidol.

Anticonvulsants include valproic acid, phenytoin, trimethadione, mephenytoin (Mesantoin), ethosuximide, and carbamazepine.

Antithyroid drugs include thiouracil, propylthiouracil, methimazole, carbimazole, potassium perchlorate, and thiocyanate.

Cardiovascular drugs include procainamide, captopril, aprindine, propranolol, hydralazine, methyldopa, quinidine, diazoxide, nifedipine, propafenone, ticlopidine, and vesnarinone.

Antihistamines include cimetidine, ranitidine, tripelennamine (Pyribenzamine), methaphenilene, thenalidine, brompheniramine, and mianserin.

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

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

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

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 may be associated with the following:

Acute bacterial infection

Glucocorticoid administration

Hypogammaglobulinemia

Physical stress

Thymoma

Decreased circulating basophils may be associated with the following:

Anaphylaxis

Acute infection

Drug-induced hypersensitivity

Congenital absence of basophils

Hemorrhage

Hyperthyroidism

Ionizing radiation

Neoplasia

Ovulation

Urticaria

Drugs (eg, corticosteroid, adrenocorticotropic hormone [ACTH] therapy, chemotherapeutic agents, thyroid hormones)

Go to Pediatric Autoimmune and Chronic Benign 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. ^[28]

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 has a short length of stay; the majority had no serious infections, with viral infection or upper respiratory infection being the most common. ^[29]

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. ^[20] Go to Pediatric Autoimmune and Chronic Benign Neutropenia for complete information on this topic.

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.

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. ^[30] 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. ^[31] 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%. ^[31]

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. ^{[24, 32, 33]} 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 inhospital 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. ^[34]

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

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. ^[35]

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.

Patients with neutropenia should be instructed to avoid exposure to people with respiratory tract infections. ^[36] 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 the Blood and Lymphatic System Center and Immune System Center, as well as Anemia, Sepsis (Blood Infection), Leukemia, and Lymphoma.

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Syndrome

Inheritance

Gene

Clinical Features

Cyclic neutropenia

Autosomal dominant

ELA2

Alternate 21-day cycling of neutrophils and monocytes

Kostmann syndrome

Autosomal recessive

Unknown

Stable neutropenia, no MDS or AML

Severe congenital neutropenia

Autosomal dominant

ELA2 (35-84%)

Stable neutropenia, MDS or AML

Autosomal dominant

GFI1

Stable neutropenia, circulating myeloid progenitors, lymphopenia

Sex linked

Wasp

Neutropenic variant of Wiskott-Aldrich syndrome

Autosomal dominant

G-CSFR

G-CSF–refractory neutropenia, no AML or MDS

Hermansky-Pudlak syndrome type 2

Autosomal recessive

AP3B1

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

Chediak-Higashi syndrome

Autosomal recessive

LYST

Neutropenia, oculocutaneous albinism, giant lysosomes, impaired platelet function

Barth syndrome

Sex linked

TAZ

Neutropenia, often cyclic; cardiomyopathy, methylglutaconic aciduria

Cohen syndrome

Autosomal recessive

COH1

Neutropenia, mental retardation, dysmorphism

Source: Modified from Berliner et al, 2004. ^[20]

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

Christopher D Braden, DO Hematologist/Oncologist, Chancellor Center for Oncology at Deaconess Hospital; Medical Director, Deaconess Hospital Outpatient Infusion Centers; Chairman, Deaconess Hospital Cancer Committee

Christopher D Braden, DO is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College

Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology

Disclosure: Received honoraria from Novartis for speaking and teaching; Received consulting fee from Novartis for speaking and teaching; Received honoraria from Celgene for speaking and teaching.

Ariel Distenfeld, MD Clinical Professor, Department of Medicine, New York University School of Medicine

Disclosure: Nothing to disclose.

John E Godwin, MD, MS Professor of Medicine, Chief Division of Hematology/Oncology, Associate Director, Simmons Cooper Cancer Institute, Southern Illinois University School of Medicine

John E Godwin, MD, MS is a member of the following medical societies: American Association for the Advancement of Science, American Heart Association, and American Society of Hematology

Disclosure: Nothing to disclose.

Kush Sachdeva, MD Southern Oncology and Hematology Associates, South Jersey Healthcare, Fox Chase Cancer Center Partner

Disclosure: Nothing to disclose.

Neutropenia

Research & References of Neutropenia|A&C Accounting And Tax Services
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