Neutrophil Function

Question 1

Describe the hematopoesis/myelopoesis of neutrophils.

Answer 1

• Hematopoietic elements emerge from the bone marrow following a programmed development sequence involving several morphologically recognizable maturation stages, with simultaneous expansion of cell number at each stage
  
  • The earliest progenitors for each lineage are referred to as stem cells
  • The term “myeloid” is often used to refer broadly to the nonlymphoid, nonerythroid components of the BM, including granulocytic and monocytic lineages
• The progressive maturation of granulocytes or polymorphonuclear leukocytes (PMNs) occurs over a 10–14 day period in the BM
  
  • Mature granulocytes are distinguished based on the immune functions imparted by their different cytoplasmic granules
• Granulopoiesis can occur more quickly in emergency states such as overwhelming infection which results in an increase of immature forms in the marrow and in the circulation
  
  • i.e., “left-shifted” myelopoiesis with increased immature neutrophils or “band” forms

Question 2

Describe the function of neutrophils.

Answer 2

• Neutrophils, the predominant granulocyte cell type representing 50%–60% of all peripheral blood white blood cells (leukocytes), contain granules rich in:
  
  • proteases (e.g., elastase)
  • acid hydrolases (e.g., cathepsins)
  • anti-microbial compounds (e.g., myeloperoxidase and defensins)
• They produce free radicals through catalase activity that aid in tissue cleanup and bacterial clearance from sites of active inflammation
• Neutrophils have a limited life span in blood of 1–2 days, and mediate their effects by migrating to sites of inflammation by binding to blood vessel endothelium and transmigrating into tissues
  
  • Overproduction of granulocytes is seen in infection, reactive stress conditions, and in myeloid leukemias.
• After migrating to the site of inflammation, neutrophils (PMN) phagocytose and digest the invading microbes
  
  • Release NETs, which likely trap bacteria
  • Produce cytokines, which contribute to the inflammatory reaction
  • Once infection is cleared, neutrophils die by apoptosis and trigger an active program to resolve inflammation

Question 3

What is the definition of neutropenia?

Answer 3

• Neutropenia is defined as a decrease in the absolute numbers of circulating segmented neutrophils and band forms in the blood (ANC)
• The ANC is determined by multiplying the total WBC count by the percentage of segmented and band forms
  
  • ​ANCs vary widely in healthy individuals
  • The ANC for the general population normally ranges between 1.5 and 8.0 109/L
  • About 30% of the African-American population may have ANC levels as low as 0.8 109/L (0.8.0 109/L) and still considered healthy
• Regardless of ethnicity, acute neutropenia is neutropenia of less than 3 months’ duration, whereas chronic neutropenia is neutropenia of 6 or more months’ duration
• Severe acute neutropenia arising from chemotherapy, marrow failure, or marrow exhaustion often is associated with a greater risk of bacterial infection than severe chronic neutropenia.

Question 4

What is the general classification of neutropenias?

Answer 4

• Patients can be defined as having:
  
  • mild neutropenia when the ANC is 1.0 to 1.5 109/L
  • moderate neutropenia when the ANC is 0.5 to 1.0 109/L
  • severe neutropenia when the ANC is less than 0.5 109/L
• The classification of neutropenia as mild, moderate, or severe predicts the risk for pyogenic infections in patients who have neutropenia resulting from disorders of bone marrow production
• Neutropenia may be characterized further by whether it is acquired or arising from an intrinsic defect affecting production of myeloid progenitor cells

Question 5

How is neutropenia evaluated?

Answer 5

• Evaluation begins with confirmation of neutropenia on manual examination of counts/blood smear
• The physician should obtain a thorough history to establish the onset of neutropenia
  
  • the type, frequency, and severity of infections
  • drug history for toxic exposures
  • and family history of recurrent infection or unexplained infant deaths
• The physical examination should note:
  
  • growth and development
  • phenotypic abnormalities
  • the presence of bacterial infections at various sites in the body, including mucous membranes, gingiva, skin, tympanic membranes, and rectum
• Lymphadenopathy, hepatosplenomegaly, and signs of possible underlying disease also should be noted
• The severity and duration of the neutropenia determine the extent of laboratory evaluation

Question 6

What are the most common infections and findings in patients with neutropenia?

Answer 6

• Patients who have neutropenia are infected most frequently by endogenous flora or hospital acquired organisms
  
  • The types of pyogenic infections occurring most frequently among patients who have profound neutropenia are:
    
    • cellulitis and abscesses
    • furunculosis
    • pneumonia
    • septicemia
  • In addition, stomatitis, gingivitis, perirectal inflammation, and otitis media are common

Question 7

What are some general principles involved in the management of neutropenia?

Answer 7

• Management of neutropenia is based on:
  
  • severity of the disorder
  • chronicity
  • the etiology of the neutropenia
• The general approach to treatment of neutropenic patients involves preventive measures to limit the number and severity of infections as well as direct efforts to rapidly identify and treat infections that do arise
• Preventive measures begin with close attention to areas of high infection risk-mouth and oral mucosa are common sites of infection and good oral hygiene is imperative, including cleaning and attention to and correction of dental problems
  
  • The perirectal area should be protected by avoidance of trauma, such as rectal temperature measurement
  • The skin is the other common site of bacterial entry in neutropenic patients and should be kept clean
• Skin abrasions or cuts need prompt cleaning and topical antibacterial therapy
• Presence of fever in a severely neutropenic patient must provoke the presumption of infection
  
  • Febrile neutropenic patients should have laboratory samples obtained for culture, and broad-spectrum antimicrobial agents should be initiated promptly

Question 8

What are some specific therapies for neutropenia?

Answer 8

• In some neutropenic patients with severe bacterial or fungal infections that progress despite appropriate antimicrobial therapy, GCSF (granulocyte-colony stimulating factor) therapy may be considered
• Hematopoetic stem cell transplant is reserved for bone marrow failure syndromes and neutrophil disorders that have a risk of malignant transformation