Neutropenia

Essentials of Diagnosis

• Neutrophils < 1800/mcL

• Severe neutropenia if neutrophils < 500/mcL

General Considerations

• Patients with neutropenia are vulnerable to gram-positive and gram-negative bacterial and fungal infections

• Risk of infection is related to the severity of neutropenia

• Patients with "chronic benign neutropenia" are free of infection despite very low stable neutrophil counts

• In patients with cyclic neutropenia, the neutrophil count oscillates (usually in 21-day cycles) between normal and low, with infections occurring during the nadirs

• Congenital neutropenia is lifelong neutropenia punctuated with infection

• Both cyclic neutropenia and congenital neutropenia represent problems in mutations in the neutrophil elastase gene ELANE (also called ELA-2)

Etiology

• A variety of bone marrow disorders and nonmarrow conditions may cause neutropenia (Table 13–12)

• All the causes of aplastic anemia and pancytopenia may cause neutropenia

  • Causes of aplastic anemia

    • Autoimmune: idiopathic, systemic lupus erythematosus

    • Congenital: defects in telomere length maintenance or DNA repair (rare)

    • Chemotherapy, radiotherapy

    • Toxins: benzene, toluene, insecticides

    • Medications: chloramphenicol, gold salts, sulfonamides, phenytoin, carbamazepine, quinacrine, tolbutamide

    • Post-viral hepatitis (A, B, C, E, G, non-A through -G)

    • Non-hepatitis viruses (Epstein-Barr virus, parvovirus, cytomegalovirus, echovirus 3, others)

    • Pregnancy

    • Paroxysmal nocturnal hemoglobinuria

  • Causes of pancytopenia

    • Aplastic anemia

    • Myelodysplasia

    • Acute leukemia

    • Chronic idiopathic myelofibrosis

    • Infiltrative disease: lymphoma, myeloma, carcinoma, hairy cell leukemia, etc

    • Hypersplenism (with or without portal hypertension)

    • Systemic lupus erythematosus

    • Infection: tuberculosis, HIV, leishmaniasis, brucellosis, cytomegalovirus, parvovirus B19

    • Nutritional deficiency (megaloblastic anemia)

    • Medications

    • Cytotoxic chemotherapy

    • Ionizing radiation

• New onset of an isolated neutropenia is most often due to an idiosyncratic reaction to a drug

• Agranulocytosis (complete absence of neutrophils in the peripheral blood) is almost always due to a drug reaction

• Neutropenia in the presence of a normal bone marrow may be due to

  • Immunologic peripheral destruction (autoimmune neutropenia)

  • Sepsis

  • Hypersplenism

• Isolated neutropenia is an uncommon presentation of hairy cell leukemia or a myelodysplastic syndrome

• Myelosuppressive cytotoxic chemotherapy causes neutropenia in a predictable manner

• Neutropenia results in

  • Stomatitis

  • Infections due to gram-positive or gram-negative aerobic bacteria or to fungi such as Candida or Aspergillus

• Most common infectious syndromes

  • Septicemia

  • Cellulitis

  • Pneumonia

  • Neutropenic fever of unknown origin

• Fever should always be assumed to be of infectious origin until proven otherwise

• Neutrophil count < 1800/mcL

• In certain population groups (eg, blacks, Asians), normal neutrophil counts may be as low as 1200/mcL or even less

• Depends on its cause

• Potential causative drugs should be discontinued

• Myeloid growth factors (filgrastim or sargramostim or biosimilar myeloid growth factors) help facilitate neutrophil recovery after offending drugs are stopped

• Chronic myeloid growth factor administration (daily or every other day) is effective at dampening the neutropenia seen in cyclic or congenital neutropenia

• When Felty syndrome leads to repeated bacterial infections,

  • Splenectomy has been the treatment of choice

  • However, sustained use of myeloid growth factors is effective and provides a nonsurgical alternative

• Autoimmune neutropenia

  • Often responds briefly to immunosuppression with corticosteroids and is best managed with intermittent doses of myeloid growth factors

  • Splenectomy is held in reserve for failure to respond to corticosteroids and myeloid growth factors

• Neutropenia associated with large granular lymphoproliferative disorder may respond to therapy with oral methotrexate, cyclophosphamide, or cyclosporine

• Febrile neutropenia

  • Enteric gram-negative bacteria are of primary concern and often empirically treated with fluoroquinolones or second-generation cephalosporins

  • For protracted neutropenia, fungal infections are problematic and empiric coverage with azoles (fluconazole for yeast and voriconazole, itraconazole, posaconazole, or isavuconazole for molds) or echinocandins is recommended

• Neutropenia following myelosuppressive chemotherapy is partially ameliorated by the use of myeloid growth factors

When to Refer

• Refer to a hematologist if neutrophils are persistently and unexplainably < 1000/mcL

When to Admit

• Neutropenia by itself is not an indication for hospitalization

• However, many patients with severe neutropenia have a serious underlying disease that may require inpatient treatment

• Most patients with febrile neutropenia require hospitalization to treat infection