Neutropenia is a decrease in circulating (ie, nonmarginal) neutrophils in the blood.[1] The nonmarginal pool constitutes only 4-5% of total body neutrophil stores; most of the neutrophils in the body are contained in the bone marrow, either as mitotically active (one-third) or postmitotic mature cells (two-thirds).[2] Granulocytopenia is defined as a reduced number of blood granulocytes, namely neutrophils, eosinophils, and basophils. However, the term granulocytopenia is often used synonymously with neutropenia and, in that sense, is again confined to the neutrophil lineage alone.
A common reference range for the absolute neutrophil count (ANC), which is calculated based on the percentage of neutrophils in the white blood cell count (see the Absolute Neutrophil Count calculator) is 2500-8000/µL. The formula for calculating ANC is ANC = WBC (cells/μL) × [percent (PMNs + bands) ÷ 100]. Because neutrophils play a vital role in protecting against infection, the duration and severity of neutropenia directly correlates with the total incidence of all infections, including those that are life-threatening.
The risk of opportunistic infection increases as the ANC falls below 1500/μL, and the risk of serious infection increases as the ANC falls to the severely neutropenic range (< 500/µL). Vulnerability to infection is extremely high in patients with agranulocytosis, which is the virtual absence of neutrophils in peripheral blood, with ANC typically lower than 100/μL.
Neutropenia has a wide range of causes, both hereditary and acquired (see Etiology).[3] Principal causes of acquired neutropenia are infection, drugs (through direct toxicity or immune effects), and autoimmunity.
Signs and symptoms
Common presenting manifestations 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, irritation, and infection of the genital areas
Patients with severe agranulocytosis usually present with the following:
Sudden onset of malaise
Sudden onset of fever, possibly with chills and prostration
Stomatitis and periodontitis accompanied by pain
Pharyngitis, with difficulty swallowing
Physical findings on examination of a patient with neutropenia may include the following:
Fever
Stomatitis
Periodontal infection
Cervical lymphadenopathy
Skin infection: The skin examination focuses on rashes, ulcers, or abscesses
Splenomegaly
Associated petechial bleeding
Perirectal or genital infections
Growth retardation in children
In agranulocytosis, the following may be present:
Fever (often 40°C or higher)
Rapid pulse and respiration
Hypotension and signs of septic shock
Painful aphthous ulcers in the oral cavity
Swollen and tender gums
See Presentation for more detail.
Diagnosis
Before undertaking a major workup, conduct a thorough history and physical examination, ruling out infectious and drug-related causes of neutropenia, and then obtain the following laboratory studies:
Complete blood count, including a manual differential in cases of agranulocytosis
Differential white blood cell count
Peripheral smear, with review by a pathologist
Blood cultures (at least two sets with a set collected simultaneously from each lumen of an existing central venous catheter (CVC), if present, and from a peripheral vein site)
Serum creatinine and blood urea nitrogen
Electrolytes
Hepatic transaminase enzymes and total bilirubin, screening for viral hepatitis and HIV infection
Vitamin B12, folate, and copper levels
The following studies are applicable in some patients with neutropenia:
Antinuclear antibody
Rheumatoid factor
Serum immunoglobulin studies[4]
Peripheral blood flow cytometry
T-cell gene rearrangement for T-cell clonality
Paroxysmal nocturnal hemoglobinuria testing: By high-sensitivity or fluorescent aerolysin (FLAER)–based flow cytometry
Antineutrophil antibodies: Tests for antineutrophil antibodies should be performed in patients with a history suggestive of autoimmune neutropenia and patients with unexplained 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 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:
Discontinue any offending drugs or agents; if the identity of the causative agent is not known, stop administration of all drugs that are associated with idiosyncratic reactions, if clinically feasible, until the etiology is established
Have patients use careful oral hygiene to prevent infections of the mucosa and teeth
Avoid rectal temperature measurements and rectal examinations
Administer stool softeners for constipation
Use proper skin care for wounds and abrasions; skin infections should be managed by personnel with experience in the treatment of infection in neutropenic patients
Antibiotics
Start specific antibiotic therapy to combat infections. Options are as follows[5, 6, 7, 8, 9, 10] :
Cefepime, meropenem, imipenem-cilastatin, or piperacillin-tazobactam can be used empirically as a single agent
Gentamicin or another aminoglycoside should be added in patients whose condition is unstable or who appear septic
Vancomycin should be added if infection with methicillin-resistant Staphylococcus aureus (MRSA) or a Corynebacterium species is suspected
A joint guideline from the American Society of Clinical Oncology (ASCO) and Infectious Diseases Society of America (ISDA) recommends antibacterial and antifungal prophylaxis for patients who are at high risk of infection, including patients who are expected to have profound, protracted neutropenia, which is defined as less than 100 neutrophils/µL for more than 7 days. The guideline states that the preferable agent for antibacterial prophylaxis is an oral fluoroquinolone, while that for antifungal prophylaxis is an oral triazole or parenteral echinocandin.[11]
A companion ASCO/IDSA guideline contains recommendations on outpatient management of fever and neutropenia in patients with cancer. The guideline recommends using clinical judgment and the Multinational Association for Supportive Care in Cancer (MASCC) scoring system or Talcott's rules to identify patients who may be candidates for outpatient management. In patients with solid tumors who have undergone mild- to moderate-intensity chemotherapy, who appear to be clinically stable, and who are in close proximity to an appropriate medical facility that can provide 24-hour access, the Clinical Index of Stable Febrile Neutropenia (CISNE) may be used as an additional tool to determine the risk of major complications.[5]
Colony-stimulating factors
Hematopoietic growth factors can be given to accelerate neutrophil recovery and shorten the duration of neutropenic fever; they are also used in the treatment of chronic neutropenia. Such agents include the following:
Filgrastim
Sargramostim
Pegfilgrastim
Eflapegrastim
Efbemalenograstim
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. Neutropenia associated with systemic lupus erythematosus is typically mild, but severe or even life-threatening neutropenia may occur; treatment with splenectomy has been reported in severe cases, but colony-stimulating factors are more often used.[12]
Neutrophils are myeloid leukocytes that play an important role in innate immunity. These cells are the initial host defense against numerous pathogens, including bacteria, fungi, and protozoa.
Neutrophils are multi-functional cells, utilizing several mechanisms to combat invading organisms. They act as robust phagocytes, engulfing microbes following opsonization. They also contain several types of cytoplasmic granules that aid them in killing pathogens. Finally, neutrophils can destroy pathogens by creating neutrophil extracellular traps (NETs). Neutrophils form NETS by expelling their DNA into a weblike configuration covered with antimicrobial molecules, neutrophil proteases, and other toxic molecules. These NETs trap invading microorganisms and destroy them.[13]
Neutropenia is defined as a decrease in circulating neutrophils. Only about 4-5% of total body neutrophil stores are contained in the central pool; most neutrophils are in the bone marrow.[12, 14]
Neutropenia is defined in terms of the absolute neutrophil count (ANC). The ANC is calculated by multiplying the total white blood cell (WBC) count by the percentage of neutrophils (segmented neutrophils or granulocytes) plus the immature (band) forms of neutrophils in the complete blood cell count (CBC) differential. See the Absolute Neutrophil Count calculator.
Note that many modern automated instruments calculate and provide the ANC in their reports. These instruments do not analyze bands separately from more mature segmented neutrophils, so the combined number represents both bands and segmented neutrophils. If a band number is reported separately, usually by smear review, then one can divide the ANC into bands and segmented neutrophils by subtracting the absolute band number from the total ANC.
The lower limit of the reference value for ANC in adults varies in different laboratories from 1.5-1.8 109/L or 1500-1800/µL (mm3). For practical purposes, a value lower than 1500 cells/µL is generally used to define neutropenia in adults and children greater than 1 year of age. Age, race, genetic background, environment, and other factors can influence the neutrophil count. For example, people of African descent may have a lower but normal ANC value of 1000 cells/µL, with a normal total WBC count.
Neutropenia is classified as mild, moderate, or severe, based on the ANC, as follows:
Mild neutropenia: ANC 1000-1500 cells/µL
Moderate neutropenia: ANC 500-1000/µL
Severe neutropenia: ANC < 500 cells/µL
The risk of bacterial infection increases as the severity of neutropenia increases and is also dependent on the duration.
The term agranulocytosis is used to describe a more severe subset of neutropenia. Agranulocytosis refers to a virtual absence of neutrophils in peripheral blood. In these cases, the ANC is typically lower than 100/μL.[14, 15, 16, 17] The reduced number of neutrophils makes patients more prone to infection.[14, 18] Cardinal signs include fever, sepsis, and other manifestations of infection. Causes can include drugs, chemicals, infective agents, ionizing radiation, immune mechanisms, primary bone marrow failure syndromes, and heritable genetic aberrations.
Some cases, including benign familial neutropenia (see Pediatric Autoimmune Neutropenia), are characterized by only mild neutropenia and do not have an increased propensity to acquire infections as neutrophils can be mobilized from the reserves when required.[14] This article is limited to discussing neutropenia (ANC < 1500/µL) and agranulocytosis (ANC < 100/µL). It does not address the transient neutropenia associated with cancer chemotherapy (for that, see Antimicrobial Agents in Neutropenic Cancer Patients), nor does it consider agranulocytosis occurring as part of primary marrow-failure syndromes (eg, aplastic anemia, pancytopenia, acute leukemia, myelodysplastic syndromes).
Neutrophils are produced by precursors in the bone marrow. The total body neutrophil content can be divided conceptually into three compartments: the bone marrow, the blood, and the tissues. In the marrow, the neutrophils exist in two divisions: the proliferative, or mitotic compartment (myeloblasts, promyelocytes, myelocytes) and the maturation-storage compartment (metamyelocytes, bands, mature neutrophils, polymorphonuclear leukocytes ["polys"]).
Mature neutrophils leave the marrow storage compartment and enter the blood without reentry into the marrow. In the blood, two compartments are also present, the marginal compartment and the circulating compartment. Approximately half of the total neutrophils in the blood compartment belong in the marginal compartment, these neutrophils do not circulate freely but are adherent to the vascular surface.
Neutrophils randomly leave the blood pool and enter the tissues, where they are destined for cellular action or death. Typically, neutrophils have a lifespan of about 6-8 hours. However, their longevity can increase profoundly during an acute infection. [19]
Neutropenia can involve any of the three compartments or their subcomponents: bone marrow (mitotic or mature storage pools); blood (circulating and marginal pools); or tissues (sequestration). For example, in benign congenital neutropenias, only the pool of circulating neutrophils is decreased; affected individuals have entirely normal marrow pools, marginal blood pools, and tissue neutrophils.
Neutropenia can be caused by any of the following, alone or in combination:
Insufficient or injured bone marrow stem cells
Shifts in neutrophils from the circulating pool to the marginal blood or tissue pools
Increased destruction in the circulation
Intravascular stimulation of neutrophils by plasma-activated complement 5 (C5a) and endotoxin may cause increased margination along the vascular endothelium, decreasing the number of circulating neutrophils. Pseudoneutropenia refers to neutropenia caused by increased margination.[1, 2, 20, 21, 22]
Disorders of the pluripotent myeloid stem cells and committed myeloid progenitor cells, which cause decreased neutrophil production, include some congenital forms of neutropenia, aplastic anemia, acute leukemia, and myelodysplastic syndromes. Other examples include bone marrow tumor infiltration, radiation, infection (especially viral), and bone marrow fibrosis. Cancer chemotherapy, other drugs, and toxins may damage hematopoietic precursors by directly affecting bone marrow.
The clinical sequelae of neutropenia usually manifest 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 can also be affected. However, the usual clinical signs of infection, including local warmth and swelling, may be absent, as these require the presence of significant numbers of neutrophils. Fever, however, is often present, and requires urgent attention in the setting of severe neutropenia.
The risk of serious infection increases as the ANC falls to the severely neutropenic range (< 500/µL). The duration and severity of neutropenia directly correlate with the total incidence of infection. 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 infections in neutropenic patients. Gram-negative aerobic bacteria (eg, Escherichia coli, Klebsiella species, Pseudomonas aeruginosa) have been the most common organisms causing infections in these patients. However, gram-positive cocci, especially Staphylococcus species and Streptococcus viridans, have emerged as the most common pathogens causing 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 these settings.
The list for all the potential causes of neutropenia is extensive. The etiology of neutropenia can conceptually be viewed in two broad ways, by mechanism or etiologic category.
The mechanisms that cause neutropenia are varied and not completely understood. In many cases, neutropenia occurs after prolonged exposure to a drug or other substance, resulting in decreased neutrophil production by hypoplastic bone marrow. This suggests a direct stem cell toxic effect. In other cases, repeated but intermittent drug or other exposure is needed. This suggests an immune mechanism, although this idea has not been proven. In many clinical situations, the exact exposure and its duration in relation to the onset of neutropenia are not known.
In view of this incomplete understanding of the mechanisms for neutropenia, classification by broad etiologic category is simpler to retain. In this schema, the etiology of neutropenia can be classified as either congenital (hereditary) or acquired.
Hereditary neutropenias
The Table below lists some of the genetic conditions that can lead to neutropenia. Of note, these syndromes are all rare.
Table 1. Genetic (Hereditary) Conditions in Neutropenia
View Table
See Table
Congenital neutropenia with associated immune defects
Neutropenia with abnormal immunoglobulins is observed in individuals with X-linked agammaglobulinemia, isolated immunoglobulin A (IgA) deficiency, X-linked hyperimmunoglobulin M (XHIGM) syndrome, and dysgammaglobulinemia type I.[24] In XHIGM, which is due to mutations in the CD40 ligand, patients can have normal or elevated levels of IgM but markedly decreased serum IgG levels. In all these disorders, the infection risk is high, and the treatment is intravenous immunoglobulin (IVIG).
Patients with reticular dysgenesis demonstrate severe neutropenia, no cell-mediated immunity, agammaglobulinemia, and lymphopenia.[24] Life-threatening infections occur that are refractory to granulocyte colony-stimulating factor (G-CSF).[25, 26, 27] Bone marrow transplantation is the treatment of choice.
Congenital or chronic neutropenias
Severe congenital neutropenia (SCN), or Kostmann syndrome, is most often caused by a recessive inheritance and is found in remote, isolated populations with a high degree of consanguinity.[28] Autosomal dominant and sporadic cases have also been reported, most often due to mutations in the G-CSF receptor. No uniform genetic defect exists in this syndrome. Mutations in ELA2, which are causative for cyclic neutropenia (see below) are not sufficient to explain the phenotype of Kostmann-like SCN.
Patients present by age 3 months with recurrent bacterial infections. The mouth and perirectum are the most common sites of infection. This type of neutropenia is severe, and the treatment is G-CSF. The 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 the accelerated apoptosis of myeloid progenitor cells.[1] Some cases may be genetically determined with an autosomal recessive inheritance. Other cases may be due to an autosomal dominant inheritance. In some sporadic cases of CN, patients have mutations in ELA2.
People with CN typically present as infants or children, though acquired forms of CN in adulthood exist. The prognosis is good, with a benign course; however, 10% of patients can experience life-threatening infections. The treatment for cyclic neutropenia is daily G-CSF.
Chronic benign neutropenia
Familial chronic benign neutropenia, or benign ethnic neutropenia, is a disorder with an autosomal dominant pattern of inheritance observed in African, Yemenite Jewish, Ethiopian Jewish, Arab, Caribbean, and West Indian descent. In populations of African and Yemenite Jewish ancestry, genetic studies show a strong association with a single-nucleotide polymorphism in the DARC gene. Patients are typically asymptomatic, and the infections are mild. Affected individuals with chronic benign neutropenia do no thave an increased risk of infection and no specific therapy is required for this condition. [29]
In nonfamilial chronic benign neutropenias, mild infections with a benign course typify this disorder. The ANC, however, does respond to stress, such as infection, corticosteroids, and catecholamines.
Idiopathic chronic severe neutropenia
Idiopathic chronic severe neutropenia is a diagnosis of exclusion. Affected patients exhibit infections and severe neutropenia.
Neutropenia associated with phenotypic abnormalities
Shwachman syndrome (Shwachman-Diamond) has an autosomal recessive inheritance pattern. The neutropenia is moderate to severe, with a mortality rate of 15-25%, and the syndrome presents in infancy, with recurrent infections, diarrhea, and difficulty in feeding. Dwarfism, chondrodysplasia, and pancreatic exocrine insufficiency can occur.
Shwachman-Diamond syndrome and X-linked dyskeratosis congenita (DC), cartilage-hair hypoplasia (CHH), and Diamond-Blackfan anemia (DBA) all appear to share common gene defects involved in ribosome synthesis. Most cases of Shwachman-Diamond syndrome are caused by mutations in the SBDS gene.[30] The precise function of this gene is still being elucidated; however, it is involved in ribosome synthesis and RNA processing reactions. The treatment is G-CSF.
In CHH, the inheritance pattern is autosomal recessive on chromosome 9, and it is observed in Amish and Finnish families. CHH is caused by mutations in the RMRP gene, which encodes the RNA component of the ribonuclease mitochondrial RNA processing (RNase MRP) complex. The neutropenia is moderate to severe. CHH presents with cell-mediated immunity defects, macrocytic anemia, gastrointestinal disease, and dwarfism. It also shows a predisposition to cancer, especially lymphoma. The treatment is bone marrow transplantation.
Dyskeratosis congenita (Zinsser-Cole-Engman syndrome) presents with intellectual disability, pancytopenia, and defective cell-mediated immunity. Dyskeratosis congenita is more common in men as compared to women and is hematologically similar to Fanconi anemia. Dyskeratosis congenita is usually X-linked recessive, although autosomal dominant and autosomal recessive forms are also present.
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, oculo-cutaneous albinism, neuropathy, bleeding disorders, gingivitis, and lysosomal granules in various cells. The neutropenia is moderate to severe, and the treatment is bone marrow transplantation.
Thrombocytopenia with absent radii syndrome (TAR) is an autosomal recessive disorder characterized by bilateral radial dysplasia and hyper megakaryocytic thrombocytopenia
Myelokathexis
Myelokathexis presents in infancy as moderate neutropenia and is associated with recurrent infections. The condition is due to accelerated apoptosis and decreased expression of bcl-x in neutrophil precursors. Neutrophils have an abnormal nuclear appearance, with hypersegmentation with nuclear strands, pyknosis, and cytoplasmic vacuolization. The treatment is G-CSF and GM-CSF.
Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a severe congenital neutropenia caused by an autosomal dominant gain-of-function mutation in the CXCR4 gene encoding chemokine receptor type 4. Management includes treatment of infections and warts, correction of neutropenia with G-CSF, and supplementing immunoglobulin deficiency when present. Allogeneic hematopoietic stem cell transplantation has provided cures. CXCR4 blocking agents are undergoing clinical trials.[31]
Lazy leukocyte syndrome
Lazy leukocyte syndrome is a severe neutropenia with associated abnormal neutrophil motility. The etiology is unknown, and the treatment is generally supportive.
Metabolic disorders
These are chronic neutropenias with variable ANCs. They include glycogen storage disease type 1b and various acidemias, such as isovaleric, propionic, and methylmalonic. In glycogen storage disease type 1b, the treatment is G-CSF and GM-CSF.
Acquired neutropenias
Intrinsic bone marrow diseases that may cause neutropenia include the following:
A drug may act as a hapten and induce antibody formation. This mechanism operates in cases due to gold, aminopyrine, and antithyroid drugs. The antibodies destroy the granulocytes and may not require the continued presence of the drug for their action. Alternatively, the drug may form immune complexes that attach to the neutrophils. This mechanism operates with quinidine.
Drug immune-mediated neutropenia may be caused by the following:
Aminopyrine
Quinidine
Cephalosporins
Penicillins
Sulfonamides
Phenothiazines
Hydralazine
Autoimmune neutropenia is the neutrophil analog of autoimmune hemolytic anemia and 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
Infections are the most common form of acquired neutropenia. Infections that may cause neutropenia include, but are not limited to, the following:
Bacterial sepsis
Viral infections (eg, influenza, measles, Epstein Barr virus [EBV], cytomegalovirus [CMV], viral hepatitis, human immunodeficiency virus [HIV]-1) (see first image below)
Toxoplasmosis
Brucellosis
Typhoid
Tuberculosis (see second and third images below)
Malaria
Dengue fever
Rickettsial infection
Babesiosis
The most commonly involved organisms are from endogenous flora, such as Staphylococcus aureus in cases of skin infections. Gram-negative organisms are observed in infections of the urinary and gastrointestinal tracts, particularly Escherichia coli and Pseudomonas species. Candida albicans infections may also occur. Mixed flora may be found in the oral cavity.
Viral infections often lead to mild or moderate neutropenia. Agranulocytosis is uncommon but may occur. The most common organisms are Epstein-Barr virus, hepatitis B virus, yellow fever virus, cytomegalovirus, and influenza. Many overwhelming infections, both viral and bacterial, may cause severe neutropenia.
Nutritional deficiency
Nutritional deficiencies that can cause neutropenia include vitamin B-12, folate, and copper deficiency.
Drugs and chemicals, excluding cytotoxic chemotherapy
Numerous drugs have been associated with neutropenia. Drug-induced neutropenia usually occurs within 6 months of starting the offending drug. Once the offending agent is stopped, neutrophil counts tend to recover within 1 week. Some drugs with a significantly high risk of neutropenia require weekly blood counts for monitoring (eg, clozapine, sulfasalazine). Other highest-risk categories include antithyroid medications, macrolides, and procainamides.
As stated above, many drugs act by an immune-mediated mechanism. However, some drugs appear to have direct toxic effects on marrow stem cells or neutrophil precursors in the mitotic compartment. For example, drugs such as antipsychotics, antidepressants, and chloramphenicol may act as direct toxins in some individuals, based on metabolism and sensitivity in this manner. Other drugs may have a combination of immune and nonimmune mechanisms or may have unknown mechanisms of action.
Analgesics and anti-inflammatory agents include indomethacin, ibuprofen, acetylsalicylic acid, diflunisal, sulindac, tolmetin, benoxaprofen, barbiturates, mesalazine, and quinine. Aminopyrine and dipyrone have been withdrawn from the market in many countries due to the risk of agranulocytosis.
Antipsychotics, antidepressants, and neuropharmacological 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.
Exposure to drugs or chemicals is the most common cause of agranulocytosis: about one-half of patients have a history of medication or chemical exposure. Any chemical or drug that can depress the bone marrow and cause hypoplasia or aplasia is capable of causing agranulocytosis. Some drugs do this to everyone if they are administered in large enough doses. Other agents seem to cause idiosyncratic reactions that affect only certain susceptible individuals.
Some agents (eg, valproic acid, carbamazepine, and beta-lactam antibiotics) act by direct inhibition of myelopoiesis. In bone marrow cultures, these agents inhibit granulocyte colony formation in a dose-related fashion. Direct damage to the bone marrow microenvironment or myeloid precursors plays a role in most other cases.
Many drugs associated with agranulocytosis have been reported to the US Food and Drug Administration (FDA) under its adverse reactions reporting requirement. Many agents are also reported to a registry maintained by the American Medical Association (AMA). The reported drugs were used alone, in combination with another drug known to be potentially toxic, or with another drug without known toxicity. Several drugs are particularly salient because of their high frequency of association with agranulocytosis. They include the following:
Phenothiazine
Antithyroid drugs (thiouracil and propylthiouracil)
Aminopyrine
Chloramphenicol
Sulfonamides
Miscellaneous immunologic neutropenias
Immunologic neutropenias may occur after bone marrow transplantation and blood product transfusions.
Felty syndrome is a syndrome of rheumatoid arthritis, splenomegaly, and neutropenia. Splenectomy produces an initial response, but neutropenia may recur in 10-20% of patients. Treatment is directed toward rheumatoid arthritis.
In complement activation–mediated neutropenia, hemodialysis, cardiopulmonary bypass, and extracorporeal membrane oxygenation (ECMO) expose blood to artificial membranes and can cause complement activation with subsequent neutropenia.
In splenic sequestration, the degree of neutropenia resulting from this process is proportional to the severity of the splenomegaly and the bone marrow’s ability to compensate for the reduction in circulating bands and neutrophils.
Eosinopenia and basophilopenia
Eosinopenia may be associated with the following:
Acute bacterial infection
Glucocorticoid administration
Hypogammaglobulinemia
Physical stress
Thymoma
Decreased circulating basophils may be associated with the following:
The incidence of drug-induced neutropenia is one case per million persons per year. The exact frequency of agranulocytosis is unknown; the estimated frequency is 1.0-3.4 cases per million population per year.
In a Danish study that comprised more than 370,000 primary care patients, neutropenia was found on approximately 1% of routine complete blood cell counts. Neutropenia was particularly associated with HIV infection, acute leukemias, and myelodysplastic syndromes. [33]
A United States study found that in 2012, children with cancer accounted for 1.8% of pediatric hospital discharges, and of those, 12.2% (n = 13,456) met the criteria for fever and neutropenia. Two-fifths of children with fever and neutropenia had a shorter stay; most of them had no serious infections, with viral infection or upper respiratory infection being the most common.[34]
Age distribution for neutropenia
Age can influence the neutrophil counts. Elderly individuals have a higher incidence rate of neutropenia than younger individuals.
Agranulocytosis occurs in all age groups. The congenital forms are most common in childhood; acquired agranulocytosis is most common in the elderly population.[23] Go to Pediatric Autoimmune and Chronic Benign Neutropenia for complete information on this topic.
Sex distribution for neutropenia
Neutropenia occurs more commonly in females than in males. Agranulocytosis occurs slightly more frequently in women than in men, possibly because of their increased rate of medication usage. Whether the discrepancy in incidence 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 the US National Health and Nutritional Examination 1999 to 2004 survey found the prevalence of neutropenia to be 4.5% among black participants, 0.79% in white individuals, and 0.38% in Mexican-Americans.[35] .
The incidence rate of neutropenia was studied in New York City in 2008 in 261 healthy women aged 20-70 years of varying ethnicity.[36] The incidence rate was 10.5% among US blacks. American and European white individuals and those from the Dominican Republic had a 0% incidence rate. Other ethnic groups included those from Haiti, 8.2% incidence rate; Barbados/Trinidad-Tobago, 6.4%; and Jamaica, 2.7%.[36]
Agranulocytosis on the other hand has no racial predilection.
The prognosis of a patient with neutropenia depends on the primary etiology, duration, and severity of the neutropenia. Improved broad-spectrum antibiotic agents, combined with improved supportive care, have improved the prognosis for most patients with severe neutropenia. Ultimately, patient survival depends on the recovery of adequate neutrophil numbers.
Morbidity in those with neutropenia usually involves infections during severe, prolonged episodes of neutropenia. The infections may be superficial, involving mainly the oral mucosa, gums, skin, and sinuses, or they may be systemic, with life-threatening septicemia.
Serious medical complications occur in 21% of patients with cancer and neutropenic fever. Mortality correlates with the duration and severity of the neutropenia and the time elapsed until the first dose of antibiotics is administered for neutropenic fever.[27, 37, 38] Neutropenic fever in cancer patients typically carries an overall mortality rate of 4-30%. A study of febrile neutropenia-related hospitalizations in patients with breast cancer reported an average in-hospital mortality rate during 2009-2011 of 2.6%, but a rate of 4.4% in patients 65 years of age and older. Mean length of hospital stay was 5.7 days.[39]
The three identified high-risk groups among cancer patients with neutropenic fever (many of whom have received aggressive chemotherapy) are as follows:
Inpatients with fever while developing neutropenia
Outpatients requiring acute hospital care for problems beyond neutropenia and fever
Stable outpatients with uncontrolled cancer
However, a posthoc 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 prolonged overall survival (median 16.3 versus 14.0 months), a twice-longer progression-free survival (median 5.3 versus 2.6 months) and a higher confirmed prostate-specific antigen response ≥50% (49.8% versus 24.4%), as compared with patients who did not develop grade ≥3 neutropenia. These authors concluded that the inferior outcome in patients who failed to experience grade ≥3 neutropenia during therapy may suggest insufficient drug exposure or a limited impact on the tumor-associated immune response.[40]
Mortality increases if agranulocytosis remains untreated, mortality is high. Death can occur from uncontrolled sepsis. 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, patients with drug-induced agranulocytosis have a good prognosis.
Patients with neutropenia should be instructed to avoid exposure to people with respiratory tract infections.[41] They should avoid overcrowded areas, and if their ANC is less than 1000/µL, they should wear a facemask in public places.
Patients should be instructed to avoid any drug that was previously implicated in causing them neutropenia. They should be educated about the importance of frequent CBC testing in the initial period when a new drug with a high propensity to cause neutropenia is introduced. The exact frequency of testing depends on the specific drug and the time course of neutropenia association. At the first sign of a drop in the ANC, the drug should be discontinued.
The Centers for Disease Control and Prevention offers patient education information on neutropenia and infection risk for cancer patients receiving chemotherapy and preventing infections during cancer therapy. In the workplace, people must be educated to follow regulations from the Occupational Safety and Health Administration (OSHA) that cover safety precautions when they deal with toxic substances.
For patient education information, see Neutropenia.
Patients with neutropenia often present with recurrent infections. 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
Signs and 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 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. Several 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, 42, 12]
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, a detailed history is appropriate. A history of occupational or accidental exposure to chemicals or physical agents (eg, ionizing radiation) may be noted.[43, 44]
Go to Pediatric Autoimmune and Chronic Benign Neutropenia for complete information on this topic.
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
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. [11] In agranulocytosis, fever may be 40°C or higher. Rapid pulse and respirations may be evident. Hypotension and signs of septic shock may also be apparent. Painful aphthous ulcers and 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.
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 Pediatric Autoimmune Neutropenia.
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
Blood cultures (at least two sets with a set collected simultaneously from each lumen of an existing central venous catheter (CVC), if present, and from a peripheral vein site)
Serum creatinine and blood urea nitrogen
Electrolytes
Hepatic transaminase enzymes and total bilirubin
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 the 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
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 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, hence 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 B12 and folate levels to evaluate for nutritional deficiency and pernicious anemia in individuals with neutropenia. Copper deficiency can be considered in patients who have a history of gastric surgery.
Perform HIV testing if clinical risk factors are present.
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. This study also allows evaluation of hepatocellular function and colloid shift, which occurs when hypersplenism is caused by cirrhosis with portal hypertension.
Ultrasonography of the left upper quadrant or computed tomography (CT) scanning could also be done to evaluate splenomegaly (see the image below).
View Image
Doppler sonogram at the splenic hilum reveals hepatofugal venous flow in a patient with portal hypertension.
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 Clostridioides (formerly Clostridium) difficile
Skin biopsy, if new erythematous and tender skin lesions are present
Broad-spectrum antibiotics should be started within 1 hour of cultures.
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.
Medical care for patients with neutropenia is mostly supportive and is based on the etiology, severity, and duration of the neutropenia. Fever and infections occurring as complications of neutropenia require specific treatment; see Antimicrobial Agents in Neutropenic Cancer Patients. Treatment must be instituted promptly or the infection may progress to generalized sepsis, which can become life-threatening. Surgical care is not usually indicated but may be employed in certain contexts. Hematopoietic growth factors (colony-stimulating factors) can be given to accelerate neutrophil recovery and shorten the duration of neutropenic fever; they are also used in the treatment of chronic neutropenia.
Go to Pediatric Autoimmune Neutropenia for complete information on this topic.
General measures to be taken include the following:
Discontinuation 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 all drugs until the etiology is established.
Have patients 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 frequent rectal examinations.
Administer stool softeners for constipation.
Use good skin care for wounds and abrasions; skin infections should be managed by a clinician with experience in the treatment of infection in neutropenic patients.
Do not allow plants and dried or fresh flowers in the rooms of hospitalized neutropenic patients.
Start specific antibiotic therapy to combat infections. (Fever may be considered to represent infection.) This often involves the use of third-generation cephalosporins or equivalents. Typical empiric choices are as follows[6, 7, 8, 9, 10] :
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).
Special considerations in chemotherapy-related neutropenia
In adult patients with cancer who develop febrile neutropenia while undergoing chemotherapy, joint guidelines from the American Society of Clinical Oncology (ASCO) and the Infectious Diseases Society of America (IDSA) recommend using clinical criteria or a validated tool such as the Multinational Association of Support Care in Cancer (MASCC) risk index to determine whether outpatient therapy is appropriate.[5]
Anticipated prolonged (> 7 days) and profound neutropenia (absolute neutrophil count [ANC] ≤100 cells/mm3 following cytotoxic chemotherapy are high-risk criteria. The MASCC Febrile Neutropenia Risk calculator also considers factors including hypotension, type of cancer being treated, and dehydration in order to determine risk of complications in patients with febrile neutropenia. A MASCC score of 20 or less indicates high risk, while a score of 21 or greater indicates low risk.
High-risk patients should be admitted to the hospital and started on empiric IV antibiotics. Low-risk patients (those who do not meet high-risk criteria) may be candidates for an outpatient course of oral antibiotics. For empiric outpatient therapy, the ASCO/IDSA guidelines recommend an oral fluoroquinolone plus amoxicillin/clavulanate (or clindamycin, if the patient is penicillin allergic), unless the patient was receiving fluoroquinolone prophylaxis before fever developed. Patients who remain febrile after 2 to 3 days of antibiotic therapy should be re-evaluated and considered for inpatient treatment.[5]
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 (eg, those with systemic lupus erythematosus[45] ). 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.
Filgrastim, which was approved by the US Food and Drug Administration in 1991, was the first recombinant human G-CSF to enter the market, and its availability altered the management of agranulocytosis. Filgrastim 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[46] :
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.[46]
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.[46]
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.[46]
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.[46]
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[47] :
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. The choice of mobilization strategy depends in part on the 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.[48]
Primary prophylaxis with biosimilar filgrastim is cost-effective.[49]
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 somewhat 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.[50] Granulocyte transfusion could be considered in cases of gram-negative sepsis with no improvement in 24-48 hours.
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. Neutropenia associated with systemic lupus erythematosus is typically mild, but severe or even life-threatening neutropenia may occur; treatment with splenectomy has been reported in severe cases, but colony-stimulating factors are more often used.[12, 45]
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, can lead to polymicrobial sepsis, despite antibiotic therapy.
Neutropenic patients should follow the following dietary restrictions:
Avoid raw and undercooked meat
Do not drink well water.
Commercial fruit juices, beer, milk, and milk products should be pasteurized.
Do not consume aged cheese or cheese-based dressings.
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.
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.
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 for further management.
Medications are used to treat fevers or possible infections and to stimulate bone marrow 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 receive initial doses of empiric antibacterial therapy within 1 hour of triage and be monitored for ≥4 hours before discharge.[5] 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 empiric 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.
Clinical Context:
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.
Clinical Context:
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.
Clinical Context:
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.
Clinical Context:
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.
Clinical Context:
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.
Clinical Context:
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]
Clinical Context:
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.
Clinical Context:
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.
Clinical Context:
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.
Clinical Context:
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.
Clinical Context:
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.
Clinical Context:
Voriconazole is a triazole antifungal agent that inhibits fungal CYP450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis.
Antifungal agents exert their action by inhibiting fungal cell membrane formation or the inhibition of essential components of the cell wall of susceptible fungi.
Clinical Context:
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.
Clinical Context:
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.
Clinical Context:
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.
Clinical Context:
Recombinant human granulocyte growth factor (G-CSF) that binds to G-CSF receptors on myeloid progenitor cells and neutrophils, triggering signaling pathways that control cell differentiation, proliferation, migration, and survival. It is indicated to decrease incidence of infection, as manifested by febrile neutropenia, in adults with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with clinically significant incidence of febrile neutropenia.
Clinical Context:
Leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in adults with non-myeloid malignancies who are receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.
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.
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 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?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?Which conditions should be included in the differential diagnoses of neutropenia?What are the differential diagnoses for Neutropenia?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?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 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?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?
Madeeha Subhan Waleed, MD, Chief Resident Physician, Department of Internal Medicine, Lower Bucks Hospital
Disclosure: Nothing to disclose.
Coauthor(s)
Claudia M da Costa Dourado, MD, Clinical Assistant Professor of Medicine, Sidney Kimmel Medical College of Thomas Jefferson University; Program Director, Hematology and Medical Oncology Fellowship Program, Attending Physician, Division of Hematology and Medical Oncology, Department of Medicine, Einstein Medical Center Philadelphia
Disclosure: Nothing to disclose.
Specialty Editors
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.
Chief Editor
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
Disclosure: Nothing to disclose.
Additional Contributors
Carly DeFaria, MD, Resident Physician, Department of Internal Medicine, Einstein Medical Center
Disclosure: Nothing to disclose.
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
Disclosure: Nothing to disclose.
Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College
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.
Acknowledgements
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.
References
Jacobson CA, Berliner N. Neutropenia. Greer JP, Arber DA, Glader B, et al, eds. Wintrobe’s Clinical Hematology. 13th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2014. 1279-89.
Smith CW. Production, Distribution, and Fate of Neutrophils. Kaushansky K, Lichtman MA, Prchal JT, et al. Williams Hematology. 9th ed. New York, NY: McGraw-Hill; 2016.
[Guideline] National Comprehensive Cancer Network. Prevention and Treatment of Cancer-Related Infections. NCCN. Available at http://www.nccn.org/professionals/physician_gls/pdf/infections.pdf. Version 2.2020 — June 5, 2020; Accessed: March 25, 2021.
[Guideline] National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology, Hematopoietic Growth Factors. Available at https://www.nccn.org/professionals/physician_gls/pdf/growthfactors.pdf. Version 1.2024 — October 19, 2023; Accessed: November 21, 2023.
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.
Doppler sonogram at the splenic hilum reveals hepatofugal venous flow in a patient with portal hypertension.
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.
Doppler sonogram at the splenic hilum reveals hepatofugal venous flow in a patient with portal hypertension.
Two neutrophils among red blood cells. Courtesy of Britannica (https://www.britannica.com/science/neutrophil).
Syndrome
Inheritance
Gene
Clinical Features
Cyclic neutropenia
Autosomal dominant
ELA2
Alternate 21-day cycling of neutrophils and monocytes
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