Neutropenia 

Updated: Sep 18, 2018
Author: Christopher D Braden, DO; Chief Editor: Emmanuel C Besa, MD 

Overview

Practice Essentials

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.

Anteroposterior chest radiograph in a young ED pat Anteroposterior chest radiograph in a young ED patient presenting with cough and malaise. The radiograph shows a classic posterior segment right upper lobe density consistent with active tuberculosis. This woman was admitted to isolation and started empirically on a 4-drug regimen in the ED. Tuberculosis was confirmed on sputum testing. Image courtesy of Remote Medicine, remotemedicine.org.

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 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.

Diagnosis

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.

Management

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.

Background

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.

Pathophysiology

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.

Etiology

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.

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.[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.

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.[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.

Chronic benign neutropenia

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

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.[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

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

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 neutropenia caused by intrinsic bone marrow disease

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

  • 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.

Acquired neutropenia caused by infection

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

    Bilateral interstitial infiltrates in a 31-year-ol Bilateral interstitial infiltrates in a 31-year-old patient with influenza pneumonia.
    Anteroposterior chest radiograph in a young ED pat Anteroposterior chest radiograph in a young ED patient presenting with cough and malaise. The radiograph shows a classic posterior segment right upper lobe density consistent with active tuberculosis. This woman was admitted to isolation and started empirically on a 4-drug regimen in the ED. Tuberculosis was confirmed on sputum testing. Image courtesy of Remote Medicine, remotemedicine.org.
    Lateral chest radiograph in a 31-year-old patient Lateral chest radiograph in a 31-year-old patient with influenza pneumonia. Image courtesy of Remote Medicine, remotemedicine.org.

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.

Acquired neutropenia caused by nutritional deficiency

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

Acquired neutropenia caused by drugs and chemicals, excluding cytotoxic chemotherapy

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

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 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 and basophilopenia

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.

Epidemiology

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 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.[20] 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.[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.

Prognosis

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:

  • 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.[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.

Patient Education

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.

 

Presentation

History

Patients with neutropenia often present with infection. Other sequelae may reflect concurrent pancytopenia, such as anemic symptoms (eg, fatigue, weakness, dyspnea on exertion) and manifestations of thrombocytopenia (eg, petechiae, purpura, epistaxis). For further information on pancytopenia, refer to Bone Marrow Failure.

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 in swallowing

Determine if a fever is present, because the physician must be aware of a possible life-threatening infection. Obtaining a history of infections may aid in the current diagnostic workup. A history of periodically recurring infections is suggestive of cyclic neutropenia. A strong family history of recurrent infections, usually beginning in childhood, is strongly indicative of a genetic defect. Congenital neutropenia is suggested by a personal history of lifelong infections, family history of recurrent infections, documentation of longstanding neutropenia since childhood or adolescence, and absence of any other blood abnormality.

A family history of infections or sudden death may be an indication of inherited disorders. The maternal medical history (in neonatal neutropenia) may indicate inherited disorders or adverse effects of maternal medications. Records of past complete blood counts (CBCs) establish the chronicity of the neutropenia. Determining the age at onset aids in the differential diagnosis.

A patient with agranulocytosis may have experienced a recent viral infection, although such infections are rarely associated with severe neutropenia. Certain bacterial infections may also precede agranulocytosis.

Chronic, benign familial neutropenia is suggested by a history of long-standing neutropenia without an increased risk of infection. These patients do not generate increased leukocyte counts with infection, but they have fevers and other symptoms, such as tachycardia, when infected.

A history of autoimmune diseases may be associated with antineutrophil antibodies. Such antibodies may also be the only manifestation of autoimmune disease. A number of test methods are available, but none is widely used.

Primary immune neutropenia is uncommon. Secondary immune neutropenia may be associated with systemic lupus erythematosus, rheumatoid arthritis, and Felty syndrome.[2, 37, 11]

Obtaining a careful drug history may reveal the offending agent and spare the patient from an extensive diagnostic workup. Patients often report a history of a new drug being used or a recent change in medication. However, the offending medication may no longer be in use; therefore, the inquiry should extend back for some time. A history of occupational or accidental exposure to chemicals or physical agents (eg, ionizing radiation) may be noted.[38, 39]

If treatment is not promptly instituted, the infection progresses to generalized sepsis, which may become life threatening.

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

Physical Examination

Physical examination of a patient with neutropenia should focus on finding signs of an infection. The skin examination focuses on rashes, ulcers, or abscesses. The oral mucosa examination assesses for aphthous ulcers, thrush, or periodontal disease. Lymphadenopathy is a possible indication of a disseminated infection or, possibly, malignancy. For perirectal infections, look for abscesses or mucous membrane abnormalities. For perineal infections, look for rashes, abscesses, or lymphadenopathy. 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

  • Splenomegaly (see the image below)

  • Associated petechial bleeding

  • Perirectal infection

  • Growth retardation in children

    The margins of this massive spleen were palpated e The margins of this massive spleen were palpated easily preoperatively. Medially, the 3.18-kg (7-lb) spleen crosses the midline. Inferiorly, it extends into the pelvis.

Febrile neutropenia is defined as a single oral temperature measurement of ≥38.3° C (101° F) or a temperature of ≥38.0° C (100.4° F) sustained over 1 hour.[10] In agranulocytosis, fever may be 40°C or higher. Rapid pulse and respiration may be evident. Hypotension and signs of septic shock may be apparent if infection has been present. Painful aphthous ulcers may be found in the oral cavity. Swollen and tender gums may be present. Usually, purulent discharge is not present, because not enough neutrophils exist to form pus. Skin infections are associated with painful swelling, but erythema and suppuration are usually absent.

 

DDx

Diagnostic Considerations

Other conditions to be considered include the following:

  • Large granular lymphocyte leukemia

  • Autoimmune diseases

  • Chronic myelomonocytic leukemia

  • Congenital neutropenia

  • Cyclic neutropenia

  • Drug-induced neutropenia

  • Large granular lymphocytic leukemia

  • Pseudoneutropenia

Obtain a detailed history in patients with neutropenia or agranulocytosis, with particular emphasis on medication use. The inquiry must extend back in time to include discontinued medications. Over-the-counter drugs must be included in the inquiry, because patients often do not consider these agents to be medications. Any possible occupational or accidental exposure to toxic chemicals or physical agents must be excluded. Agranulocytosis should be differentiated from other syndromes of bone-marrow failure, including pancytopenia and aplastic anemia. Leukemia should be excluded.

Differential Diagnoses

 

Workup

Approach Considerations

The workup for neutropenia may include blood and urine studies, diagnostic imaging, and bone marrow aspiration and biopsy. Hospital protocols indicate expediting the first dose of antibiotics in patients with neutropenic fever, which helps improve the prognosis for the patient.

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

Lab Studies

Before initiating a major workup, rule out infections and drugs as causes of neutropenia. Then obtain the following laboratory studies:

  • Complete blood cell count (CBC), including a manual differential in evaluating cases of agranulocytosis

  • Differential white blood cell (WBC) count

  • Peripheral blood smear, with review by pathologist

A Wright-stained peripheral smear will show a marked decrease or absence of neutrophils. In addition, careful evaluation of the peripheral blood smear provides information about red blood cell (RBC) and platelet morphology; associated anemia and/or thrombocytopenia and the presence of immature leukocyte precursors on peripheral smear suggest a hematologic malignancy. Abnormal lymphocytes could suggest T-cell clonal large granular lymphocytic leukemia.

The following studies are applicable in some patients with neutropenia:

  • Antinuclear antibody (ANA)

  • Rheumatoid factor (RF)

  • Serum immunoglobulin (Ig) studies

  • Liver function tests (LFTs)

  • Peripheral blood flow cytometry

  • T-cell gene rearrangement for T-cell clonality

  • Testing for paroxysmal nocturnal hemoglobinuria with high-sensitivity or fluorescent aerolysin (FLAER)–based flow cytometry

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 the agranulocytosis. Various methods for detecting antineutrophil autoantibodies have different limitations; therefore, more than one assay method is recommended. In addition, data are limited on false-negative results, and, thus, only a positive test is likely meaningful.

In congenital neutropenia and cyclic neutropenia, genetic analysis should be done to correctly classify the condition.

Obtain vitamin B-12 and folate levels to evaluate for nutritional deficiency and pernicious anemia in individuals with neutropenia.

Perform HIV testing if clinical risk factors are present.

Imaging Studies

No specific imaging study establishes the diagnosis of agranulocytosis. As part of the workup for localization of infection, appropriate radiographs (eg, chest images) are indicated. Other imaging studies are determined by the specific circumstances of each case.

Perform long-bone radiographs if a form of congenital neutropenia is suspected. If the neutropenic patient is febrile, obtain a posterior-anterior and lateral chest radiograph to assess for signs of pneumonia.

Obtain liver-spleen radionuclide scans if the presence of splenomegaly and splenic sequestration are suspected in a patient with neutropenia (see the image below). This study also allows evaluation of hepatocellular function and colloid shift, which occurs when hypersplenism is caused by cirrhosis with portal hypertension.

The margins of this massive spleen were palpated e The margins of this massive spleen were palpated easily preoperatively. Medially, the 3.18-kg (7-lb) spleen crosses the midline. Inferiorly, it extends into the pelvis.

Ultrasonography of the left upper quadrant or computed tomography (CT) scanning could also be done to evaluate splenomegaly (see the image below).

Doppler sonogram at the splenic hilum reveals hepa Doppler sonogram at the splenic hilum reveals hepatofugal venous flow in a patient with portal hypertension.

Fever/Infection Workup

If a patient with neutropenia presents with fever, perform an infection workup, including blood cultures for anaerobic and aerobic organisms. Obtain two sets of blood culture samples, 10-15 minutes apart, from peripheral veins; obtain samples from each port of a catheter if the patient has central venous access.

Other laboratory studies used for a complete fever workup include the following:

  • Urinalysis

  • Urine culture and sensitivity

  • Culture of wound or catheter discharge

  • Sputum Gram stain and culture

  • Stool for Clostridium difficile

  • Skin biopsy, if new erythematous and tender skin lesions are present

Broad-spectrum antibiotics should be started within 1 hour of cultures.

Bone Marrow Aspiration and Biopsy

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. In suspected drug-induced neutropenia, a bone marrow examination may be elected early or delayed based on the clinical stability of the patient and considerations for the use of myeloid growth factors.

Bone marrow biopsy assesses for an intrinsic marrow defect, maturation arrest, congenital neutropenia, fungal infection, and a vitamin B-12 or folate deficiency. It helps to exclude metastatic carcinoma, lymphoma, granulomatous infection, and myelofibrosis. If mycobacterial or fungal infection is suspected, the aspirate can be cultured.

Examine bone marrow smears and biopsy samples with techniques including flow cytometry. The bone marrow may show myeloid hypoplasia or absence of myeloid precursors. In many cases, the bone marrow is cellular with a maturation arrest at the promyelocyte, myelocyte, or even band neutrophil stage of maturation. This latter finding is common in drug-induced and immune neutropenias, as the destruction may be selective of the more mature neutrophils only. On occasion, the marrow may be hypercellular.

 

Treatment

Approach Considerations

Medical care for patients with neutropenia is mostly supportive and based on the etiology, severity, and duration of the neutropenia. Fever and infections occurring as complications of neutropenia require specific treatment. Surgical care is not usually indicated but may be employed in certain contexts.

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

General Care

General measures to be taken include the following:

  • Removal of any offending drugs or agents is the most important step in most 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; control oral and gingival lesion pain with saline and hydrogen peroxide rinses and local anesthetic gels and gargles

  • 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

Antibiotic Therapy

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

  • Cefepime, a carbapenem (eg, meropenem or imipenem-cilastatin), or piperacillin-tazobactam can be used as a single agent

  • Agents from other antimicrobial classes (eg, aminoglycosides, fluoroquinolones, vancomycin) may be added for management of complications (eg, hypotension and pneumonia) or antimicrobial resistance (suspected or proven)

With blood culture results suspicious for resistant bacteria, early addition of the following antimicrobials may be considered:

  • Methicillin-resistant Staphylococcus aureus (MRSA) - Vancomycin, linezolid, or, in the absence of evidence for pneumonia, daptomycin

  • Vancomycin-resistant enterococcus (VRE) - Linezolid or daptomycin

  • Extended-spectrum β-lactamase (ESBL)–producing gram-negative bacteria - A carbapenem

  • Carbapenemase-producing organisms, including Klebsiella pneumoniae carbapenemase (KPC) - Polymyxin-colistin or tigecycline, or a newer β-lactam with activity against resistant gram-negative organisms as a less toxic and potentially more effective alternative

If the neutropenic patient’s fever does not respond within 4-5 days or if the fever recurs with the administration of broad-spectrum antibiotics after an initial afebrile interval, consider adding empiric antifungal coverage with amphotericin B (preferably lipid formulation), a broad-spectrum azole (eg, voriconazole), or an echinocandin (eg, caspofungin)

Fever in patients with low-risk neutropenia can be treated on an outpatient basis with oral antibiotics. Fluoroquinolones (eg, ciprofloxacin, ofloxacin) are oral antibiotics that are used frequently, either alone or in combination with amoxicillin-clavulanate or clindamycin. In some studies, patients are defined as being at low risk if they have all the following:

  • Known cause of neutropenia
  • Hemodynamic stability
  • Expected duration of neutropenia of less than 7 days
  • Tumor is under control
  • No comorbid conditions, nausea, vomiting, or mucositis

Colony-Stimulating Factor Therapy

Myeloid growth factors—specifically, granulocyte colony-stimulating factors (G-CSFs) and granulocyte-macrophage colony-stimulating factor (GM-CSFs)—may shorten the duration of neutropenia in patients who have undergone chemotherapy.

G-CSFs are lineage-specific for the production of functionally active neutrophils and can also be used in patients with severe, chronic neutropenia. GM-CSFs stimulate the production of neutrophils, monocytes, and eosinophils. Filgrastim and pegfilgrastim are examples of G-CSFs; sargramostim is an example of a GM-CSF. These agents are typically administered no sooner than 24 hours after chemotherapy completion. Filgrastim is often the agent of choice if a G-CSF is chosen.

The availability of filgrastim has altered the management of agranulocytosis. It has been shown to shorten the period to recovery and the duration of infection when administered before infection is established. This agent is especially indicated in the management of congenital neutropenia, idiopathic severe chronic neutropenia (SCN), and cyclic neutropenia (CN) when serious infections are involved. If the condition is mild, with only neutropenia without a serious infection, filgrastim may be withheld.

Guidelines for use of myeloid growth factors issued by the National Comprehensive Cancer Network (NCCN) include recommendations that address the following areas[40] :

  • Prophylactic use in chemotherapy patients at risk of neutropenia

  • Therapeutic use for acute febrile neutropenia

  • Therapeutic use for severe chronic neutropenia

Prophylactic therapy recommendations in the NCCN guidelines are based on evaluation of the individual’s risk of febrile neutropenia associated with chemotherapy. Risk assessment should take place before the initial cycle of chemotherapy and before each subsequent cycle. Disease type, chemotherapy dose regimen, and patient risk factors should be assessed, and the intention of chemotherapy (curative, life-extending, or symptom management) noted.[40]

Prophylactic use of G-CSF is recommended for patients at high risk (> 20%) of febrile neutropenia. For patients whose treatment is intended to be curative or life-extending, the recommendation is supported by class 1 evidence. CSF therapy may be considered in patients at intermediate risk (10-20%), but the NCCN acknowledges that this is a difficult decision that requires careful discussion with the patient. CSF therapy appears to increase the risk of developing acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), and it is not recommended for patients at low risk (< 10%) of neutropenic fever.[40]

The NCCN guidelines state that there is less evidence for therapeutic use than for prophylactic use. If patients with acute neutropenic fever are receiving prophylactic filgrastim or sargramostim, the CSF treatment should be continued. Pegfilgrastim should be discontinued, as it is long-acting and evidence for its therapeutic benefits is lacking. If the patient is not receiving prophylactic CSF, their risk of infection complications or poor outcome should be assessed. CSF should be considered for patients at high risk.[40]

The NCCN guidelines affirm the effectiveness of G-CSF therapy for SCN, CN, and congenital neutropenia. Patients with cyclic or idiopathic neutropenia appear to benefit at lower doses of G-CSF than those with congenital neutropenia. Patients with severe congenital neutropenia, requiring high doses of G-CSF, seem to be at greater risk of AML and MDS.[40]

An American Society of Clinical Oncology (ASCO) guideline on the use of white blood cell growth factors includes the following strong recommendations based on high-quality evidence[41] :

  • Primary prophylaxis with a CSF, starting with the first chemotherapy cycle and continuing through subsequent cycles, in patients who have an approximately 20% or higher risk for febrile neutropenia
  • Primary CSF prophylaxis in patients receiving dose-dense chemotherapy, when considered appropriate; consideration should be given to alternative, equally effective, and safe chemotherapy regimens not requiring CSF support when available
  • Secondary prophylaxis with a CSF for patients who experienced a neutropenic complication from a prior cycle of chemotherapy (for which primary prophylaxis was not received), in which a reduced dose or treatment delay may compromise disease-free or overall survival or treatment outcome (in many clinical situations, dose reduction or delay may be a reasonable alternative)
  • CSFs should not be routinely used for patients with neutropenia who are afebrile.
  • CSFs should not be routinely used as adjunctive treatment with antibiotic therapy for patients with fever and neutropenia. However, CSFs should be considered in patients with fever and neutropenia who are at high risk for infection-associated complications or who have prognostic factors predictive of poor clinical outcomes.
  • Dose-dense regimens with CSF support should be used only if supported by convincing efficacy data or within an appropriately designed clinical trial. Efficacy data support the use of dose-dense chemotherapy in the adjuvant treatment of high-risk breast cancer. Data on the value of dose-dense regimens with CSF support in non-Hodgkin lymphoma are limited and conflicting, and this practice cannot routinely be recommended at this time.
  • CSFs may be used alone, after chemotherapy, or in combination with plerixafor to mobilize peripheral-blood progenitor cells. Choice of mobilization strategy depends in part on type of cancer and type of transplantation.
  • CSFs should be administered after autologous stem-cell transplantation to reduce the duration of severe neutropenia (the guideline also contains a weak recommendation for the administration of CSFs after allogeneic stem-cell transplantation)
  • Pegfilgrastim, pegfilgrastim-jmdb, filgrastim, tbo-filgrastim, and filgrastim-sndz (and other biosimilars, as they become available) can be used for the prevention of treatment-related febrile neutropenia. The choice of agent depends on convenience, cost, and clinical situation.

European guidelines also recommend prophylactic treatment with G-CSFs in patients receiving chemotherapy regimens that pose a high risk of febrile neutropenia.With chemotherapy regimens associated with moderate risk, primary prophylaxis may also be advisable for cases in which patient-related factors increase the overall risk, or to maintain chemotherapy in cases where dose-dense or dose-intense chemotherapy strategies are used because of survival benefits, or reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis.[42]

Primary prophylaxis with biosimilar filgrastim has been shown to be cost-effective.[43]

Granulocyte Transfusion

Neutrophil (granulocyte) transfusions have undergone a cycle of popularity followed by disfavor. These transfusions are accompanied by many complications, including severe febrile reactions. Their use is controversial.

Although disappearing from clinical practice, granulocyte transfusions have some clinical usefulness in treating neonatal sepsis. Their usefulness in adults with neutropenia, in whom adequate increments of WBC counts are difficult to achieve, has not been demonstrated in randomized clinical trials.[44] Granulocyte transfusion could be considered in cases of gram-negative sepsis with no improvement in 24-48 hours.

Other Medical Measures

Other measures that may be taken in the care of the patient with neutropenia include the following:

  • Corticosteroid therapy (potentially effective in immune-mediated neutropenia)

  • Correction of nutritional (eg, cobalamin or folic acid) deficiency if detected

  • In cases caused by heavy metals such as gold, chelation with British anti-Lewisite (dimercaprol)

  • Careful handwashing before and after direct contact with patients with neutropenia

  • Meticulous care of indwelling venous catheters and avoidance of urinary catheters and other invasive maneuvers that violate natural infection barriers

Splenectomy and Other Surgical Procedures

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. Idiopathic autoimmune neutropenia may also respond to immune therapy.[11]

Indwelling central venous catheters should be removed in febrile neutropenic patients if septic thromboembolism is suspected. Other indications for catheter removal include the following:

  • Corynebacterium jeikeium infection

  • Infection with Candida species

  • Polymicrobial infection

  • Persistent fevers

  • Pocket-space abscess

  • Tunnel infections

In general, surgery should be avoided in a patient with neutropenia; however, surgical drainage of abscesses that have pus or watery exudate under pressure may occasionally be lifesaving. Perirectal abscesses and cholecystitis with cholangitis are examples of infections that, if left undrained, lead to polymicrobial sepsis, despite antibiotic therapy.

Dietary Measures

Neutropenic patients should follow the following dietary restrictions:

  • Avoid raw and undercooked meat or well water

  • Commercial fruit juices, beer, milk, and milk products should be pasteurized

  • Aged cheese and cheese-based dressings should not be used

  • Avoid unwashed raw fruits and vegetables; these may contain large numbers of bacteria. All food should be cooked. Fresh flowers should be avoided as well

  • Outdated products and all moldy products should not be consumed

In patients with periodontitis and stomatitis, a soft or full liquid diet is indicated. Spicy and acidic foods should be avoided until recovery is complete.

Consultations

Request a hematology consultation for review of the bone-marrow slides and peripheral blood smears to confirm the diagnosis and to assist in G-CSF dosing and evaluation.

Request an infectious disease consultation for advice and assistance in the selection of appropriate antibiotics, especially in patients with complicated infections or prolonged neutropenic fever that is not responding to standard therapy.

Long-Term Monitoring

Obtain daily CBC counts with manual differential to monitor the neutropenic patient’s recovery from an etiologic agent or to monitor the neutropenia’s response to G-CSF or GM-CSF.

If septic shock occurs, the patient should be transferred to the ICU. Intubation may be required.

 

Medication

Medication Summary

Medications are used to treat fevers or possible infections and to stimulate bone marrow in order to increase the production of neutrophils. Current joint guidelines of the American Society of Clinical Oncology (ASCO) and the Infectious Diseases Society of America (IDSA) recommend that neutropenic cancer patients with fever receiive initial doses of empirical antibacterial therapy within 1 hour of triage and be monitored for ≥4 hours before discharge.[10] Delays in administering the first dose are associated with higher mortality.

The antibiotics of choice are those shown by culture and sensitivity studies to be the most effective for the organism causing the infection. If no causative organism is identified, use empirical broad-spectrum antibiotic coverage. Granulocyte growth factors and general supportive care should also be provided. Cytokines (growth factors) are used to stimulate production of neutrophils by acting on precursor cells.

Antibiotics

Class Summary

Antibiotic therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting.[45]

Imipenem and cilastatin (Primaxin)

Imipenem-cilastatin is a broad-spectrum antibiotic formulation for the treatment of serious infections and neutropenic fever.

Meropenem (Merrem I.V.)

Meropenem is a bactericidal broad-spectrum carbapenem antibiotic that inhibits cell-wall synthesis. It is effective against most gram-positive and gram-negative bacteria. It has slightly increased activity against gram-negative bacteria and slightly decreased activity against staphylococci and streptococci compared to imipenem.

Ceftazidime (Fortaz, Tazicef)

Ceftazidime is a third-generation cephalosporin shown in randomized trials to be a safe alternative to double antibiotic regimens for treating neutropenic fever in patients with cancer. It has broad-spectrum, gram-negative activity. Ceftazidime has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. It arrests bacterial growth by binding to 1 or more penicillin-binding proteins.

Ciprofloxacin (Cipro, Cipro XR)

Ciprofloxacin is a fluoroquinolone with activity against pseudomonads, streptococci, methicillin-resistant S aureus (MRSA), Staphylococcus epidermidis, and most gram-negative organisms, but it has no activity against anaerobes. It inhibits bacterial DNA synthesis and, consequently, growth.

Continue treatment for at least 2 days (7-14 d typical) after signs and symptoms disappear.

Two prospective randomized clinical trials showed that oral antibiotics could be safely substituted for intravenous (IV) antibiotics in low-risk patients with neutropenic fever. Until this finding is validated in large randomized trials, routine outpatient treatment is not recommended. Chemoprophylactic use has shown decreased mortality resulting from aerobic gram-negative bacteria.

Ofloxacin

Ofloxacin is a quinolone antibiotic with a broad spectrum of activity against aerobic bacteria. It binds to DNA-gyrase, promoting the breakage of the double-stranded DNA helix for a bactericidal effect.

Amphotericin B

Amphotericin B is empirically indicated in persistent neutropenic fever after a minimum of 4 d of broad-spectrum antibiotics (eg, imipenem or ceftazidime). It is used for empirical therapy for fungal infections or for documented fungal infections. It is produced by a strain of Streptomyces nodosus and can be fungistatic or fungicidal. Amphotericin B binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak, with subsequent fungal cell death.

Liposomal amphotericin B (AmBisome)

Liposomal amphotericin B was found by a large, multicenter, randomized, double-blind trial to be as effective as standard amphotericin B for empiric treatment of neutropenic fever and showed less breakthrough fungal infections and toxicity.[48]

Amoxicillin-clavulanate (Augmentin, Augmentin XR)

Amoxicillin-clavulanate, a beta-lactam antibiotic with a beta-lactamase inhibitor (clavulanic acid), is the combination used to treat bacteria resistant to beta-lactam antibiotics. Two prospective randomized clinical trials showed that oral antibiotics were safely substituted for IV antibiotics in low-risk patients with neutropenic fever. Until this is validated in large randomized trials, routine outpatient treatment for these patients is not recommended.

Cefepime (Maxipime)

Cefepime is a fourth-generation cephalosporin with good gram-negative coverage. It is used as monotherapy for the treatment of febrile neutropenia. It is similar to third-generation cephalosporins but has better gram-positive coverage.

Vancomycin (Vancocin)

Vancomycin is a potent antibiotic directed against gram-positive organisms and active against Enterococcus species. It is useful in the treatment of septicemia and skin structure infections. Vancomycin is indicated for patients who cannot receive or whose condition has failed to respond to penicillins and cephalosporins or for patients who have infections with resistant staphylococci. For abdominal penetrating injuries, this drug is combined with an agent active against enteric flora and/or anaerobes.

To avoid toxicity, the current recommendation is to assay vancomycin trough levels after the third dose, drawn 0.5 h before the next dosing. Use the creatinine clearance to adjust the dose in patients diagnosed with renal impairment.

Vancomycin is used in conjunction with gentamicin for prophylaxis in penicillin-allergic patients undergoing gastrointestinal or genitourinary procedures.

Gentamicin

Gentamicin is a bactericidal drug that blocks the functioning of the initiation complex and causes misreading of mRNA. Gentamicin or another aminoglycoside should be added to other broad-spectrum antibiotics if the neutropenic patient's condition is unstable or the individual appears septic. Gentamicin is an aminoglycoside antibiotic for gram-negative coverage. It is used in combination with both an agent against gram-positive organisms and one that covers anaerobes.

Gentamicin is not the drug of choice. It should be considered if penicillins or other less toxic drugs are contraindicated, if it is clinically indicated, and if the patient has a mixed infection caused by susceptible staphylococci and gram-negative organisms.

Piperacillin-tazobactam (Zosyn)

Piperacillin is a fourth-generation penicillin that has broad-spectrum coverage with activity against Pseudomonas aeruginosa. Piperacillin interferes with bacterial cell wall synthesis during active multiplication. Tazobactam prevents degradation of piperacillin by binding to the active site on beta lactamase.

Antifungal Agents

Class Summary

Antifungal agents exert their action by inhibiting fungal cell membrane formation or the inhibition of essential components of the cell wall of susceptible fungi.

Voriconazole (VFEND)

Voriconazole is a triazole antifungal agent that inhibits fungal CYP450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis.

Caspofungin (Cancidas)

Caspofungin inhibits synthesis of beta-(1,3)-D-glucan, an essential component of the fungal cell wall.

Hematopoietic Growth Factors

Class Summary

Hematopoietic growth factors are administered to accelerate neutrophil recovery and shorten the duration of neutropenic fever. These agents are also indicated to treat patients with chronic neutropenia. However, although many benefits exist with using hematopoietic growth factors in acute neutropenic fever after chemotherapy, a survival benefit has not been shown.

The FDA approved filgrastim-sndz (Zarxio), the first biosimilar product available in the United States, in March 2015. The approval was based on a phase 3 trial, randomized, double-blind, multicenter study compared the efficacy of filgrastim-sndz and filgrastim in the prevention of neutropenic complications in breast cancer patients treated with myelosuppressive chemotherapy. The study demonstrated that biosimilar and the reference filgrastim are similar with no clinically meaningful differences regarding efficacy and safety in prevention of severe neutropenia. Biosimilar filgrastim could represent an important alternative to the reference product, potentially benefiting public health by increasing access to filgrastim treatment.[46]

FDA also approved Fulphila (pegfilgrastim-jmbd), a biosimilar to pegfilgrastim, to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. The approval was supported by nonclinical and clinical data (including pharmacokinetic, pharmacodynamic, clinical immunogenicity, structural and functional characterization data), which demonstrated Fulphila was highly similar to Neulasta.  

Filgrastim (Neupogen, tbo-filgrastim, Granix, Zarxio, filgrastim-sndz)

Filgrastim is a granulocyte colony-stimulating factor (G-CSF) that activates and stimulates the production, maturation, migration, and cytotoxicity of neutrophils. It has been shown to accelerate neutrophil recovery and shorten the duration of neutropenic fever. Antibiotic treatment duration, amphotericin B use, hospital stay duration, and mortality, however, are unchanged. Filgrastim is most efficacious in severe neutropenia and documented infections.

Sargramostim (Leukine)

Sargramostim is a granulocyte-macrophage colony-stimulating factor (GM-CSF) that is indicated in the acceleration of neutrophil recovery after chemotherapy, the mobilization of autologous peripheral blood progenitor cells, bone marrow transplantation, and the delay or failure of bone marrow transplant engraftment.

Pegfilgrastim (Neulasta, Fulphila, pegfilgrastim-jmbd)

Pegfilgrastim is a long-acting filgrastim created by the covalent conjugate of recombinant G-CSF (ie, filgrastim) and monomethoxypolyethylene glycol. Like filgrastim, it acts on hematopoietic cells by binding to specific cell surface receptors, thereby activating and stimulating the production, maturation, migration, and cytotoxicity of neutrophils. Although no clinically meaningful differences in safety, purity, and potency between the biosimilar product and Neulasta were noted, pegfilgrastim-jmbd has not been approved as an interchangeable product.

 

Questions & Answers

Overview

What is neutropenia?

What are the signs and symptoms of neutropenia?

What are the signs and symptoms of agranulocytosis?

Which physical findings are characteristic of neutropenia?

Which physical findings are characteristic of agranulocytosis?

Which lab tests are performed in the workup of neutropenia?

When is bone marrow aspiration indicated in the diagnostic workup of neutropenia?

How is neutropenia treated?

What is the role of antibiotic therapy in the treatment of neutropenia?

What are the ASCO/ISDA treatment guidelines for neutropenia?

What is the role of splenectomy in the treatment of neutropenia?

What is neutropenia?

How is neutropenia classified?

What is the pathophysiology of neutropenia?

What is the pathogenesis of neutropenia?

What is the role of infection in the pathophysiology of neutropenia?

What causes neutropenia?

What are the genetic causes of neutropenia?

What causes acquired neutropenia?

What causes congenital neutropenia with associated immune defects?

What is severe congenital neutropenia (SCN) (Kostmann syndrome)?

What is chronic benign neutropenia?

What is idiopathic chronic severe neutropenia?

Which phenotypic abnormalities are associated with neutropenia?

What is myelokathexis?

What is lazy leukocyte syndrome?

Which metabolic disorders are associated with neutropenia?

Which bone marrow diseases cause neutropenia?

Which medications cause drug immune-mediated neutropenia?

What causes autoimmune neutropenia?

What is isoimmune neonatal neutropenia?

What causes chronic autoimmune neutropenia and how is it treated?

What is T-gamma lymphocytosis neutropenia?

Which infections may cause neutropenia?

Which nutritional deficiencies cause neutropenia?

Which medications cause neutropenia?

What causes immunologic neutropenia?

Which conditions are associated with eosinopenia?

Which conditions are associated with basophilopenia?

What is the prevalence of neutropenia?

Which age groups have the highest prevalence of neutropenia?

What are the sexual predilections of neutropenia?

What are the racial predilections of neutropenia?

What is the prognosis of neutropenia?

What is the prognosis of neutropenia in persons with cancer?

What is the prognosis of agranulocytosis?

What is included in patient education about neutropenia?

Where can patient education resources about neutropenia be found?

Presentation

What are the signs and symptoms of neutropenia?

What are the signs and symptoms of agranulocytosis?

What is the focus of the clinical history for neutropenia?

What is included in the physical exam for evaluation of neutropenia?

Which physical findings are characteristic of neutropenia?

How is febrile neutropenia defined?

DDX

Which conditions should be included in the differential diagnoses of neutropenia?

What are the differential diagnoses for Neutropenia?

Workup

Which tests are performed in the workup of neutropenia?

Which lab tests are performed in the workup of neutropenia?

What is the role of Wright-stained peripheral smear in the diagnosis of neutropenia?

Which lab tests may be useful in the evaluation of neutropenia?

What is the role of antineutrophil antibody testing in the diagnosis of neutropenia?

What is the role of imaging studies in the evaluation of neutropenia?

What is included in the workup of fever in patients with neutropenia?

What is the role of bone marrow aspiration and biopsy in the diagnosis of neutropenia?

Treatment

How is neutropenia treated?

Which supportive measures should be taken in patients with neutropenia?

Which antibiotics are used to treat fever in neutropenia?

Which antimicrobials are used to treat resistant infections in neutropenia?

How is fever treated in low-risk neutropenia?

What is the role of colony-stimulating factor therapy in the treatment of neutropenia?

What are the NCCN guidelines for use of myeloid growth factors in the treatment of neutropenia?

What are the ASCO guidelines for the use of white blood cell growth factors in the treatment of neutropenia?

What are the European guidelines for use of G-CSFs in the treatment of neutropenia?

What is the role of granulocyte transfusion in the treatment of neutropenia?

What supportive treatments may be beneficial to patients with neutropenia?

What is the role of splenectomy in the treatment of neutropenia?

When is catheter removal indicated in the treatment of neutropenia?

What dietary measures are indicated in patients with neutropenia?

Which specialist consultations are beneficial to patients with neutropenia?

What is included in the long-term monitoring of neutropenia?

Medications

What is the role of medications in the treatment of neutropenia?

Which medications in the drug class Hematopoietic Growth Factors are used in the treatment of Neutropenia?

Which medications in the drug class Antifungal Agents are used in the treatment of Neutropenia?

Which medications in the drug class Antibiotics are used in the treatment of Neutropenia?