About the Condition

Description/definition:

Neutropenia is defined as an absolute neutrophil count (ANC) in the blood that is less than 1.5 × 109/L.

Isolated neutropenia is neutropenia in absence of anemia and/or thrombocytopenia.

Severity of neutropenia (determines risk of infection):

  • Mild 1-1.5 × 109/L; does not impair host defense.
  • Moderate 0.5-1 × 109/L; slight increased risk of infection if other arms of immune system also impaired.
  • Severe < 0.5 × 109/L; increased risk of infection in most patients.
  • Most severe/agranulocytosis ≤ 0.2 × 109/L; risk of severe, life-threatening infections.

Chronic neutropenia is neutropenia on at least 3 occasions in a 3 month period.

Chronic idiopathic neutropenia (CIN) is an acquired neutropenia lasting for at least for 3 months and not attributable to drugs or a specific genetic, infectious, inflammatory, autoimmune or malignant cause. Stated in other ways CIN is:

  • “Neutropenia that is acquired in adulthood but eludes a specific diagnosis is termed chronic idiopathic neutropenia (CIN)”. Blood. 2014;124:1251-8.
  • “Persistent reduction of peripheral blood (PB) absolute neutrophil counts that cannot be attributed to any underlying congenital or acquired disease, nutritional deficiency, or exposure to drugs, chemical compounds, or ionizing irradiation.” Blood. 2021;138:1249-1257.

Autoimmune neutropenia (AIN) is presumed secondary to autoantibodies, but the term is often used synonymously with CIN because it is difficult to accurately detect circulating antibodies directed toward antigens present on the surface of neutrophils, and clinical interpretation of the anti-neutrophil antibody test result is difficult. Some reserve the term autoimmune neutropenia for cases of chronic idiopathic neutropenia in which anti-neutrophil antibodies are positive.

As far back as 60 years ago, CIN and AIN were considered under the same umbrella! Am J Med. 1958 Jan;24(1):145-52

Idiopathic cytopenia of undetermined significance (ICUS), which was coined by the experts in the myelodysplasia field, describes patients with persistent (4 months) cytopenia(s) of any degree who are suspected of having MDS but do not fulfill the minimal diagnostic criteria nor have evidence of any underlying disease associated with cytopenia. ICUS and isolated neutropenia is also known as ICUS-N. There is overlap between this group and patients with CIN.

Pathophysiology:

Pathogenesis of chronic idiopathic neutropenia (CIN) is unknown. But there is evidence that it is related to an inflammatory bone marrow microenvironment. Some believe that CIN is an immune-mediated bone marrow failure syndrome that impairs normal production of neutrophils in the bone marrow. Previous studies have implicated increased apoptosis of the granulocytic progenitor cells within an inhibitory bone marrow microenvironment consisting of myelosuppressive oligoclonal T lymphocytes, activated monocytes, and mesenchymal stem cells with altered properties.

Clinical presentation:

In adults there is a female predominance of chronic idiopathic neutropenia (CIN)/autoimmune neutropenia (AIN) with female to male ratio estimated to be as high as 8:1. CIN/AIN affects mainly middle-aged women.

Patients with may present:

  • Incidentally
  • With recurrent aphthous stomatitis (45% of patients)
  • With infections (23% of patients) – rarely serious, most commonly:
    • Respiratory infections
    • Periodontal disease
    • Skin infections

Diagnosis:

Chronic idiopathic neutropenia (CIN)/autoimmune neutropenia (AIN) is a diagnosis of exclusion.

Consider diagnosis if:

  • Routine blood count reveals:
    • Low total white blood cell count.
    • Low absolute neutrophil count (ANC) – most patients with CIN and AIN have mild to moderate neutropenia.
    • Normal absolute counts for monocytes, eosinophils and basophils (lymphocytopenia may occur and monocytosis is observed in 13% of cases, possibly reflecting a compensating mechanism to the defective innate immunity).
  • Rule out underlying disease that might be associated with neutropenia:
    • Drug effect
    • Pattern of cycling
    • Infectious cause for neutropenia, for example:
      • CMV
      • EBV
      • HBV
      • HCV
      • HIV infection
    • Clonal rearrangement of T-cell receptor gene (LGL syndrome)
    • Rheumatoid arthritis, systemic lupus erythematosus, Sjogren’s syndrome and other autoimmune disease
    • Nutritional deficiency
    • Myelodysplastic syndrome (MDS) presenting as isolated neutropenia

The following are clinical and hematological features from a study of 76 consecutive patients with chronic idiopathic and autoimmune neutropenia:

Neutropenia was mild in 44 patients (median neutrophils 1.27 × 103 /μL, range 1.06–1.61 × 103/μL), moderate in 23 (median neutrophils 0.8 × 103 /μL, range 0.6–1 × 103 /μL), and severe in 9 (median 0.4 × 103 /μL, range 0.1–0.5 × 103 /μL).

Treatment:

Management of chronic idiopathic neutropenia (CIN)/autoimmune neutropenia (AIN)

  • Good hygiene
  • Observation for early signs of infection
  • Treatment with antibiotics when infections occur
  • Granulocyte colony-stimulating factor (G-CSF):
    • An effective therapy for CIN and AIN.
    • Increases blood neutrophil counts – in one study, mean increase in neutrophils was from 0.59 × 109 /L to 2.06 × 109 /L.
    • Administration should be guided by the patient’s history, rather than simply their blood counts.
    • Typically reserved G-CSF for patients with recurrent or severe infections or symptomatic mucosal erosions or skin infections.
    • When initiating cytokine therapy, consider using G-CSF (filgrastim, Neupogen), which causes less bone pain than pegylated G-CSF (pegfilgrastim, Neulasta).
    • Consider starting with the minimum dose and frequency (dosing one to three times weekly) to maintain a neutrophil count in a range to prevent symptoms (e.g., an ANC > 0.25 – 0.3 x 109/L).
    • No evidence that G-CSF increases the risk of developing leukemia in adult patients.

Prognosis:

Neutrophil counts

In the study of 76 consecutive patients with chronic idiopathic and autoimmune neutropenia (CIN/AIN), all cases displayed steadily low neutrophil values. There as significant inter-subject variability of neutrophil values, but little single-patient oscillations.

Infections

In the study of 76 consecutive patients with CIN/AIN:

  • Only 25% of patients showed infectious episodes, without need of hospitalization or granulocyte-colony stimulating factor treatment.
  • No opportunistic bacterial, viral or fungal infection occurred, even in patients with neutrophils stably under 0.5 × 103 /μL.
  • According to the authors, this finding, further strengthened by retrospective analyses, may be consistent with the fact that the circulating pool represents only the 5% of the entire subpopulation; moreover, previous studies showed that the risk of infections correlates with the capability of delivering neutrophils to the tissues rather than with neutrophil numbers per se.

Transformation to clonal disorder

It was previously believed that patients with CIN/AIN were not at increased risk for for transformation to an acute leukemia. However, a recent study showed that patients with CIN who carried somatic mutations had an increased risk for transformation.

In the study of 76 consecutive patients with CIN/AIN:

  • 4 developed hairy cell leukemia
  • 5 developed chronic NK expansion
  • 3 developed myelodysplastic syndrome:
    • One chronic myelomonocytic leukemia
    • One refractory cytopenia with unilineage dysplasia
    • One multilineage dysplasia
  • Diagnosis of the hematological malignancy was 30 months (range 12–48 months from enrolment).
  • No association with neutrophil values (both at enrolment and mean counts over time), nor with age, gender, presence of anti-neutrophil antibodies, non-organ specific autoantibodies (detected in 2 cases), monocytosis, splenomegaly, electrophoresis abnormalities or infections.

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