Neutropenia is a reduction in the blood neutrophil (granulocyte) count. If it is severe, the risk and severity of bacterial and fungal infections increase. Focal symptoms of infection may be muted, but fever is present during most serious infections. Diagnosis is by WBC count, but evaluation requires identification of the cause. If fever is present, infection is presumed, and immediate, empiric broad-spectrum antibiotics are necessary. Treatment with granulocyte-macrophage colony-stimulating factor or granulocyte colony-stimulating factor is sometimes helpful.

Neutrophils are the body's main defense against bacterial and fungal infections. When neutropenia is present, the inflammatory response to such infections is ineffective. Normal lower limit of the neutrophil count (total WBC × % neutrophils and bands) in whites is 1500/μL, somewhat lower in blacks (about 1200/μL).

Severity of neutropenia relates to the relative risk of infection: mild (1000 to 1500/μL), moderate (500 to 1000/μL), or severe (< 500/μL). When neutrophil counts fall to < 500/μL, endogenous microbial flora (eg, in the mouth or gut) can cause infections. If the count falls to < 200/μL, inflammatory response may be nonexistent. Acute, severe neutropenia, particularly if another factor (eg, cancer) also impairs the immune system, predisposes 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 pyogenic infections in patients with profound neutropenia are cellulitis, liver abscesses, furunculosis, pneumonia, and septicemia. Vascular catheters and other puncture sites confer extra risk of skin infections; the most common bacterial causes are coagulase-negative staphylococci and Staphylococcus aureus. Stomatitis, gingivitis, perirectal inflammation, colitis, sinusitis, paronychia, and otitis media often occur. Patients with prolonged neutropenia after bone marrow transplantation or chemotherapy and those receiving high doses of corticosteroids are predisposed to fungal infections.

Etiology

Acute neutropenia (occurring over hours to a few days) can develop from rapid neutrophil utilization or destruction or from impaired production. Chronic neutropenia (lasting months to years) usually arises from reduced production or excessive splenic sequestration. Neutropenia may be classified as due to an intrinsic defect in marrow myeloid cells or as secondary (due to factors extrinsic to marrow myeloid cells—see Table 1: Neutropenia and Lymphocytopenia: Classification of Neutropenias).

Table 1
Classification of Neutropenias Classification Etiology Neutropenia due to intrinsic defects in myeloid cells or their precursors* Aplastic anemia Chronic idiopathic neutropenia, including benign neutropenia Cyclic neutropenia Myelodysplasia Neutropenia associated with dysgammaglobulinemia Paroxysmal nocturnal hemoglobinuria Severe congenital neutropenia (Kostmann syndrome) Syndrome-associated neutropenias (eg, cartilage-hair hypoplasia, dyskeratosis congenita, glycogen storage disease type IB, Schwachman-Diamond syndrome) Secondary neutropenias† Alcoholism Autoimmune neutropenia, including chronic secondary neutropenia in AIDS Bone marrow replacement by cancer, myelofibrosis (eg, due to granuloma), or Gaucher's cells Cytotoxic chemotherapy or radiation Drug-induced neutropenia Folate or vitamin B12 deficiency Hypersplenism Infection T γ-lymphoproliferative disease *Rare disorders. †Common disorders.

Neutropenia caused by intrinsic defects in myeloid cells or their precursors

This type of neutropenia is uncommon. Cyclic neutropenia is a rare congenital granulocytopoietic disorder, usually transmitted in an autosomal dominant fashion. It is characterized by regular, periodic oscillations in the number of peripheral neutrophils. The mean oscillatory period is 21 ± 3 days.

Severe congenital neutropenia (Kostmann syndrome) is a rare disorder that occurs sporadically in the US and is characterized by an arrest in myeloid maturation at the promyelocyte stage of the bone marrow, resulting in an absolute neutrophil count of < 200/μL.

Chronic idiopathic neutropenia is a group of uncommon, poorly understood disorders involving stem cells committed to the myeloid series; RBC and platelet precursors are unaffected. The spleen is not enlarged. Chronic benign neutropenia is a type of chronic idiopathic neutropenia in which the rest of the immune system appears to remain intact; even with neutrophil counts < 200/μL, serious infections usually do not occur, probably because neutrophils are sometimes produced in adequate quantities in response to infection.

Neutropenia can also result from bone marrow failure due to rare syndromes (eg, cartilage-hair hypoplasia, Chédiak-Higashi syndrome, dyskeratosis congenita, glycogen storage disease type IB, Schwachman-Diamond syndrome). Neutropenia is also a prominent feature of myelodysplasia (see Leukemias: Diagnosis—where it may be accompanied by megaloblastoid features in the bone marrow) and of aplastic anemia (see Anemias Caused by Deficient Erythropoiesis: Aplastic Anemia) and can occur in dysgammaglobulinemia and paroxysmal nocturnal hemoglobinemia.

Secondary neutropenia

Secondary neutropenia can result from use of certain drugs, bone marrow infiltration or replacement, certain infections, or immune reactions.

Drug-induced neutropenia is one of the most common causes of neutropenia. It can decrease neutrophil production through toxic, idiosyncratic, or hypersensitivity mechanisms or increase peripheral neutrophil destruction through immune mechanisms. Only the toxic mechanism (eg, with phenothiazines) produces dose-related neutropenia. Idiosyncratic reactions are unpredictable and occur with a wide variety of drugs, including alternative medicine preparations or extracts, and toxins. Hypersensitivity reactions are rare and occasionally involve anticonvulsants (eg, phenytoin, phenobarbital). These reactions may last only a few days or months or years. Often, hepatitis, nephritis, pneumonitis, or aplastic anemia 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 wk after the drug is stopped. It may result from aminopyrine, propylthiouracil, or penicillin or other antibiotics. Severe dose-related neutropenia occurs predictably after cytotoxic cancer drugs or radiation therapy suppresses bone marrow production. Neutropenia due to ineffective marrow production can occur in megaloblastic anemias caused by vitamin B₁₂ or folate deficiency. Usually, macrocytic anemia and sometimes mild thrombocytopenia develop simultaneously.

Drugs Commonly Associated With Neutropenia Drug Class Drugs Antiarrhythmics Procainamide Propranolol Quinidine Tocainide Antibiotics p-Aminosalicylic acid (PAS) Chloramphenicol Isoniazid Nitrofurantoin Penicillins Rifampin Sulfonamides Vancomycin Anticonvulsants Carbamazepine Ethosuximide Mephenytoin Phenytoin Trimethadione Antihistamines Brompheniramine Cimetidine Tripelennamine Antihypertensives Captopril Methyldopa Anti-inflammatory drugs Aminopyrine Gold salts Ibuprofen Indomethacin Phenylbutazone Antimalarials Dapsone Pyrimethamine Quinine Antithyroid drugs Methimazole Propylthiouracil Thiouracil Cytotoxic drugs Alkylating drugs Antimetabolites Anthracyclines Cisplatin Dactinomycin Hydroxyurea Vinca alkaloids Diuretics Acetazolamide Chlorthalidone Hydrochlorothiazide Hypoglycemic drugs Chlorpropamide Tolbutamide Immunosuppressants Antimetabolites Mycophenolate Phenothiazines Chlorpromazine Prochlorperazine Promazine Other drugs Allopurinol Ethanol Levamisole Penicillamine Recombinant interferons Streptokinase Zidovudine

Bone marrow infiltration by leukemia, myeloma, lymphoma, or metastatic solid tumors (eg, breast, prostate) can impair neutrophil production. Tumor-induced myelofibrosis may further exacerbate neutropenia. Myelofibrosis can also occur from granulomatous infections, Gaucher's disease, and radiation therapy. Hypersplenism 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 utilization of neutrophils. Sepsis 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 response of the marrow during some infections (eg, pneumococcal pneumonia).

Infections That Can Cause Neutropenia Type Examples Bacterial Brucellosis Gram-negative sepsis Paratyphoid fever TB (disseminated) Tularemia Typhoid fever Viral Colorado tick fever Cytomegalovirus Dengue fever Hepatitis HIV-1 infection Infectious mononucleosis Influenza Lymphocytic choriomeningitis virus Measles Mumps Parvovirus Psittacosis Respiratory syncytial virus Roseola Rubella Sandfly fever Varicella Yellow fever Rickettsial Rickettsialpox Rocky Mountain spotted fever Typhus fever Fungal Histoplasmosis (disseminated) Protozoal Leishmaniasis (kala-azar) Malaria

Chronic secondary neutropenia often accompanies HIV infection because of impaired production of neutrophils and accelerated destruction of neutrophils by antibodies. Autoimmune neutropenias may be acute, chronic, or episodic. They may involve antibodies directed against circulating neutrophils or neutrophil precursor cells. Most patients with autoimmune neutropenia have an underlying autoimmune disease or lymphoproliferative disorder (eg, SLE, Felty's syndrome).

Symptoms and Signs

Neutropenia is asymptomatic until infection develops. Fever is often the only indication of infection. Focal symptoms may develop but are often subtle. Patients with drug-induced neutropenia due to hypersensitivity may have a fever, rash, and lymphadenopathy from the hypersensitivity.

Some with chronic benign neutropenia and neutrophil counts < 200/μL do not experience many serious infections. Patients with cyclic neutropenia or severe congenital neutropenia tend to have oral ulcers, stomatitis, or pharyngitis and lymph node enlargement during severe chronic neutropenia. Pneumonias and septicemia often occur.

Diagnosis

Neutropenia is suspected in patients with frequent, severe, or unusual infections or in patients at risk (eg, those receiving cytotoxic or radiation therapy). Confirmation is by CBC with differential.

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); lungs; abdomen; urinary tract; skin and fingernails; venipuncture sites; and vascular catheters.

If neutropenia is acute, laboratory evaluation must proceed rapidly. At least 2 sets of bacterial and fungal blood cultures are obtained from all febrile patients; if an indwelling IV catheter is present, cultures are obtained from the lumen and from a separate peripheral vein. Persistent or chronic drainage is also cultured for fungi and atypical mycobacteria. Skin lesions are aspirated or biopsied for cytology and culture. Urinalysis, urine cultures, and chest x-rays are obtained on all patients. If diarrhea is present, stool is evaluated for enteric bacterial pathogens and Clostridium difficile toxins.

Radiography, preferably CT scan, 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.

Next, mechanism and cause of neutropenia are determined. The history addresses all drugs, other preparations, and possible toxins ingested. Physical examination addresses the presence of splenomegaly and signs of other underlying disease (eg, arthritis, lymphadenopathy).

The presence of antineutrophil antibodies suggests immune neutropenia. In a patient at risk of deficiency, levels of folate and vitamin B₁₂ are determined. The most important test is bone marrow examination, which determines whether neutropenia is due to decreased marrow production or is secondary to increased destruction or utilization of the cells (determined by normal or increased production of the cells). Bone marrow may also indicate the specific cause of the neutropenia (eg, aplastic anemia, myelofibrosis, leukemia). Additional marrow studies (eg, cytogenetic analysis; special stains and flow cytometry for detecting leukemia, other malignant disorders, and infections) are obtained. Patients who have had chronic neutropenia since infancy and a history of recurrent fevers and chronic gingivitis have WBC counts with differential obtained 3 times/wk for 6 wk, so that periodicity suggestive of cyclic neutropenia can be evaluated. Platelet and reticulocyte counts are obtained simultaneously. Eosinophils, reticulocytes, and platelets frequently cycle synchronously with the neutrophils, whereas monocytes and lymphocytes may cycle out of phase. Further testing for the cause of neutropenia may be necessary, depending on the diagnoses suspected. Differentiation between neutropenia caused by certain antibiotics and infection can sometimes be difficult. The WBC count just before the start of antibiotic treatment usually reflects the change in blood count due to the infection. If neutropenia develops during treatment with a drug known to induce low counts (eg, chloramphenicol), then switching to an alternative antibiotic may be helpful.

Treatment

Acute neutropenia

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 agents are suspected.

Antimicrobial Regimens for Infection in Acute Neutropenia Indications Regimen Advantages Disadvantages Patients presenting with febrile neutropenia Imipenem/cilastin or Monotherapy with broad gram-positive and gram-negative coverage Common potential toxicity: skin rash Cefepime or Monotherapy with broad gram-positive and gram-negative coverage Common potential toxicity: diarrhea, allergic reactions Aminoglycoside plus an antipseudomonal β-lactam* Activity against anaerobes; potential synergistic activity against some gram-negative bacilli Lack of activity against some gram-positive bacteria; potential nephrotoxicity and ototoxicity Patients with persistent catheter infections, skin infections, abscesses, or known resistant Staphylococcus infections Vancomycin added to initial treatment* Active against most methicillin-resistant Staphylococcus Potential selection of resistant organisms, especially enterococci Patients with persistent fevers despite 4 days of appropriate broad-spectrum antibiotic therapy (suspected fungal infection) Add antifungal drug: amphotericin or Broad antifungal activity Nephrotoxicity, fevers and chills Itraconazole, voriconazole, or caspofungin or Broad antifungal activity Expensive Fluconazole Well tolerated Limited antifungal spectrum *If this regimen is used, drug levels (aminoglycoside or vancomycin) should be monitored, and doses adjusted appropriately.

Indwelling vascular catheters can usually remain in place even if bacteremia is suspected or documented, but removal is considered in infections involving S. aureus or Bacillus , Corynebacterium , or Candida sp, or if blood cultures are persistently positive despite appropriate antibiotics. Infections caused by coagulase-negative staphylococci generally resolve with antimicrobial therapy alone.

If cultures are positive, antibiotic therapy is adjusted to the results of sensitivity tests. If a patient defervesces within 72 h, 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/μL; however, stopping antimicrobial coverage can be considered in selected patients with persistent neutropenia, especially those in whom symptoms and signs of inflammation have resolved, if cultures remain negative.

Fever that persists > 72 h despite antibiotic therapy suggests a nonbacterial cause, infection with a resistant species, a superinfection with a 2nd bacterial species, inadequate serum or tissue levels of the antibiotics, or localized infection, such as an abscess. Neutropenic patients with persistent fever are reassessed q 2 to 4 days with physical examination, cultures, and chest x-ray. If the patient is well except for the presence of fever, the initial antibiotic regimen can be continued. If the patient is deteriorating, alteration of the antimicrobial regimen is considered.

Fungal infections are the most likely cause of persistent fevers and deterioration. Antifungal therapy (eg, itraconazole, voriconazole, amphotericin, fluconazole) is added empirically if unexplained fever persists after 4 days of broad-spectrum antibiotic therapy. If fever persists after 3 wk of empiric therapy (including 2 wk of antifungal therapy) and the neutropenia has resolved, then stopping all antimicrobial drugs is considered and the cause of fever reevaluated.

Antibiotic prophylaxis in afebrile neutropenic patients remains controversial. Trimethoprim-sulfamethoxazole (TMP-SMX) prevents Pneumocystis jiroveci (formerly P. carinii) pneumonia in neutropenic and nonneutropenic patients with impaired cell-mediated immunity. Also, TMP-SMX may prevent bacterial infections in patients expected to be profoundly neutropenic for > 1 wk. The disadvantages of TMP-SMX prophylaxis include adverse effects, potential myelosuppression, and development of resistant bacteria and oral candidiasis. Antifungal prophylaxis is not routinely recommended for neutropenic patients, but patients at high risk of developing fungal infections (eg, after bone marrow transplantation and after receiving high doses of corticosteroids) may benefit.

Myeloid growth factors (granulocyte-macrophage colony-stimulating factor [GM-CSF] and granulocyte colony-stimulating factor [G-CSF]) are now widely used to increase the neutrophil count and to prevent infections in patients with severe neutropenia (eg, after bone marrow transplantation and intensive cancer chemotherapy). They are expensive. However, if the risk of febrile neutropenia is ≥ 30% (as assessed by neutrophil count < 500, presence of infection on a previous cycle of chemotherapy, associated comorbid disease, or age > 75), growth factors are indicated. In general, most clinical benefit occurs when the growth factor is administered beginning about 24 h after completion of chemotherapy. Patients with neutropenia caused by an idiosyncratic drug reaction may also benefit from myeloid growth factors, particularly if a delayed recovery is anticipated. The dose for G-CSF is 5 μg/kg sc once/day; for GM-CSF, 250 μg/m² sc once/day.

Glucocorticoids, anabolic steroids, and vitamins do not stimulate neutrophil production but can affect distribution and destruction. If acute neutropenia is suspected to be drug or toxin induced, all potentially offending agents are stopped.

Saline or hydrogen peroxide gargles every few hours, anesthetic lozenges (benzocaine 15 mg q 3 or 4 h), or chlorhexidine mouth rinses (1% solution) bid or tid 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 qid; swallowed if esophagitis) or with systemic antifungal drugs (eg, fluconazole). A semisolid or liquid diet may be necessary during acute stomatitis or esophagitis to minimize discomfort.

Chronic neutropenia

Neutrophil production in congenital, cyclic, and idiopathic neutropenia can be increased with administration of G-CSF 1 to 10 μg/kg sc once/day. Effectiveness can be maintained with daily or alternate-day G-CSF for months or years. Patients with oropharyngeal inflammation (even low grade), fever, or cellulitis or other suspected bacterial infections need appropriate antibiotics. Long-term G-CSF has also been used in other patients with chronic neutropenia, including those with myelodysplasia, HIV, and autoimmune disorders. In general, neutrophil counts increase, although clinical benefits are less clear, especially for patients who do not have severe neutropenia. For patients with autoimmune disorders or who have had an organ transplant, cyclosporine can also be beneficial.

In some patients with accelerated neutrophil destruction caused by autoimmune disorders, corticosteroids (generally, prednisone 0.5 to 1.0 mg/kg po once/day) increase blood neutrophils. This increase often can be maintained with alternate-day G-CSF therapy.

Splenectomy increases the neutrophil count in some patients with splenomegaly and splenic sequestration of neutrophils (eg, Felty's syndrome, hairy cell leukemia). However, splenectomy should be reserved for patients with severe neutropenia (ie, < 500/μL) and with serious problems with infections because it predisposes the patient to infection by encapsulated organisms.

Last full review/revision November 2005