Effect of Circadian Variation on Neutrophil Mobilization to Peripheral Blood in Benign Constitutional Neutropenia

Background and Objective:

Benign constitutional neutropenia (BCN) or benign ethnic neutropenia (BEN) is an asymptomatic condition characterized by mild chronic neutropenia in patients with no history of recurrent infections. In most of these patients neutropenia is discovered incidentally in a complete blood count ordered for routine screening. This is particularly concerning for general practitioners because neutropenia is associated with infections and hematologic malignancies. Thus, many patients are commonly referred to a specialist for evaluation, which leads to further testing and increased costs of care without evidence of improved personal or public health.

To ensure that individuals with BCN are healthy, some diagnostic methods can be used to assess neutrophil mobilization from reserve compartments, including epinephrine, corticosteroids, endotoxins and vigorous exercise. We herein present an alternative form of assessment for individuals with BCN based on neutrophil circadian variation.

Neutrophils in healthy individuals have a physiological increase of between 10 and 20% by early afternoon. In this study, we hypothesized that because patients with BCN have higher G-CSF basal levels and a greater physiological response to this cytokine, a larger increase in neutrophils can be detected in a blood test performed in the afternoon compared to routine tests performed in the morning. A physiological increase in neutrophil levels in individuals with BCN would be of great practical interest. This could reduce costs of laboratory tests and reduce medical and patient concerns.

Methods:

We studied patients who had neutropenia that was detected in routine blood count and with suspected BCN. Patients with clinical symptoms, laboratory test result changes and history of chronic, inflammatory, autoimmune or neoplastic diseases were excluded. Patients >60 years were excluded because they have a higher prevalence of myelodysplasia and other concomitant diseases. Neutrophil counts were evaluated in patients with BCN using paired blood counts performed in the early morning (between 7:00 and 9:00 am) and in the early afternoon (between 1:00 and 3:00 pm). The neutrophil counts were stratified into the following four groups: < 500, 500-1000, 1000-1500 and 1500-2000/µL.

Results:

We evaluated 157 patients with neutropenia and 118 individuals met the entry criteria. Their median age was 36 years (range, 3-60 years), and 41 (35%) were male. Median blood count results were as follows: white blood count, 2880/µL; hemoglobin, 12.9 g/dL; and platelets, 223,000/µL.

The difference between the median neutrophil counts performed in the morning (1164/µL) and afternoon (2070/µL) was 904/µL (95% CI=770-1040; p<0.001). This difference reflects an increase of 94.3% in neutrophil counts between the two tests. The percent increase in neutrophils between the two assessments was higher in patients with a lower neutrophil count in the morning examination (OR=20.9; p<0.001). The lower the morning neutropenia, the greater the increase observed (513.8%, 110.6%, 70.5% and 46.8%, respectively, in the 500, 500-1000, 1000-1500 and 1500-2000/µL groups).

We evaluated categories of neutrophil levels in the blood count in the morning and afternoon. Among the 118 subjects with baseline neutrophil count <2000/µL, 52 (44%) had values >2000/µL in the afternoon. Of the 65 who had remain with neutrophils <2000/µL, 48 (40%) showed an increase to neutrophil categories higher than the initial examination, 18 (15%) remained in the same category and no individual showed a decrease in neutrophil counts between the morning and afternoon.

Conclusions:

Our findings identify a simple, easy and feasible way to assess neutrophil reserve in patients with BCN, with a potential reduction in costs of the assessment.