by Dr. Adele Visser

Introduction

Neutrophils are the most abundant white cell subgroup found in circulation. It forms an essential part of the innate immune system and facilitates regulatory functions for the adaptive immune response. In the laboratory setting, normal reference values of both absolute and percentage counts are provided for various age groups, as this changes throughout development. However, these reference values do not allow for ethnic-specific values. This may lead to the unnecessarily investigating certain population groups for underlying pathology, even though the finding may be benign.

Classification of neutropenia

Neutropenia is typically classified based on the level of the absolute counts in peripheral blood. Values of 1-1,5 x 109 cells/L are considered to be mild, 0,5-1 x 109 cells/L as moderate and <0,5 x 109 cells/L severe neutropenia. The risk of life-threatening infection increases as the neutrophil count declines, with levels <0,2 x 109 cells/L considered as agranulocytosis, and is associated with significant susceptibility of infection. Moderate neutropenia confer an increased infection risk if other immune deficiencies are also present.

Causes of neutropenia

The etiology of neutropenia can be evaluated in terms of the patient background, age and concomitant features, however, the approach most useful is to distinguish between decreased bone marrow production versus increased peripheral destruction (table 1).

 

Table 1
Table 1.

Summary of various causes of neutropenia based on underlying etiology.

 

Evaluation of a patient with neutropenia

In the event that a patient is acutely ill, this needs to be handled as a matter of priority. Once the patient is stable enough, persistent neutropenia needs to be demonstrated, and worked up. In an otherwise healthy patient, serial testing is of immense value.

The evaluation of a neutropenic patient will be guided by determining whether it is a consistent feature, new onset of fluctuating finding, however, the differential diagnosis remains constant.

A comprehensive clinical examination of the patient should actively evaluate for hepatomegaly, splenomegaly and/or lymphadenopathy. The evaluation of the full history should be sought to exclude underlying autoimmune features, persistent infections or constitutional symptoms.

The morphological evaluation of the peripheral blood smear in addition to the serological and molecular exclusion of viral infections, autoimmune disease and as a last port of call, a bone marrow aspirate with trephine biopsy will allow for a more comprehensive clinical evaluation.

Benign causes of neutropenia

Chronic benign neutropenia, familial benign neutropenia and benign ethnic neutropenia are conditions that hold no clinical relevance to the patient in terms of mortality or morbidity risk. For this reason, it may be of value to diagnose, to avoid unnecessary diagnostic testing.

These patients typically have neutrophil counts below 1,5 x 109 cells/L but above 1,0 x 109 cells/L as well as normal full blood counts for all other cell lines and parameters, no features of organomegaly or histories of recurrent infections.

Although genetic association studies have shown a correlation with a polymorphism in the promotor region of the Duffy antigen receptor, this is not diagnostic as 25-50% of African patients with this genetic variant, do not show features of benign ethnic neutropenia.

Conclusion

Neutropenia is a common laboratory finding that does not always hold clinical relevance. For this reason, it should prompt a thorough history and clinical examination to determine its importance within the context of the patient’s health.

References

1. Zhou, J et al. Prevalence of neutropenia in US residents: a population based analysis of NHANES 2011-2018. BMC Public Health. 2023. 23, 1254

2. Mpofu, R et al. Benign ethnic neutropenia in a South African population, and its association with HIV acquisition and adverse event reporting in an HIV vaccine clinical trial. PLos One. 2021; 16(1): e0242708

3. Lakhotia, R et al. Natural history of benign ethnic neutropenia in individuals of African ancestry. Blood Cells Mol Dis. 2019; 77:12-16