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The following are partial results from the patient’s complete blood count (CBC) when you see her in clinic:

WBC (109/L)Hb (g/dL)MCV (fL)PLT (109/L)
3.114.388220

What’s what: WBC, white blood cell count; Hb, hemoglobin; MCV, mean cell volume; MCHC, mean cellular hemoglobin concentration; RDW-SD, red cell distribution width-standard deviation; platelets, PLT; Normal values: WBC 5-10 x 109/L, RBC 4-6 x 1012/L, Hb 12-16 g/dL, Hct 35-47%, MCV 80-100 fL, MCHC 32-36 g/dL, RDW-SD < 45%, platelets (PLT) 150-450 x 109/L

The following is the patient’s white cell differential:

What is most important to consider:

a
Percentage counts of white cell subsets
b
Absolute counts of white cell subsets
Correct. This is how lower- and higher-than-normal counts are defined (see table on next slide).

The following is the patient’s white cell differential:

Here is our “cheat sheet”:

Expressed as cell number x 106/L. Just divide by 1000 to get values in 109/L. You will hear colleagues refer towhite cell counts in both 106/L and 109/L, and it pays to get used to both systems.

What other lab tests would you like to order?

a
Rheumatoid factor
Yes, this is to screen for rheumatoid arthritis, which might be associated with immune neutropenia.
b
Antinuclear antibodies (ANA)
Yes, this is to screen for systemic lupus erythematosus (SLE), which might be associated with immune neutropenia.
c
C-reactive protein (CRP)
Correct. This test is used for detecting underlying inflammation associated with other autoimmune diseases.
d
Uric acid
e
Antineutrophil antibodies
Their usefulness is debated. They are generally not ordered in adults with chronic neutropenia.

This patient’s rheumatoid factor, antinuclear antibodies and double-stranded DNA antibodies (another test for systemic lupus erythematosus) were negative. C-reactive protein was normal:

Anti-neutrophil antibodies were in fact ordered in this case and were negative:

What other tests might you consider?

a
Serial complete blood counts and differentials twice weekly for 4-6 weeks
The patient states these studies were done years ago, but you do not have access to the results. It is reasonable to repeat the time series to rule out cyclical neutropenia.
b
Flow cytometry to evaluate for LGL
Most authorities recommend this test in a patient with chronic, unexplained neutropenia.
c
Thyroid stimulating hormone
d
Bone marrow biospy
Should be considered in all patients with unexplained neutropenia to establish that there are no signs of dysplasia, cytogenetic abnormalities, or involvement by a neoplastic process such as leukemia, lymphoma, or myeloma. However, may not be necessary in a patient with a long history of mild isolated neutropenia.

Flow cytometry was ordered:

“Diagnostic immunophenotypic features of involvement by leukemia/lymphoma are not seen in this specimen. Correlation with clinical and other ancillary findings is recommended. Flow cytometry immunophenotyping may not detect all abnormal populations due to topography, sampling or artifacts of sample preparation.”

A bone marrow aspirate and biopsy were ultimately performed on a follow-up visit. The following are the results:

Overview of recommended tests in a patient with isolated neutropenia (that is, without concomitant anemia or thrombocytopenia) according to two authorities in the field:

Test/assayGibson and Berliner*Dale**
Testing for cyclic neutropenia (CN)Consider twice weekly blood counts for 4 to 6 weeks or sequence
analysis of the ELANE gene, which is mutated in nearly 100% of
patients with CN.
Consider 20 counts over a 40-50 day period.
Antinuclear antibodyConsiderConsider
Rheumatoid factorConsiderNM
C-reactive proteinConsiderNM
FACS analysis to identify a causal clonal hematological disease, e.g., large granular lymphocyte (LGL) syndromeAll patientsConsider
HIV testIf one has not been performed recently.NM
Bone marrow examProbably not necessary in patients with long history of mild isolated neutropenia.Not necessary when patients have a long history of mild to moderate isolated neutropenia.
Anti-neutrophil antibody testingRarely helpful in diagnosing adult patients.Generally not very helpful in adults; positive test results may occur in patients with congenital as well as autoimmune neutropenia.
Vitamin B12, folate and other vitamin levelsNMConsider
NM, not mentioned

*Gibson and Berliner. Blood 2014 Aug 21;124(8):1251-8.

**Dale DC. Curr Opin Hematol. 2016 Jan;23(1):1-4

A word about antineutrophil antibodies:

  • Can be found in some cases of both autoimmune disease–associated or idiopathic neutropenia.
  • Very useful in evaluating neonatal neutropenia, but rarely helpful in diagnosing adult patients.
  • Relatively high rate of false-positive results.
  • Even if the positive predictive value of the test was assured to be high, the clinical significance remains unclear; a substantial portion of the normal population can be shown to have circulating antineutrophil antibodies, such that detection of antibodies does not necessarily imply pathogenicity.
  • A reliable correlation between the detection of antineutrophil autoantibodies and response to treatment with immune-suppressive therapies has never been demonstrated.

A word about bone marrow aspirate and biopsy:

  • Should be considered in all patients with unexplained neutropenia to establish that there are no signs of dysplasia, cytogenetic abnormalities, or involvement by a neoplastic process such as leukemia, lymphoma, or myeloma.
  • However, in patients with a long history of mild isolated neutropenia, the results of bone marrow aspiration and biopsy are nearly uniformly inconclusive, deeming the procedures probably unnecessary.

Gibson and Berliner. Blood 2014 Aug 21;124(8):1251-8.

Why idiopathic neutropenia (CIN) or autoimmune neutropenia (AIN) of all possibilities? Let’s return to our differential diagnosis and reorder it in table format:

Congenital neutropenia

Cause of neutropeniaComments
Cyclic neutropeniaA rare congenital disease characterized by episodes of self-limited neutropenia that recur every 2 to 5 weeks. Often diagnosed earlier in life. Associated with recurrent painful mouth ulcers, fever, respiratory symptoms, cellulitis, abscesses, and bacterial infections, none of which the patient complained about.
Severe congenital neutropeniaA group of inherited disorders characterized by agranulocytosis and recurrent, severe infections that begin during infancy. The profile does not fit our patient.
Constitutional/ethnic neutropeniaTypically mild chronic neutropenia (absolute neutrophil count [ANC] > 1 × 109/L), most commonly in those of Mediterranean, African, and Middle Eastern descent. Our patient was not of the right ethnicity and her ANC was lower than is typical for this condition.
Benign familial neutropeniaMild chronic neutropenia (ANC > 1 × 109/L), may not be diagnosed until adulthood. Typically does not lead to recurrent infections. Similar to ethnic neutropenia, clearly hereditary but not linked to a particular ethnic group. Again, our patient’s ANC was lower than is typical for this condition.

Acquired neutropenia

Cause of neutropeniaComments
Transient (many causes)This patient’s neutropenia was not transient.
ChronicHer neutropenia is chronic.
Immune mediatedOur patient had no evidence of a secondary autoimmune condition. Primary autoimmune neutropenia manifests without other signs or symptoms of an underlying autoimmune disorder. It usually occurs during the first year of life and lasts until about age 3–5 years with an average duration of 17 months. In may also occur in adults, where it rarely remits.
Chronic idiopathicDiagnosis of exclusion. Term is often used synonymously with autoimmune-mediated neutropenia since there are no definitive tests to diagnose the latter.
DietaryB12 deficiency almost always associated with other abnormalities on the complete blood count. The patient’s vitamin B12 levels were normal.

Chronic idiopathic neutropenia (CIN), then, is neutropenia lasting for at least for 3 months and not attributable to drugs or a specific genetic, infectious, inflammatory, autoimmune or malignant cause is called. CIN and autoimmune neutropenia (AIN) are very similar and are often considered overlapping conditions 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 also difficult. Thus, we can conclude that our patient has CIN/AIN.

Dale and Bolyard. Curr Opin Hematol. 2017; 24: 46–53.

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