Granulocytopenia

Granulocytopenia is a topic covered in the 5-Minute Emergency Consult.

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Basics

Description

  • A significant decrease in the number of granulocytes in the peripheral blood
  • 3 classes of granulocytes:
    • Neutrophils or polymorphonuclear (PMN) cells and bands
    • Eosinophils
    • Basophils
  • As PMN cells predominate, the term neutropenia is often used interchangeably with granulocytopenia, as almost all granulocytopenic patients are neutropenic
  • Leucocyte count:
    • Normal range 4,500/mm311,000/mm3
  • Four basic mechanisms cause granulocytopenia:
    • Decreased production
    • Ineffective granulopoiesis
    • Shift of circulating PMN cells to vascular endothelium
    • Enhanced peripheral destruction
  • The risk of complications of granulocytopenia increases dramatically with falling levels of the absolute neutrophil count (ANC)
  • Neutropenia:
    • Usually defined in clinical practice by an ANC <1,400/mm3
    • ANC = WBC × percentage (PMN + bands)
    • Modern automated instruments often calculate and report ANC
    • Risk of infection increases rapidly once the neutrophil count falls below 1,000 cells/mm3
    • The National Cancer Institute (NCI) criteria for medication adverse hematologic event uses a 4-grade system
      • NCI grade 1: Lower limit of normal to 1,500
      • Mild neutropenia or NCI grade 2: 1,000–1,500
      • Moderate neutropenia or NCI grade 3: Between 500–1,000
      • Severe neutropenia or NCI grade 4: <500
    • Agranulocytosis:
      • ANC <100
      • Most often due to drug reaction
    • Risk of infection is also influenced by the underlying cause of neutropenia, the bone marrow myeloid reserve, and risk factors for infection
    • Patients with a count <1,000 that has recently or rapidly fallen are at greater risk for infection than those with a rising count <500
    • Patients with myelodysplastic syndromes should be considered granulocytopenic with higher counts because of defective neutrophils
  • Mortality of fever and neutropenia is as high as 50% if untreated:
    • Mortality correlates with the duration and severity of the neutropenia and the time elapsed until the first dose of antibiotics
  • When treated, inpatient mortality rate at 6.6%
  • 16% of patients on chemotherapy will experience at least on episode of febrile neutropenia
  • Unexplained fever is the most common presentation of febrile neutropenia:
    • Only 20%–30% have a clinically detectable infection in the ED
  • 21% of patients with cancer and neutropenic fever develop serious complications

Pediatric Considerations
  • Severe congenital neutropenia:
    • Heterogeneous genetic disorders
    • Severe forms present with stomatitis or recurrent bacterial infections
  • Newborn infants have a physiologically elevated ANC in the first few days of life and may be granulocytopenic with levels >1,500/mcL
  • Children >3 mo with isolated neutropenia without immunodeficiency or a central venous catheter are at low risk of serious bacterial infection

Etiology

  • Myelosuppressive drug therapy or radiation treatment for neoplasms
  • Most common 5–10 d after chemo
  • Adverse reaction to drugs (second most common cause):
    • Discontinuation usually results in resolutions within 30 d
    • Nonchemotherapy medications:
      • Clozapine
      • Dapsone
      • Hydroxychloroquine
      • Infliximab
      • Lamotrigine
      • Methimazole
      • Oxacillin
      • Penicillin G
      • Procainamide
      • Propylthiouracil
      • Quinidine/quinine
      • Rituximab
      • Sulfasalazine
      • Trimethoprim–sulfamethoxazole
      • Vancomycin
    • Drugs with the highest risk:
      • Antipsychotic: Clozapine
      • Antibiotic: Sulfasalazine
      • Antithyroid: Thioamides
    • Antiplatelet agents
    • Antiepileptic drugs
    • NSAIDs
  • Drugs that suppress the bone marrow:
    • Methotrexate
    • Cyclophosphamide
    • Colchicine
    • Azathioprine
    • Ganciclovir
  • Chemicals
  • Bacterial infections:
    • Typhoid
    • Shigella enteritis
    • Brucellosis
    • Tularemia
    • Tuberculosis
  • Parasitic infections:
    • Kala azar
    • Malaria
  • Rickettsial infections:
    • Rickettsialpox
    • Ehrlichiosis
    • Rocky Mountain spotted fever
  • Viral infections:
    • HIV
    • Hepatitis B
    • Epstein–Barr viral infections
    • Respiratory syncytial virus
    • Cytomegalovirus
  • Immune-related:
    • Primary immune neutropenia:
      • Due to antineutrophil antibodies
    • Crohn disease
    • Systemic lupus erythematosus
    • Rheumatoid arthritis
    • Goodpasture disease
    • Wegener granulomatosis
    • Thymoma
    • Compliment activation
  • Bone marrow infiltration
  • Transfusion reaction
  • Alcoholism:
    • Bone marrow suppression
    • Splenic sequestration in patients with enlarged spleen secondary to portal hypertension
  • Hypersplenism most commonly due to liver disease with portal hypertension
  • Vitamin deficiency (B12/folate/copper)
  • Chronic idiopathic neutropenia
  • Pure white cell aplasia

Pediatric Considerations
  • Congenital neutropenia:
    • Neutropenia with abnormal immunoglobulins
    • Reticular dysgenesis
    • Severe congenital neutropenia or Kostmann syndrome
    • Cyclic neutropenia
  • Chronic benign neutropenia
  • Neonatal isoimmune neutropenia
  • Shwachman–Diamond syndrome
  • Cartilage–hair hypoplasia
  • Dyskeratosis congenita
  • Barth syndrome
  • Chédiak–Higashi syndrome
  • Myelokathexis
  • Lazy leukocyte syndrome
  • Cohen syndrome
  • Hermansky–Pudlak syndrome type 2

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Basics

Description

  • A significant decrease in the number of granulocytes in the peripheral blood
  • 3 classes of granulocytes:
    • Neutrophils or polymorphonuclear (PMN) cells and bands
    • Eosinophils
    • Basophils
  • As PMN cells predominate, the term neutropenia is often used interchangeably with granulocytopenia, as almost all granulocytopenic patients are neutropenic
  • Leucocyte count:
    • Normal range 4,500/mm311,000/mm3
  • Four basic mechanisms cause granulocytopenia:
    • Decreased production
    • Ineffective granulopoiesis
    • Shift of circulating PMN cells to vascular endothelium
    • Enhanced peripheral destruction
  • The risk of complications of granulocytopenia increases dramatically with falling levels of the absolute neutrophil count (ANC)
  • Neutropenia:
    • Usually defined in clinical practice by an ANC <1,400/mm3
    • ANC = WBC × percentage (PMN + bands)
    • Modern automated instruments often calculate and report ANC
    • Risk of infection increases rapidly once the neutrophil count falls below 1,000 cells/mm3
    • The National Cancer Institute (NCI) criteria for medication adverse hematologic event uses a 4-grade system
      • NCI grade 1: Lower limit of normal to 1,500
      • Mild neutropenia or NCI grade 2: 1,000–1,500
      • Moderate neutropenia or NCI grade 3: Between 500–1,000
      • Severe neutropenia or NCI grade 4: <500
    • Agranulocytosis:
      • ANC <100
      • Most often due to drug reaction
    • Risk of infection is also influenced by the underlying cause of neutropenia, the bone marrow myeloid reserve, and risk factors for infection
    • Patients with a count <1,000 that has recently or rapidly fallen are at greater risk for infection than those with a rising count <500
    • Patients with myelodysplastic syndromes should be considered granulocytopenic with higher counts because of defective neutrophils
  • Mortality of fever and neutropenia is as high as 50% if untreated:
    • Mortality correlates with the duration and severity of the neutropenia and the time elapsed until the first dose of antibiotics
  • When treated, inpatient mortality rate at 6.6%
  • 16% of patients on chemotherapy will experience at least on episode of febrile neutropenia
  • Unexplained fever is the most common presentation of febrile neutropenia:
    • Only 20%–30% have a clinically detectable infection in the ED
  • 21% of patients with cancer and neutropenic fever develop serious complications

Pediatric Considerations
  • Severe congenital neutropenia:
    • Heterogeneous genetic disorders
    • Severe forms present with stomatitis or recurrent bacterial infections
  • Newborn infants have a physiologically elevated ANC in the first few days of life and may be granulocytopenic with levels >1,500/mcL
  • Children >3 mo with isolated neutropenia without immunodeficiency or a central venous catheter are at low risk of serious bacterial infection

Etiology

  • Myelosuppressive drug therapy or radiation treatment for neoplasms
  • Most common 5–10 d after chemo
  • Adverse reaction to drugs (second most common cause):
    • Discontinuation usually results in resolutions within 30 d
    • Nonchemotherapy medications:
      • Clozapine
      • Dapsone
      • Hydroxychloroquine
      • Infliximab
      • Lamotrigine
      • Methimazole
      • Oxacillin
      • Penicillin G
      • Procainamide
      • Propylthiouracil
      • Quinidine/quinine
      • Rituximab
      • Sulfasalazine
      • Trimethoprim–sulfamethoxazole
      • Vancomycin
    • Drugs with the highest risk:
      • Antipsychotic: Clozapine
      • Antibiotic: Sulfasalazine
      • Antithyroid: Thioamides
    • Antiplatelet agents
    • Antiepileptic drugs
    • NSAIDs
  • Drugs that suppress the bone marrow:
    • Methotrexate
    • Cyclophosphamide
    • Colchicine
    • Azathioprine
    • Ganciclovir
  • Chemicals
  • Bacterial infections:
    • Typhoid
    • Shigella enteritis
    • Brucellosis
    • Tularemia
    • Tuberculosis
  • Parasitic infections:
    • Kala azar
    • Malaria
  • Rickettsial infections:
    • Rickettsialpox
    • Ehrlichiosis
    • Rocky Mountain spotted fever
  • Viral infections:
    • HIV
    • Hepatitis B
    • Epstein–Barr viral infections
    • Respiratory syncytial virus
    • Cytomegalovirus
  • Immune-related:
    • Primary immune neutropenia:
      • Due to antineutrophil antibodies
    • Crohn disease
    • Systemic lupus erythematosus
    • Rheumatoid arthritis
    • Goodpasture disease
    • Wegener granulomatosis
    • Thymoma
    • Compliment activation
  • Bone marrow infiltration
  • Transfusion reaction
  • Alcoholism:
    • Bone marrow suppression
    • Splenic sequestration in patients with enlarged spleen secondary to portal hypertension
  • Hypersplenism most commonly due to liver disease with portal hypertension
  • Vitamin deficiency (B12/folate/copper)
  • Chronic idiopathic neutropenia
  • Pure white cell aplasia

Pediatric Considerations
  • Congenital neutropenia:
    • Neutropenia with abnormal immunoglobulins
    • Reticular dysgenesis
    • Severe congenital neutropenia or Kostmann syndrome
    • Cyclic neutropenia
  • Chronic benign neutropenia
  • Neonatal isoimmune neutropenia
  • Shwachman–Diamond syndrome
  • Cartilage–hair hypoplasia
  • Dyskeratosis congenita
  • Barth syndrome
  • Chédiak–Higashi syndrome
  • Myelokathexis
  • Lazy leukocyte syndrome
  • Cohen syndrome
  • Hermansky–Pudlak syndrome type 2

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