ASH has developed new reference ranges for children and adults with Duffy-null status, a common genetic trait associated with naturally lower circulating white blood cell counts that affects more than 66% of people with African or Mediterranean ancestry in the US. These personalized reference ranges are the first of their kind and will help clinicians accurately determine normal and abnormal white blood cell counts, preventing unnecessary testing. The reference ranges have been published in Blood Advances.
Under standard reference ranges, people with Duffy-null status may be inaccurately flagged as having neutropenia, a type of abnormally low white blood cell count, which is associated with infection or underlying illness and can lead to unnecessary testing like bone marrow biopsies, exclusion from clinical trials, or discontinuation of necessary therapies like chemotherapy.
This is a significant step for individuals with Duffy-null status, who are often told that something is wrong, even when there are no problems with their health. The establishment of these reference ranges addresses a critical health equity concern that has long been needed and will make a lasting impact on the lives of individuals with Duffy-null status."
Robert Negrin, MD, ASH President
What is Duffy-null status?
The Duffy antigen is a protein found on red blood cells, and some individuals have a genetic adaptation in which the protein is naturally absent. People who have the Duffy antigen are considered Duffy-positive, while people without it are considered Duffy-null.
The lack of the Duffy antigen (Duffy-null status) protects against infection with malaria parasites. Individuals from areas of the world where malaria is common, such as Africa or the Mediterranean, have evolved over thousands of years to lose the Duffy marker to help protect them from malaria.
The Duffy antigen also impacts the distribution of the most common type of white blood cell, neutrophils, which help fight infection. Without the Duffy antigen, these individuals also have more neutrophils concentrated in the body's tissues and fewer circulating in the blood, which is where blood draws occur for laboratory testing. As a result, when someone who is Duffy-null undergoes blood testing to measure overall white blood cell count and neutrophil count, their numbers are lower than someone who is Duffy-positive. This can be mistaken as a signal for an illness like infection or cancer.
Reference ranges establish expected laboratory values for Duffy-null individuals
Researchers across 23 sites in the U.S. collected 1,412 samples from Duffy-null individuals to validate adult reference ranges and collect the first data for pediatric ranges. The researchers assessed average absolute neutrophil count (ANC, the number of neutrophils in the blood) and white blood cell count (WBC, the total number of white blood cells in the blood) values for adults and children across four age categories, establishing the following ranges:
- Adults: ANC between 1.03 to 7.30×109/L and WBC between 3.0 to 10.7 ×109/L
- Children 6 months to 2 years: ANC between 0.53 to 4.50×109/L and WBC between 4.4 to 12.6 ×109/L
- Children 3 to 6 years: ANC between 0.78 to 4.67×109/L and WBC between 3.8 to 10.8 ×109/L
- Children 7 to 12 years: ANC between 0.87 to 5.34×109/L and WBC between 2.9 to 10.1 ×109/L
- Children 13 to 17 years: ANC between 0.90 to 4.89×109/L and WBC between 3.1 to 9.2 ×109/L
"Although clinicians have long been aware of Duffy-null status, this knowledge has not yet translated into clinical practice," said study author Maureen Achebe, MD, MPH, clinical director of hematology services at Brigham and Women's Hospital and Dana Farber Cancer Institute and associate professor of medicine and global health equity at Harvard Medical School. "These reference ranges mark a concrete, implementable step for making it easier to recognize what is normal for Duffy-null individuals to avoid unnecessary testing, clinical trial exclusions, and medication restrictions."
Despite different collection strategies and patient populations across the sites, there were no meaningful differences in the reference ranges when these factors were accounted for. Further research is needed to understand the reference intervals for children under 6 months old.
What patients should know
Duffy-null status is not a disease, but a genetic variant associated with lower levels of white blood cells circulating in the blood; this can be misunderstood as a signal of an underlying health condition, leading to unnecessary follow-up testing, cessation of certain medications, and exclusion from clinical trials.
Knowing your Duffy status can help you advocate for appropriate care throughout your health care journey. Duffy status can be determined through a simple blood test, and everyone is encouraged to talk with their healthcare provider about getting tested.
Individuals who have Duffy-null status are encouraged to share their status with health care providers and request that it be captured in their health record using dedicated codes and taken into account for decisions regarding their care.
ANC by Duffy Status Project
This study is part of the ANC by Duffy Status Project, an initiative by the American Society of Hematology (ASH) with support from the Doris Duke Foundation. The project aims to improve care for individuals with Duffy-null status by redefining reference ranges, empowering health care systems, educating health care professionals, and advancing systemic interventions.
As part of its initiative, ASH also published a study in Blood Advances demonstrating that universal pediatric testing for the Duffy-null variant is cost effective, making a strong case for testing for and documenting Duffy status for all children.
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