Preparing to see the patient

Before seeing the patient, it will help to brush up on the subject of chronic neutropenia. The causes do not necessarily roll of the tongue like they do for anemia. There is no neat and tidy diagnostic algorithm akin to the morphological classification of anemia. Why is that?

  • Chronic neutropenia is rare and few practicing physicians have much experience with the condition.
  • We don’t fully understand the pathophysiology of neutropenia, let alone the role of neutrophils in health and disease.
  • Unlike red cells, which are released from the bone marrow in a predictable number and manner, and survive for about 120 days in the circulation, neutrophils comprise multiple dynamic interacting pools, including:
    • Bone marrow
    • Circulation
    • Vessel wall (marginated pool)
    • Tissue
  • Many of these pools elude our diagnostic tools.

There are several ways to classify neutropenia that we should keep in mind when we see a patient with neutropenia:

  • Chronic vs acute:
    • Chronic or persistent defined as lasting > 3 months and documented on 3 separate occasions.
    • Acute or transient defined as lasting < 3 months.
  • Congenital vs. acquired
  • Severity (according to absolute neutrophil count [ANC]):
    • Mild 1-1.5 × 109/L
    • Moderate 0.5-1 × 109/L
    • Severe < 0.5 × 109/L
    • Most severe/agranulocytosis ≤ 0.2 × 109/L
  • Persistent vs. cyclical
  • Isolated neutropenia vs. neutropenia associated with other abnormalities in the complete blood count.

Let’s consider the differential diagnosis of isolated neutropenia, which will be helpful in guiding our questioning of the patient.

Causes of isolated neutropenia:

  • Congenital:
    • Not associated with recurrent infections:
      • Constitutional/ethnic neutropenia
      • Benign familial neutropenia
    • Associated with recurrent infections:
      • Cyclic neutropenia
      • Severe congenital neutropenia
  • Acquired:
    • Transient:
      • Infection-related:
        • Post-infectious
        • Active infection
      • Drug induced, most commonly:
        • Chemotherapy agents
        • Cotrimoxazole
        • Antithyroid drugs
        • Ticlopidine
        • Clozapine
        • Amoxicillin
        • Carbimazole 
    • Chronic:
      • Immune-mediated:
        • Primary autoimmune neutropenia
        • Secondary autoimmune neutropenia associated with other autoimmune diseases, such as:
          • Systemic lupus erythematosus (SLE)
          • Rheumatoid arthritis
          • Felty syndrome
          • Large granular lymphocyte (LGL) leukemia
      • Chronic idiopathic/benign neutropenia
      • Dietary:
        • Vitamin B12 deficiency
        • Folate deficiency
        • Copper deficiency

The following are important questions to ask in the history:

  • History of infection(s):
    • Cellulitis
    • Sinusitis
    • Otitis
    • Pharyngitis
    • Pneumonia
    • Gastrointestinal symptoms
    • Perirectal infections
    • Deep tissue infections
    • Tonsillitis
    • Urinary tract infections
  • History of oral inflammation:
    • Mouth ulcers
    • Gingivitis
    • Periodontitis
    • Tooth loss and replacement
  • History of drug exposure
  • History or symptoms of other autoimmune disease:
    • Arthralgia
    • Arthritis
    • Skin rash
    • Dry eyes
    • Dry mouth
  • History of cyclical symptomatology – every 21 days or so
  • Ethnic background
  • Family history of congenital neutropenia, severe infections

Initial triage of the neutropenic adult:

Before beginning an evaluation of newly discovered neutropenia in an adult patient, clinicians should consider a fundamental question: Is the patient acutely ill?

  • Evaluation and treatment of an acutely ill patient not previously known to be neutropenic is a medical emergency.
  • On the other hand, neutropenia discovered on a routine blood count in an otherwise healthy individual is usually benign, although additional evaluation must always be considered before making that determination.

Berliner N et al. Hematology Am Soc Hematol Educ Program. 2004:63-79.

Based on what we know so far, this patient can be safely investigated as an outpatient. Let’s consider her history next.

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