Neutrophils Neutrophils The immune system consists of cellular components and molecular components that work together to destroy antigens. (See also Overview of the Immune System.) Although some antigens (Ags) can... read more (granulocytes) are the body’s main defense against bacterial infections Overview of Bacteria Bacteria are microorganisms that have circular double-stranded DNA and (except for mycoplasmas) cell walls. Most bacteria live extracellularly, but some preferentially reside and replicate intracellularly... read more and fungal infections Overview of Fungal Infections Fungal infections are often classified as either Opportunistic Primary Opportunistic infections are those that develop mainly in immunocompromised hosts. Primary infections can develop in immunocompetent... read more . When neutropenia is present, the inflammatory response to such infections is blunted.
The normal lower limit of the neutrophil count (total white blood cell count × % neutrophils and bands) is 1500/mcL (1.5 × 109/L) in White patients and is somewhat lower in Black patients (about 1200/mcL [1.2 × 109/L). Neutrophil counts are not as stable as other cell counts and may vary considerably over short periods, depending on many factors such as activity status, anxiety, infections, and medications taken. Thus, several measurements may be needed when determining the severity of neutropenia.
Severity of neutropenia relates to the relative risk of infection and is classified as follows:
Mild: 1000 to 1500/mcL (1 to 1.5 × 109/L)
Moderate: 500 to 1000/mcL (0.5 to 1 × 109/L)
Severe: < 500/mcL (< 0.5 × 109/L)
When neutrophil counts fall to < 500/mcL, endogenous microbial flora (eg, in the mouth or gut) can cause infections. If the count falls to < 200/mcL (< 0.2 × 109/L), the inflammatory response may be muted, and the usual inflammatory findings of leukocytosis or white blood cells in the urine or at the site of infection may not occur. Acute, severe neutropenia, particularly if another factor (eg, cancer) is present, significantly impairs the immune system and can lead to rapidly fatal infections. The integrity of the skin and mucous membranes, the vascular supply to tissue, and the nutritional status of the patient also influence the risk of infections.
The most frequently occurring infections in patients with profound neutropenia are
Vascular catheters and other puncture sites confer extra risk of skin infections; the most common bacterial causes are coagulase-negative staphylococci and Staphylococcus aureus, but other gram-positive and gram-negative infections also occur. Stomatitis Stomatitis Oral inflammation and ulcers, known as stomatitis, may be mild and localized or severe and widespread. They are invariably painful. (See also Evaluation of the Dental Patient and Gingivitis... read more , gingivitis Gingivitis Gingivitis is a type of periodontal disease characterized by inflammation of the gums (gingivae), causing bleeding with swelling, redness, exudate, a change of normal contours, and, occasionally... read more , perirectal inflammation, colitis, paronychia Acute Paronychia Paronychia is infection of the periungual tissues. Acute paronychia causes redness, warmth, and pain along the nail margin. Diagnosis is by inspection. Treatment is with antistaphylococcal antibiotics... read more , and otitis media Otitis Media (Acute) Acute otitis media is a bacterial or viral infection of the middle ear, usually accompanying an upper respiratory infection. Symptoms include otalgia, often with systemic symptoms (eg, fever... read more often occur. Patients with prolonged neutropenia after hematopoietic stem cell transplantation or chemotherapy and patients receiving broad-spectrum antibiotics and high doses of corticosteroids are predisposed to fungal infections.
Etiology of Neutropenia
Acute neutropenia (occurring over hours to a few days) can develop as a result of
Rapid neutrophil use or destruction
Impaired neutrophil production
Chronic neutropenia (lasting months to years) usually arises as a result of
Excessive splenic sequestration
Neutropenia also may be classified as
Primary due to an intrinsic defect in marrow myeloid cells
Secondary due to factors extrinsic to marrow myeloid cells
See also the table Classification of Neutropenias Classification of Neutropenias .
Neutropenia caused by intrinsic defects in myeloid cells or their precursors
Neutropenia caused by intrinsic defects in myeloid cells or their precursors is uncommon (1, 2 Etiology references Neutropenia is a reduction in the blood neutrophil count. If it is severe, the risk and severity of bacterial and fungal infections increase. Focal symptoms of infection may be muted, but fever... read more ). When present, the most common causes include
Chronic idiopathic neutropenia
Chronic idiopathic neutropenia is a type of chronic neutropenia in which the rest of the immune system appears to remain intact. Even when neutrophil counts are < 200/mcL (< 0.2 × 109/L), severe infections are infrequent, probably because neutrophils are produced in adequate quantities in response to infection. It is more common in women.
Severe congenital neutropenia (SCN) is a heterogenous group of rare disorders that are characterized by an arrest in myeloid maturation at the promyelocyte stage in the bone marrow, resulting in an absolute neutrophil count of < 200/mcL (< 0.2 × 109/L) and significant infections starting in infancy. Severe congenital neutropenia is usually inherited in an autosomal dominant fashion but can be recessive, X-linked, or sporadic.
Several genetic abnormalities that cause severe congenital neutropenia have been identified, including mutations affecting neutrophil elastase (ELANE), CLPB, HAX1, GFI1, and very rarely the G-CSF (granulocyte colony-stimulating factor) receptor (CSF3R). Almost all patients with severe congenital neutropenia will respond to G-CSF therapy, but hematopoietic stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more may be needed for patients who respond poorly to G-CSF and those who develop myelodysplasia Myelodysplastic Syndrome (MDS) The myelodysplastic syndrome (MDS) is group of clonal hematopoietic stem cell disorders typified by peripheral cytopenia, dysplastic hematopoietic progenitors, a hypercellular or hypocellular... read more or acute myeloid leukemia Acute Myeloid Leukemia (AML) In acute myeloid leukemia (AML), malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating numbers... read more .
Cyclic neutropenia is a rare congenital granulocytopoietic disorder, usually transmitted in an autosomal dominant fashion and usually caused by a mutation in the gene for neutrophil elastase (ELANE), that results in apoptosis. It is characterized by regular, periodic oscillations in the number of peripheral neutrophils. The mean oscillatory period is 21 ± 3 days. Cycling of other blood cells is also evident in most cases.
Benign ethnic neutropenia occurs in members of some ethnic groups (eg, some people of African, Middle Eastern, or Jewish ancestry). Patients normally have lower neutrophil counts but do not have increased risk of infection. In some cases, this finding has been linked to the Duffy red blood cell antigen; some experts think neutropenia in these populations is related to protection from malaria Malaria Malaria is infection with Plasmodium species. Symptoms and signs include fever (which may be periodic), chills, rigors, sweating, diarrhea, abdominal pain, respiratory distress, confusion... read more .
Rare congenital syndromes (eg, cartilage-hair hypoplasia syndrome, Chédiak-Higashi syndrome Chédiak-Higashi Syndrome Chédiak-Higashi syndrome is a rare, autosomal recessive immunodeficiency disorder characterized by impaired lysis of phagocytized bacteria, resulting in recurrent bacterial respiratory and other... read more , dyskeratosis congenita, glycogen storage disease type Ib, Shwachman-Diamond syndrome, warts, hypogammaglobulinemia, infections, myelokathexis [WHIM] syndrome) can involve bone marrow failure that causes neutropenia.
Neutropenia is also a feature of myelodysplasia Myelodysplastic Syndrome (MDS) The myelodysplastic syndrome (MDS) is group of clonal hematopoietic stem cell disorders typified by peripheral cytopenia, dysplastic hematopoietic progenitors, a hypercellular or hypocellular... read more , where it may be accompanied by megaloblastoid features in the bone marrow, and of aplastic anemia Aplastic Anemia Aplastic anemia is a disorder of the hematopoietic stem cell that results in a loss of blood cell precursors, hypoplasia or aplasia of bone marrow, and cytopenias in two or more cell lines ... read more . Neutropenia can occur in dysgammaglobulinemia and paroxysmal nocturnal hemoglobinemia Paroxysmal Nocturnal Hemoglobinuria (PNH) Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disorder characterized by intravascular hemolysis and hemoglobinuria. Leukopenia, thrombocytopenia, arterial and venous thromboses... read more .
Secondary neutropenia can result from use of certain drugs, bone marrow infiltration or replacement, certain infections, or immune reactions.
The most common causes include
Infections and immune reactions
Marrow infiltrative processes
Drug-induced neutropenia is one of the most common causes of neutropenia. Drugs can decrease neutrophil production through toxic, idiosyncratic, or hypersensitivity mechanisms; or they can increase peripheral neutrophil destruction through immune mechanisms. Only the toxic mechanism causes dose-related neutropenia.
Severe dose-related neutropenia occurs predictably after administration of cytotoxic cancer drugs, phenothiazine, or radiation therapy due to suppression of bone marrow production.
Idiosyncratic reactions are unpredictable and occur with a wide variety of drugs, including alternative medicine preparations or extracts, and toxins.
Hypersensitivity reactions Drug Hypersensitivity Drug hypersensitivity is an immune-mediated reaction to a drug. Symptoms range from mild to severe and include rash, anaphylaxis, and serum sickness. Diagnosis is clinical; skin testing is occasionally... read more are rare and occasionally involve antiseizure drugs (eg, phenytoin, phenobarbital), methimazole, or propylthiouracil. These reactions may last for only a few days or for months or years. Often, hepatitis Overview of Acute Viral Hepatitis Acute viral hepatitis is diffuse liver inflammation caused by specific hepatotropic viruses that have diverse modes of transmission and epidemiologies. A nonspecific viral prodrome is followed... read more , nephritis, pneumonitis, or aplastic anemia Aplastic Anemia Aplastic anemia is a disorder of the hematopoietic stem cell that results in a loss of blood cell precursors, hypoplasia or aplasia of bone marrow, and cytopenias in two or more cell lines ... read more accompanies hypersensitivity-induced neutropenia.
Immune-mediated drug-induced neutropenia, thought to arise from drugs that act as haptens to stimulate antibody formation, usually persists for about 1 week after the drug is stopped. It may result from aminopyrine, clozapine, propylthiouracil and other antithyroid drugs, penicillin, or other antibiotics.
Neutropenia due to ineffective bone marrow production can occur in megaloblastic anemias Megaloblastic Macrocytic Anemias Megaloblastic anemias result most often from deficiencies of vitamin B12 and folate. Ineffective hematopoiesis affects all cell lines but particularly red blood cells. Diagnosis is usually based... read more caused by vitamin B12 deficiency or folate deficiency. Usually, macrocytic anemia and sometimes mild thrombocytopenia develop simultaneously. Ineffective production can also accompany myelodysplastic disorders Myelodysplastic Syndrome (MDS) The myelodysplastic syndrome (MDS) is group of clonal hematopoietic stem cell disorders typified by peripheral cytopenia, dysplastic hematopoietic progenitors, a hypercellular or hypocellular... read more and acute myeloid leukemia Acute Myeloid Leukemia (AML) In acute myeloid leukemia (AML), malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating numbers... read more .
Bone marrow infiltration by leukemia Overview of Leukemia Leukemia is a malignant condition involving the excess production of immature or abnormal leukocytes, which eventually suppresses the production of normal blood cells and results in symptoms... read more , myeloma Multiple Myeloma Multiple myeloma is a cancer of plasma cells that produce monoclonal immunoglobulin and invade and destroy adjacent bone tissue. Common manifestations include lytic lesions in bones causing... read more , lymphoma Overview of Lymphoma Lymphomas are a heterogeneous group of tumors arising in the reticuloendothelial and lymphatic systems. The major types are Hodgkin lymphoma Non-Hodgkin lymphoma See table Comparison of Hodgkin... read more , or metastatic solid tumors (eg, breast cancer Breast Cancer Breast cancers are most often epithelial tumors involving the ducts or lobules. Most patients present with an asymptomatic mass discovered during examination or screening mammography. Diagnosis... read more , prostate cancer Prostate Cancer Prostate cancer is usually adenocarcinoma. Symptoms are typically absent until tumor growth causes hematuria and/or obstruction with pain. Diagnosis is suggested by digital rectal examination... read more ) can impair neutrophil production. Tumor-induced myelofibrosis may further exacerbate neutropenia. Myelofibrosis can also occur due to granulomatous infections, Gaucher disease, and radiation therapy.
Hypersplenism Splenomegaly Splenomegaly is abnormal enlargement of the spleen. (See also Overview of the Spleen.) Splenomegaly is almost always secondary to other disorders. Causes of splenomegaly are myriad, as are the... read more of any cause can lead to moderate neutropenia, thrombocytopenia, and anemia.
Infections can cause neutropenia by impairing neutrophil production or by inducing immune destruction or rapid turnover of neutrophils. Sepsis Sepsis and Septic Shock Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated response to infection. In septic shock, there is critical reduction in tissue perfusion; acute failure... read more is a particularly serious cause. Neutropenia that occurs with common childhood viral diseases develops during the first 1 to 2 days of illness and may persist for 3 to 8 days. Transient neutropenia may also result from virus- or endotoxemia-induced redistribution of neutrophils from the circulating to the marginal pool. Alcohol may contribute to neutropenia by inhibiting the neutrophilic chemotactic response of the marrow during some infections (eg, pneumococcal pneumonia).
Immune defects can cause neutropenia. Neonatal isoimmune neutropenia can occur with fetal/maternal neutrophil antigen incompatibility associated with transplacental transfer of IgG antibodies against the newborn’s neutrophils (most commonly to human neutrophil antigen [HNA-1]). Autoimmune neutropenia can occur at any age and may be operative in many cases of idiopathic chronic neutropenia. Testing for antineutrophil antibodies (immunofluorescence, agglutination, or flow cytometry) is not always available or reliable.
Autoimmune neutropenias may be acute, chronic, or episodic. They may involve antibodies directed against circulating neutrophils or neutrophil precursor cells. They may also involve cytokines (eg, gamma interferon, tumor necrosis factor) that can cause neutrophil apoptosis. Most patients with autoimmune neutropenia have an underlying autoimmune disorder or lymphoproliferative disorder (eg, large granular lymphocyte [LGL syndrome [a clonal disease of large granular lymphocytes], systemic lupus erythematosus Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more , Felty syndrome). Chronic secondary neutropenia often accompanies HIV infection Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more because of impaired production of neutrophils and accelerated destruction of neutrophils by antibodies.
1. Dale DC: How I diagnose and treat neutropenia. Curr Opin Hematol 23(1):1-4, 2016. doi: 10.1097/MOH.0000000000000208
2. Skokowa J, Dale DC, Touw IP, et al: Severe congenital neutropenias. Nat Rev Dis Primers 3:17032, 2017. doi: 10.1038/nrdp.2017.32
Symptoms and Signs of Neutropenia
Neutropenia is asymptomatic until infection develops. Fever is often the only indication of infection. If neutropenia is severe, typical signs of focal inflammation (erythema, swelling, pain, infiltrates) may be muted or absent. Focal symptoms (eg, oral ulcers) may develop but are often subtle. Patients with drug-induced neutropenia due to hypersensitivity may have a fever, rash, and lymphadenopathy as a result of the hypersensitivity reaction.
Some patients with chronic idiopathic neutropenia and neutrophil counts < 200/mcL (< 0.2 × 109/L) do not experience many serious infections. Patients with cyclic neutropenia or severe congenital neutropenia tend to have episodes of oral ulcers, stomatitis, or pharyngitis and lymph node enlargement during severe neutropenia. Pneumonias and sepsis often occur.
Diagnosis of Neutropenia
Clinical suspicion (repeated or unusual infections)
Confirmatory complete blood count (CBC) with differential
Evaluation for infection with cultures and imaging
Identification of mechanism and cause of neutropenia
Neutropenia is suspected in patients with frequent, severe, or unusual infections or in patients at risk (eg, those receiving cytotoxic drugs or radiation therapy). Confirmation is by CBC with a differential count.
Evaluation for infection
The first priority is to determine whether an infection is present. Because infection may be subtle, physical examination systematically assesses the most common primary sites of infection:
Mucosal surfaces, such as the alimentary tract (gums, pharynx, anus)
Skin and fingernails
If neutropenia is acute or severe, laboratory evaluation must proceed rapidly.
Cultures are the mainstay of evaluation. At least 2 sets of samples for bacterial and fungal blood cultures are obtained from all febrile patients. If an indwelling IV catheter is present, samples are drawn from the catheter and from a separate peripheral vein. Persistent or chronic drainage material is also cultured for bacteria, fungi, and atypical mycobacteria. Mucosal ulcers are swabbed and cultured for herpes virus and Candida. Skin lesions are aspirated or biopsied for cytology and culture. Samples for urinalysis and urine cultures are obtained from all patients. If diarrhea is present, stool is evaluated for enteric bacterial pathogens and Clostridioides (formerly Clostridium) difficile toxins. Sputum cultures are obtained to evaluate for pulmonary infections.
Imaging studies are helpful. Chest x-rays are done on all patients. A chest CT may also be necessary in patients with neutropenia. CT of the paranasal sinuses may be helpful if symptoms or signs of sinusitis (eg, positional headache, upper tooth or maxillary pain, facial swelling, nasal discharge) are present. CT scan of the abdomen is usually done if symptoms (eg, pain) or history (eg, recent surgery) suggests an intra-abdominal infection.
Identification of cause
Next, the mechanism and cause of neutropenia are determined. The history addresses family history, presence of other disorders, all medications or other preparations being taken, pets, and possible toxin exposure or ingestion.
Physical examination addresses the presence of splenomegaly Splenomegaly Splenomegaly is abnormal enlargement of the spleen. (See also Overview of the Spleen.) Splenomegaly is almost always secondary to other disorders. Causes of splenomegaly are myriad, as are the... read more , lymphadenopathy, skin lesions (eg, areas of erythema, macules, papules, pustules), and signs of other underlying disorders (eg, arthritis).
If no obvious cause is identified (eg, chemotherapy), the most important test is
Bone marrow examination
Bone marrow examination determines whether neutropenia is due to decreased marrow production or is secondary to increased cell destruction (determined by normal or increased production of the myeloid cells). Bone marrow examination may also indicate the specific cause of the neutropenia (eg, aplastic anemia Aplastic Anemia Aplastic anemia is a disorder of the hematopoietic stem cell that results in a loss of blood cell precursors, hypoplasia or aplasia of bone marrow, and cytopenias in two or more cell lines ... read more , myelofibrosis Primary Myelofibrosis Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, splenomegaly, and anemia with nucleated and teardrop-shaped red blood cells. Diagnosis... read more , a myelodysplastic disorder Myelodysplastic Syndrome (MDS) The myelodysplastic syndrome (MDS) is group of clonal hematopoietic stem cell disorders typified by peripheral cytopenia, dysplastic hematopoietic progenitors, a hypercellular or hypocellular... read more , acute leukemia Overview of Leukemia Leukemia is a malignant condition involving the excess production of immature or abnormal leukocytes, which eventually suppresses the production of normal blood cells and results in symptoms... read more , metastatic cancer, marrow necrosis).
Further testing, such as flow cytometry and T-cell receptor gene rearrangement for the LGL syndrome, may be needed to determine the cause of neutropenia, depending on the diagnoses suspected. In patients at risk of nutritional deficiencies, levels of copper Acquired Copper Deficiency Copper is a component of many body proteins; almost all of the body’s copper is bound to copper proteins. Copper deficiency may be acquired or inherited. (See also Overview of Mineral Deficiency... read more , folate Folate Deficiency Folate deficiency is common. It may result from inadequate intake, malabsorption, or use of various drugs. Deficiency causes megaloblastic anemia (indistinguishable from that due to vitamin... read more , and vitamin B12 Vitamin B12 Deficiency Dietary vitamin B12 deficiency usually results from inadequate absorption, but deficiency can develop in vegans who do not take vitamin supplements. Deficiency causes megaloblastic anemia, damage... read more are determined. Testing for the presence of antineutrophil antibodies is done if immune neutropenia is suspected.
Differentiation between neutropenia caused by certain antibiotics and infection can sometimes be difficult. The white blood cell count just before the start of antibiotic treatment usually reflects the change in blood count due to the infection.
Patients who have had chronic neutropenia since infancy and a history of recurrent fevers and chronic gingivitis should have white cell counts with differential done 3 times/week for 6 weeks, so that periodicity suggestive of cyclic neutropenia can be evaluated. Platelet and reticulocyte counts are done simultaneously. In patients with cyclic neutropenia, eosinophils, reticulocytes, and platelets frequently cycle synchronously with the neutrophils, whereas monocytes and lymphocytes may cycle out of phase.
Molecular genetic testing for ELANE and other genes is appropriate when congenital causes are considered.
Treatment of Neutropenia
Treatment of associated conditions (eg, infections, stomatitis)
Sometimes antibiotic prophylaxis
Myeloid growth factors
Discontinuation of suspected etiologic agent (eg, drug)
Suspected infections are always treated immediately. If fever or hypotension is present, serious infection is assumed, and empiric, high-dose, broad-spectrum antibiotics are given IV. Regimen selection is based on the most likely infecting organisms, the antimicrobial susceptibility of pathogens at that particular institution, and the regimen’s potential toxicity. Because of the risk of creating resistant organisms, vancomycin is used only if gram-positive organisms resistant to other drugs are suspected.
Indwelling vascular catheters can usually remain in place even if bacteremia is suspected or documented, but removal is considered if infections involve S. aureus, Bacillus, Corynebacterium, or Candida or another fungus or if blood cultures are persistently positive despite appropriate antibiotics. Infections caused by coagulase-negative staphylococci generally resolve with antimicrobial therapy alone.
Indwelling Foley catheters can also predispose to infections in neutropenic patients, and change or removal of the catheter should be considered for persistent urinary infections.
If cultures are positive, antibiotic therapy is adjusted to the results of sensitivity tests. If a patient defervesces within 72 hours, antibiotics are continued for at least 7 days and until the patient has no symptoms or signs of infection. When neutropenia is transient (such as that following myelosuppressive chemotherapy), antibiotic therapy is usually continued until the neutrophil count is > 500/mcL (> 0.5 × 109/L); however, if cultures remain negative, stopping antimicrobials can be considered in selected patients with persistent neutropenia, especially those in whom symptoms and signs of inflammation have resolved.
Fever that persists > 72 hours despite antibiotic therapy suggests
A nonbacterial cause
Infection with a resistant species
Superinfection with a 2nd bacterial species
Inadequate serum or tissue levels of the antibiotics
Localized infection, such as an abscess
Neutropenic patients with persistent fever are reassessed every 2 to 4 days with physical examination, cultures, and a chest x-ray. If the patient is well except for the presence of fever, the initial antibiotic regimen can be continued, and drug-induced fever should be considered. If the patient is deteriorating, alteration of the antimicrobial regimen is considered (1 Treatment references Neutropenia is a reduction in the blood neutrophil count. If it is severe, the risk and severity of bacterial and fungal infections increase. Focal symptoms of infection may be muted, but fever... read more ).
Fungal infections Overview of Fungal Infections Fungal infections are often classified as either Opportunistic Primary Opportunistic infections are those that develop mainly in immunocompromised hosts. Primary infections can develop in immunocompetent... read more are the most likely cause of persistent fevers and deterioration. Antifungal therapy is added empirically if unexplained fever persists after 3 to 4 days of broad-spectrum antibiotic therapy. Selection of the specific antifungal drug (eg, fluconazole, caspofungin, voriconazole, posaconazole) depends on the type of risk (eg, duration and severity of neutropenia, past history of fungal infection, persistent fever despite use of narrower spectrum antifungal drug) and should be guided by an infectious disease specialist.
If fever persists after 3 weeks of empiric therapy (including 2 weeks of antifungal therapy) and the neutropenia has resolved, then stopping all antimicrobials can be considered and the cause of fever reevaluated.
For afebrile patients with neutropenia, antibiotic prophylaxis can be considered although alterations in the bacterial microbiome may slow bone marrow recovery. Treatment with fluoroquinolones (levofloxacin, ciprofloxacin) is used in some centers for patients who receive chemotherapy regimens that commonly result in neutrophils ≤ 100/mcL (≤ 0.1 × 109/L) for > 7 days. Prophylaxis is usually started by the treating oncologist. Antibiotics are continued until the neutrophil count increases to > 1500/mcL (> 1.5 × 109/L). Also, antifungal therapy can be given for afebrile patients with neutropenia who are at higher risk of fungal infection (eg, after hematopoietic stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more or intensive chemotherapy for acute myeloid leukemia Acute Myeloid Leukemia (AML) In acute myeloid leukemia (AML), malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating numbers... read more or who have a myelodysplastic disorder Myelodysplastic Syndrome (MDS) The myelodysplastic syndrome (MDS) is group of clonal hematopoietic stem cell disorders typified by peripheral cytopenia, dysplastic hematopoietic progenitors, a hypercellular or hypocellular... read more or a history of prior fungal infections). Selection of the specific antifungal drug should be guided by an infectious disease specialist. Antibiotic and antifungal prophylaxis is not routinely recommended for afebrile patients with neutropenia and no risk factors who are anticipated to remain neutropenic for < 7 days on the basis of their specific chemotherapy regimen.
Myeloid growth factors (ie, granulocyte colony-stimulating factor [G-CSF]) are widely used to increase the neutrophil count and to prevent infections in patients after hematopoietic stem cell transplantation or intensive cancer chemotherapy. If the risk of febrile neutropenia is ≥ 30% (as assessed by neutrophil count < 500 mcL [< 0.5 × 109/L], presence of infection during a previous cycle of chemotherapy, associated comorbid disease, or age > 75), growth factors are indicated (2 Treatment references Neutropenia is a reduction in the blood neutrophil count. If it is severe, the risk and severity of bacterial and fungal infections increase. Focal symptoms of infection may be muted, but fever... read more ). In general, most clinical benefit occurs when the growth factor is administered beginning about 24 hours after completion of chemotherapy. Patients with neutropenia caused by an idiosyncratic drug reaction may also benefit from G-CSF, particularly if a delayed recovery is anticipated. The usual dose for G-CSF (filgrastim) is 5 mcg/kg subcutaneously once a day, and the dose for pegylated G-CSF (pegfilgrastim) is 6 mg subcutaneously once per chemotherapy cycle.
Glucocorticoids, anabolic steroids, and vitamins do not stimulate neutrophil production and are generally not helpful to patients with neutropenia. If acute neutropenia is suspected to caused by a drug- or a toxin, all potential etiologic agents are stopped. If neutropenia develops during treatment with an antibiotic known to induce low counts (eg, chloramphenicol), then switching to an alternative antibiotic is recommended.
Saline or hydrogen peroxide gargles every few hours, liquid oral rinses (containing viscous lidocaine, diphenhydramine, and liquid antacid), anesthetic lozenges (benzocaine 15 mg every 3 or 4 hours), or chlorhexidine mouth rinses (1% solution) twice a day or 3 times a day may relieve the discomfort of stomatitis with oropharyngeal ulcerations.
Oral or esophageal candidiasis is treated with nystatin (400,000 to 600,000 units oral rinse 4 times a day; swallowed if esophagitis is present), clotrimazole troche (10 mg slowly dissolved in the mouth 5 times a day), or systemic antifungal drugs (eg, fluconazole).
A semisolid or liquid diet may be necessary during acute stomatitis or esophagitis, and topical analgesics (eg,viscous lidocaine) may be needed to minimize discomfort.
Neutrophil production and deployment in congenital neutropenia Neutropenia caused by intrinsic defects in myeloid cells or their precursors , cyclic neutropenia Neutropenia caused by intrinsic defects in myeloid cells or their precursors , and idiopathic neutropenia Neutropenia caused by intrinsic defects in myeloid cells or their precursors is usually increased with administration of G-CSF 1 to 10 mcg/kg subcutaneously once a day, beginning with a low dose and increasing to maintain a level of about 1000/mcL (1 × 109/L)(3). Effectiveness is maintained with daily or intermittent G-CSF for months or years.
Long-term G-CSF has also been used in other patients with mild chronic neutropenia (including those with myelodysplasia, HIV infection, autoimmune disorders). Clinical benefits of treatment with G-CSF are less clear, especially for patients who do not have severe neutropenia. For patients with autoimmune disorders such as some patients who have the LGL syndrome or who have had an organ transplant, cyclosporine can also be beneficial.
In the past, splenectomy was used to increase the neutrophil count in patients with splenomegaly and splenic sequestration of neutrophils (eg, Felty syndrome); however, because growth factors and other newer therapies are often effective, splenectomy should be avoided. Splenectomy can be considered for patients with persistent painful splenomegaly or with severe neutropenia (ie, < 500/mcL [< 0.5 × 109/L]) and serious problems with infections in whom other treatments have failed. Patients should be vaccinated against infections caused by Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae before splenectomy because splenectomy predisposes patients to infection by encapsulated organisms.
1. Pizzo PA: Management of patients with fever and neutropenia through the arc of time: A narrative review. Ann Intern Med 170(6):389-397, 2019. doi: 10.7326/M18-3192
2. Becker PS, Griffiths EA, Alwan LM, et al: NCCN guidelines insights: Hematopoietic growth factors, version 1.2020. J Natl Compr Canc Netw 18(1):12-22, 2020. doi: 10.6004/jnccn.2020.0002
3. Dale DC, Bolyard AA, Shannon JA, et al: Outcomes for patients with severe chronic neutropenia treated with granulocyte colony-stimulating factor. Blood Adv 6(13):3861-3869, 2022. doi: 10.1182/bloodadvances.2021005684
Neutropenia predisposes to bacterial and fungal infections.
The risk of infection is proportional to the severity of neutropenia; patients with neutrophil counts < 500/mcL (< 0.5 × 109/L) are at greatest risk.
Because the inflammatory response is limited, clinical findings may be muted, although fever is usually present.
Febrile neutropenic patients are treated empirically with broad-spectrum antibiotics pending definitive identification of infection.
Antibiotic prophylaxis may be indicated as a short-term strategy in high-risk patients.
Drugs Mentioned In This Article
|Drug Name||Select Trade|
|Dilantin, Dilantin Infatabs, Dilantin-125, Phenytek|
|No brand name available|
|Clozaril, Fazaclo, VERSACLOZ|
|No brand name available|
|FIRVANQ, Vancocin, Vancocin Powder, VANCOSOL|
|Iquix, Levaquin, Levaquin Leva-Pak, Quixin|
|Cetraxal , Ciloxan, Cipro, Cipro XR, OTIPRIO, Proquin XR|
|Neupogen, Nivestym, Releuko, Zarxio|
|Fulphila, Fylnetra, Neulasta, Nyvepria, Stimufend, UDENYCA, Ziextenzo|
|AK-Chlor, Chloromycetin, Chloroptic, Chloroptic S.O.P., Ocu-Chlor|
|7T Lido, Akten , ALOCANE, ANASTIA, AneCream, Anestacon, Aspercreme with Lidocaine, Astero , BenGay, Blue Tube, Blue-Emu, CidalEaze, DermacinRx Lidogel, DermacinRx Lidorex, DERMALID, Ela-Max, GEN7T, Glydo, Gold Bond, LidaMantle, Lidocare, Lidoderm, LidoDose, LidoDose Pediatric, Lidofore, LidoHeal-90, LIDO-K , Lidomar , Lidomark, LidoReal-30, LidoRx, Lidosense 4 , Lidosense 5, LIDO-SORB, Lidotral, Lidovix L, LIDOZION, Lidozo, LMX 4, LMX 4 with Tegaderm, LMX 5, LTA, Lydexa, Moxicaine, Numbonex, ReadySharp Lidocaine, RectaSmoothe, RectiCare, Salonpas Lidocaine, Senatec, Solarcaine, SUN BURNT PLUS, Tranzarel, Xylocaine, Xylocaine Dental, Xylocaine in Dextrose, Xylocaine MPF, Xylocaine Topical, Xylocaine Topical Jelly, Xylocaine Topical Solution, Xylocaine Viscous, Zilactin-L, Zingo, Zionodi, ZTlido|
|Aid to Sleep, Alka-Seltzer Plus Allergy, Aller-G-Time , Altaryl, Banophen , Benadryl, Benadryl Allergy, Benadryl Allergy Children's , Benadryl Allergy Dye Free, Benadryl Allergy Kapgel, Benadryl Allergy Quick Dissolve, Benadryl Allergy Ultratab, Benadryl Children's Allergy, Benadryl Children's Allergy Fastmelt, Benadryl Children's Perfect Measure, Benadryl Itch Stopping, Ben-Tann , Compoz Nighttime Sleep Aid, Diphedryl , DIPHEN, Diphen AF , Diphenhist, DiphenMax , Dytan, ElixSure Allergy, Genahist , Geri-Dryl, Hydramine, Itch Relief , M-Dryl, Nighttime Sleep Aid, Nytol, PediaCare Children's Allergy, PediaCare Nighttime Cough, PediaClear Children's Cough, PHARBEDRYL, Q-Dryl, Quenalin , Siladryl Allergy, Silphen , Simply Sleep , Sleep Tabs, Sleepinal, Sominex, Sominex Maximum Strength, Theraflu Multi-Symptom Strip, Triaminic Allergy Thin Strip, Triaminic Cough and Runny Nose Strip, Tusstat, Unisom, Uni-Tann, Valu-Dryl , Vanamine PD, Vicks Qlearquil Nighttime Allergy Relief, Vicks ZzzQuil Nightime Sleep-Aid|
|Betasept, Chlorostat, Hibiclens, Oro Clense , Peridex, Periogard, PerioRx , Perisol|
|Bio-Statin , Mycostatin, Nyamyc, Nyata, Nystex, Nystop, Pedi-Dri|
|Alevazol , Antifungal, Anti-Fungal, Cruex, Desenex, Fungoid, Gyne-Lotrimin, Lotrimin, Lotrimin AF, Lotrimin AF Ringworm, Micotrin AC, Mycelex, Mycelex Troche, Mycozyl AC|
|Cequa, Gengraf , Neoral, Restasis, Sandimmune, SangCya, Verkazia|