Charna Albert
June 2025—The Duffy null phenotype, legal matters, and unmet needs in STI testing are three of the topics on offer at the ADLM meeting next month in Chicago.
Having grown up in Jamaica, Kisha Mitchell Richards, MD, knew anecdotally that some people with African ancestry have an absolute neutrophil count lower than that of white people, and that it doesn’t put them at increased risk for infection. “But it was not something we had a name for, as I was going through medical school,” says Dr. Richards, director of pathology and laboratory medicine at Greenwich Hospital, Yale New Haven Health. In a majority Black population like Jamaica, the lower neutrophil count—due to a genetic alteration called the Duffy null phenotype—isn’t considered low; it’s the norm, she says. The pathophysiology wasn’t necessarily investigated “because it just is.”
In a typical U.S. laboratory, though, “someone with the Duffy null phenotype may have a neutrophil count that indicates they’re neutropenic, but they’re not,” Dr. Richards says. “They just have a neutrophil count associated with the phenotype, which is lower than most of our reference ranges.”
In “Contextualizing the Use of Race in Laboratory Medicine,” Dr. Richards will offer advice and best practices for implementing Duffy status testing. Her co-presenters are Ralph Burns, MD, of the University of Texas Southwestern, who will discuss the debate over the use of race in open neural tube defect risk estimation, and Kelley Tipton, MPH, of ECRI, who will address the impact of health care algorithms on racial and ethnic disparities.
The pathophysiology of the Duffy null phenotype is still being evaluated, Dr. Richards says. But the phenotype is associated with the nonexpression on red blood cells of the Duffy antigen, a glycoprotein that acts as a receptor for the Plasmodium species. The lower ANC is strongly associated with a single nucleotide polymorphism residing in the promoter region of the Duffy antigen chemokine receptor gene that prevents transcription and results in the red blood cell Duffy null phenotype [Fy(a−b−)] (Merz LE, et al. Blood Adv. 2023;7[3]:317–320). “The data suggests this offers protection against Plasmodium vivax,” Dr. Richards says.
Over 60 percent of Black people in the U.S. have the phenotype. Still, Duffy null testing is “not a widely used test or a widely known test,” she says. She had implemented the test in her laboratory at Greenwich Hospital, but it wasn’t until a visit with her family pediatrician that she realized the laboratory would have to assist its patient-facing colleagues with how the test should be ordered and interpreted.
When her family pediatrician expressed concern that Dr. Richards’ son might be neutropenic, Dr. Richards recommended she order a Duffy null phenotype test. “The test was ordered, the result was issued, and it was reported out as Duffy A/B-negative [FyA Neg; FyB Neg], without comment or explanation,” she says. The pediatrician, thinking this meant her son was not Duffy null, wanted him to see a hematologist. It was an “aha” moment for Dr. Richards.
“I needed to change the way we offered the test and issue a comment as to what the result meant,” Dr. Richards says. “The implications of the test would need to have clarity.” Now, she says, when the result is released, “there is a comment associated [with the] result that explains how the test should be used.”
Normally, she says, the Duffy status test would be done in the blood bank. “And nobody would think to order a blood bank test to evaluate neutropenia.” Her number one piece of advice, then, is that the test be a standalone, orderable test. “Someone should not have to dig to find it.” And when the test is implemented, the laboratory should circulate a memo publicizing it and explaining how to use it. Hematologists may be most likely to order it, she says, but pediatricians and primary care physicians should be in the know. “I want them to be able to order this test easily and understand how to use it.”
Uptake at her institution has been slow, but she expects it to increase “when we are able to provide data that implements a reference range for these patients.” As of now, efforts to develop Duffy-null-specific absolute neutrophil count reference intervals are ongoing, with the American Society of Hematology leading a multisite study to validate reference ranges acceptable for clinical use. “Our institution has signed on as an observer, and our goal, once we have these established, is to implement them in our setting,” she says. “Then we can pair that with community outreach that says, ‘This is how you determine the phenotype, and once you have it, this is how you can apply it.’”
She hopes the project will provoke a larger conversation. “I want it to invoke greater thought about all our reference ranges,” she says. “We have to get to a place in medicine where we recognize that uniformity is not the best scenario. We shouldn’t label people with a disease or disorder who have a known phenotype or genetic alteration that is not necessarily a disease.”
Similarly, calling Duffy-null-associated ANC levels “neutropenic” is problematic, Dr. Richards says. (One former, antiquated term was “benign ethnic neutropenia”; an alternative suggested in the literature is “typical neutrophil count associated with the Duffy null phenotype.”) There’s harm in labeling a patient neutropenic when they aren’t, Dr. Richards says, such as unnecessary testing and referrals. “In this population that can least afford to have an extra visit, it’s this very population that we’re sending for an extra visit,” she says. Far worse, patients have had chemotherapy and critical medications like azathioprine unnecessarily withheld, or a reduction in chemotherapy or antibiotic dosage. “It has real implications.”
When should a physician order Duffy status testing?
“If you have a patient with a low neutrophil count and no other abnormality, get a Duffy null phenotype,” Dr. Richards says, noting it’s an inexpensive test. Some, she acknowledges, may worry that patients with true neutropenia will be ignored. “If someone has a low neutrophil count and a fever and low platelets,” that shouldn’t be dismissed, she says. “But I would say in any patient, even patients who identify as white or are white presenting, get a Duffy null phenotype, see what the result is, and put that in the context of all the other information you have.”
Dr. Richards, too, has changed the way she speaks about the Duffy null phenotype. In assuring the physicians involved in her own care or that of her family members that the lower neutrophil counts were clinically insignificant, she would once say, “‘We run low,’” she recalls. “But it’s not that we run low. We run normal.”
Clinical chemists and toxicologists know well that drug immunoassay screens require confirmatory testing.
But some might not be aware that the preliminary results can be subpoenaed in a court of law, even when they include a disclaimer saying the result is for patient care only, not for legal purposes.
“It’s a cumbersome system that I think does not appreciate the subtleties of urine drug screening,” says Jennifer Colby, PhD, chief scientific officer at Premier Biotech, a CAP-accredited forensic toxicology laboratory. “The community at large probably does not appreciate how often results are taken out of context and how damaging that can be.” Dr. Colby will moderate “CSI Clinical Lab: Addressing the Legal Implications of Your Lab Results.”
“The risk is that a decision has already been made long before anyone thinks to ask about the validity or how that result should be interpreted,” Dr. Colby says. She cites a fairly widespread policy, written about in the Marshall Project (https://bit.ly/3YK8UGb), in which hospitals administer drugs to patients in labor and then send the results to child welfare authorities when the patients or their newborns test positive for the same substances on subsequent drug tests. “These are drug screens only, so no confirmatory testing, no speciation of the drug, no understanding of where that [result] could have come from,” she says. One thing those in the laboratory can do is remind their patient-facing colleagues to take care with how tests are ordered, she says. “Sometimes we fall into the trap of ordering tests because that’s what we do. And we don’t necessarily think they could be used in any other context, but they can be and they are.”
“I’ve received those [records] from another laboratory in the process of discovery in a case where I was working as an expert, and I’ve had my own records subpoenaed,” she says. “My interest comes from seeing both sides of this.”
In the session, Patrick Kyle, PhD, will address how to respond when the laboratory is subpoenaed: what materials to take to trial, preparing for a deposition versus in-court testimony, and how to address chain of custody when the sample in question is no longer available. “Even your case notes can be subpoenaed,” notes Dr. Kyle, professor of pathology and director of the clinical chemistry, special chemistry, and toxicology laboratories at the University of Mississippi Medical Center.
His co-presenter, Adina Badea, PhD, will present cases she has encountered and share best practices for minimizing laboratory errors that can have legal consequences. “Everything we present will help our attendees identify scenarios likely to have legal implications and be proactive about how to prepare for them,” says Dr. Badea, assistant professor of pathology and laboratory medicine at the Warren Alpert Medical School of Brown University and director of toxicology for Brown University Health.
One of Dr. Badea’s cases involves a child exposed to street fentanyl. “Upon intubating, the EMTs tend to administer opiates, and in this case, unfortunately, they chose to administer fentanyl,” she says. Although a phone call with the parent admitting the child had been exposed to fentanyl was recorded, “upon seeing this development, the parent changed their tune. This is where it’s important to have a drug screen that includes byproducts or contaminants often found in the preparation of illicit drugs,” Dr. Badea says. “In that case, we had one of these unreacted precursors in the test result to show and to be able to prove” that the fentanyl detected was not the drug the EMTs administered.
Children may test positive for low or subthreshold amounts of substances, Dr. Badea says, “and I, as the medical director, have to decide if it’s in the patient’s best interest to report this.” In one instance, she reported a subthreshold benzoylecgonine in the case of cocaine-induced seizures in a child. “This is where the conversation with the physician comes in, to see if the clinical picture matches,” she says. It was later confirmed in interviews with the child that behaviors consistent with drug use were occurring in the home. “The nature of the exposure got confirmed later as well, but the trigger for the medical investigation was the fact that I saw a subclinical or subthreshold amount of cocaine or benzoylecgonine.”
Months later, she was contacted by a police marshal. “I had to stand firm and say, ‘That was solely for clinical management. I am not comfortable standing by that in court.’” She didn’t see a need to testify, she says, as the parent had already been removed from the care of the child. “But what we will talk about in this session is, what is your responsibility, how can you own your results, and how do you know where to draw the line.” One measure that can be taken: Always include a disclaimer with results that deviate from normal protocols or thresholds. “Another pathologist may see your result and be asked to testify based on their own experience. That’s why it’s important to include these disclaimers,” she says. “It’s like a flag for other pathologists.”
Building relationships with those who are going to be closest to any legal action is also key, she says, noting there is a section at her institution’s children’s hospital that deals with situations of potential child abuse. In one case, a pediatrician reached out to her about a positive drug test. Based on the parents’ response and willingness to be drug tested themselves, the physician was skeptical of the result. The laboratory investigated and found it was a case of a mislabeled specimen container. “That’s how you avoid mistakes that can have permanent impact,” she says, “and then legal action against you down the line.”
Another measure Dr. Badea has taken at her laboratory: If they have a queue for comprehensive drug screening, they run the children’s testing first, minimizing the potential of contamination or carryover. “Beyond that, we always put a blank between each patient to catch any carryover,” she says. And they repeat testing on the original specimen when a result is contentious, even if it has been aliquoted, to ensure the result wasn’t due to mislabeling. “That delays the analysis a bit, but the result can be a child taken away from their home, so we want to be as thorough as possible,” she says.
Dr. Kyle will discuss the timeline for general litigation. “It usually happens months or years after the result was reported, so having the sample in hand for retesting is not an option,” he says. “Often in court it comes down to defending your laboratory’s results or proving their accuracy. With the sample gone, we have to rely on CAP proficiency test results that were performed before as well as after the analysis, or quality control measurements,” or, for example, documents showing that the patients analyzed before the sample in question were negative, proving the result could not have been due to contamination.
Says Dr. Badea, “Sometimes you switch positions, or your role morphs from the time you handled the case until someone decides to contact you about it for legal purposes.” Pristine recordkeeping, she says, is important, “even when you don’t think it’s necessary.”
“Instill these methods or put into practice these safeguards now, because they’re going to serve you at some point,” she says. “And when they do, they are going to be paid back in dividends.”
New point-of-care technologies for sexually transmitted infections show promise but cost is a barrier, especially for uninsured patients, says Nikolina Babic, PhD, D(ABCC), who will moderate “Eliminating Inequities in STIs Using Point-of-Care Testing: Identifying Unmet Needs.”
Point-of-care testing has improved antibiotic stewardship, reduced transmissibility, and shortened emergency department visits, says Dr. Babic, professor of pathology and laboratory medicine and director of clinical chemistry laboratories and point-of-care testing at Medical University of South Carolina. And the recently approved over-the-counter test for chlamydia, gonorrhea, and trichomoniasis “may be a game changer,” she says, though follow-up care still presents a challenge.
Then, too, there’s the problem of how to coordinate between the laboratory, physicians, and outreach programs that test patients in underserved areas. “We keep coming up with new and improved tests, but we frequently don’t have that conversation with all the stakeholders to identify the unique care and management needs of the specific patient population these tests are intended to serve.” Such conversations are essential to developing a plan to address those needs, Dr. Babic says.
Her co-presenters, Vera Tesic, MD, MS, D(ABMM), director of the microbiology and immunology laboratories and professor of pathology, and Aniruddha Hazra, MD, associate professor in the Section of Infectious Diseases and Global Health and medical director of the Sexual Wellness Clinic, work together at University of Chicago Medicine, where the Sexual Wellness Clinic is a collaboration of the emergency department and the infectious diseases section. It provides same-day care, regardless of insurance status, for ED patients whose primary complaint is related to STIs. Dr. Tesic will address the laboratory’s role in meeting clinical needs in STI testing and Dr. Hazra will discuss managing STIs in vulnerable patient populations, after which Dr. Babic says she will lead a panel discussion, continuing “the lab-clinician collaborative dialogue.”
One question they will address: In what specific clinical settings is point-of-care testing appropriate and diagnostically justified?
“You have to offer point-of-care testing where you are able to intervene,” Dr. Babic says. In other words, for patients who can be seen and treated on the same day and would otherwise be lost to follow-up.
The U of C Sexual Wellness Clinic, which provides comprehensive sexual health care for an at-risk population, would be an ideal site for point-of-care STI testing, Dr. Tesic says. Another example is the HIV clinic at MUSC. “A patient with suspected gonorrhea exposure will be treated prophylactically,” Dr. Babic says. “In this particular case, you have to treat before the diagnostic result for gonorrhea is available.” Central laboratory testing, however, may take a few days, and if the result is negative, “you’ve contributed to unnecessary antibiotic use and the growing issue of antibiotic resistance.”
Point-of-care testing is frequently overused, underused, and misused, Dr. Babic says, with the two aforementioned settings examples of underuse. An example of misuse, she says, is when a point-of-care test is offered at a testing location that doesn’t have the means to provide immediate treatment or linkage to care. And an example of overuse would be a situation in which the patient is tested at the clinic but leaves before the test results are available. In those instances, “you might as well send the specimens to the lab,” Dr. Babic says. And in a large organization with a high volume of testing, central laboratory testing may be more effective. “It’s our job to work within our systems and institutions to figure out how and where to deploy point-of-care testing such that we get the most benefit.”
Dr. Babic advises those in the laboratory to take stock of the testing needs and programs at their institutions, particularly in community settings. “With CLIA-waived testing, a lot of physicians and physicians’ offices may implement point-of-care testing without laboratory input. You may be surprised by what’s happening at your institution unbeknownst to you,” she says. Patient-centered quality care is what drives providers to opt for testing at the point of care, Dr. Babic says, but without the lab’s engagement, the performing location and staff may not fully appreciate the chosen test’s limitations, for example. “This is how we end up with overuse and misuse situations. I don’t want the lab to be the last to the table, and to my mind, the laboratory should initiate these conversations.”
“A lot of the time we are reactive,” she continues. “We’re waiting to be asked to bring up a specific test, which is appropriate as testing should be driven by a clinical need. But as clinical consultants, it behooves us to take on a more proactive role,” especially in addressing public health or chronic disease issues with those outside the laboratory less equipped to understand the constraints the laboratory is under.
At the University of Chicago, for example, ED physicians asked the laboratory to validate a point-of-care test for chlamydia, gonorrhea, and trichomoniasis, Dr. Tesic says. The need is constant, “but we are always on the defense, and we have to decline for multiple reasons.”
One reason, she says, is many STI tests, standard as well as point of care, are not FDA cleared for patients under 18. “To better serve our population, we would need tests that would be approved for ages under 18,” she says. “It would be wonderful if we could institute a near point-of-care test in our pediatric emergency department and then confirm it with a different method, which might be needed in sexual abuse cases. But then you’re offering two different tests that are not FDA cleared for that age population, so it adds to the challenges and cost.”
One such challenge, Dr. Babic says, is the test then becomes high complexity. “It’s a staffing challenge, it’s a leadership challenge—it becomes a non-option,” she says. And the cost is an issue for the laboratory as well as the patient. “It’s much more expensive for us to buy reagents for point-of-care testing,” she notes.
Dr. Tesic agrees. “We are unable to offer it because of related costs,” she says, “which are still significantly higher than standard-of-care testing for STIs.”
Charna Albert is CAP TODAY associate contributing editor.