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Redefining (AB)Normal

December 9, 2023
Brittany Knick Ragon, MD, (@BKRagonMD)
Atrium Health Levine Cancer Institute, Charlotte, NC

What is normal? It is not uncommon for me to say to my patients, “Normal is relative.” Although that type of commentary feels a bit existential, it is appropriate to reconsider normal, and if necessary, redefine it entirely.  

Several years ago, a patient was referred to me for neutropenia. On review of their chart, I noted that they had a slight macrocytosis, and according to the reference range proffered to me at my institution, they also had neutropenia. Upon meeting them, they imparted their history to me with great pride and enthusiasm: following a cardiac event, they changed their lifestyle dramatically, now fully vegan and with a partner who has authored a book guiding others on the quest for health. Despite their obvious wellness, they asked to keep seeing me annually. Now when we sit down together yearly, we spend time learning from each other. In our most recent visit, we discussed the current science of redefining normal. They humbly supposed that perhaps our reference ranges were just conforming to an abnormal standard. I have been pondering this discussion since.  

With this discussion turning over in my head, the Spotlight Session: What is a “Normal” Neutrophil Count? The Duffy Red Cell Antigen, Ancestry, Genetics and Evolution (Monday, 2:45 p.m. to 4:00 p.m., Convention Center, Hall A) sparked my interest. Maureen Okam Achebe, MD, MPH, a leader in the Duffy Status Project, will serve as chair. Lauren E. Merz, MD, MSc, and John Mark Sloan, MD, will present in what is anticipated to be an extremely popular education session on the heels of the recent call for applications to the Absolute Neutrophil Count (ANC) by the Duffy Status Project, supported by ASH and the Doris Duke Foundation.  

Since learning of this session, I have found myself marveling at the tremendous work being undertaken to educate not only the field of hematology but also health care systems on Duffy-null status and the Duffy-null Associated Neutrophil Count (DANC). Drs. Merz and Sloan have provided valuable insight into what we can look forward to in this upcoming Spotlight Session. Dr. Merz stated that the session will discuss “the biology, genetics, and clinical implications of the Duffy-null phenotype.”

If you are wondering what exactly the Duffy-null phenotype is, well, she has an answer for you. “This is a very common variant that causes lower circulating neutrophils in the periphery without any increased risk for infection. It is most commonly found in individuals of African or Middle Eastern genetic ancestry.”   

Dr. Sloan stated that the central message he is hoping to convey through this session is “to appreciate that DANC is common and does not carry a known increased infectious risk.” He added, “Applying reference ranges and toxicity grading systems developed for white people to people with DANC results in inappropriate care.” Dr. Sloan shared that he once treated a patient with DANC on a myeloma clinical trial who had dose reductions and delays due to a low ANC. “It became really obvious that the protocol was not written for people with DANC, who are essentially living their entire life with what the Common Terminology Criteria for Adverse Events calls a grade 2 toxicity,” he said. “This prevents many investigators from recommending certain clinical trials for Black patients — at a time where we are conscientious about improving diversity on clinical trials, we need to do something about this.” 

For this session, Dr. Merz summarized, “Our main message is that the Duffy-null phenotype is common, normal, and must be better recognized by health care workers in order to provide optimal medical care and address a pervasive form of systemic racism.” She added, “We will outline expected neutrophil reference ranges for this population, provide practical guidance on an individual and systems level, and address clinical implications of under-recognizing this variant such as impact on clinical trial diversity and cancer outcomes.” 

It is as important to redefine abnormal as it is to redefine normal, and one cannot happen without the other. For me, this is a session that cannot be missed. We might witness the final farewell to the vernacular “benign ethnic neutropenia,” to be replaced by the more apt Duffy-null Associated Neutrophil Count. 

“If we don't accurately reflect health for everyone in the way we define normal, we have a rotten foundation and everything else crumbles,” Dr. Merz said. And her message to patients is this: “The Duffy-null population has been unfairly overlooked and excluded from mainstream medicine for too long, and we are finally making changes to fix that.”  

Dr. Ragon indicated no relevant conflicts of interest. 

 

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