March 2017—Some modified recombinant factor VIII and IX products for hemophilia prophylaxis show significant reagent-dependent recovery in the one-stage assay, while recovery in the chromogenic assay appears to be more consistent, especially for modified recombinant factor IX. The variable results can lead to over- or underestimating the factor level, warn Stefan Tiefenbacher, PhD, of Colorado Coagulation, and Rajiv K. Pruthi, MBBS, of Mayo Clinic.
They spoke in a recent webinar, hosted by CAP TODAY and sponsored by Novo Nordisk, on the laboratory diagnosis of hemophilia and the pitfalls associated with monitoring factor VIII and IX replacement therapy.
Dr. Tiefenbacher reviewed the status of five modified recombinant factor VIII products: Bax 855 (full length), rFVIII-Fc (B-domain deleted), and CSL627 (B-domain deleted), which have been FDA approved; and N8-GP (BDtrunc PEGylated) and BAY 94-9027 (B-domain deleted), which are in late-stage development.
“Approaches to extend the half-life and to decrease the immunogenicity of these factor VIII products include changes to the protein expression systems, such as, for example, the use of human instead of animal cell lines as well as modifications to the actual therapeutic protein, such as pegylation or Fc fusion,” said Dr. Tiefenbacher, who is technical director and vice president of Colorado Coagulation, Englewood, Colo., a member of the LabCorp Specialty Testing Group.
Three of the products—Bax 855, N8-GP, and BAY 94-9027—use attachment of hydrophilic polyethylene glycol chains to increase the molecular site or mass of the therapeutic protein, thereby reducing glomerular filtration and hepatic clearance through the LRP receptor. The Fc-fusion product uses recombinant DNA technology to link a therapeutic protein such as a recombinant factor VIII to the Fc region of IgG1, allowing the therapeutic protein to bind to the neonatal Fc receptor and thereby protecting the protein from the lysosomal degradation pathway.
“Last but not least, there is also a protein sequence modification in which a covalent bond is introduced between the heavy and light chain of factor VIII, resulting in a single chain circulating factor VIII molecule that demonstrates improved affinity to von Willebrand factor and therefore is thought to demonstrate improved stability compared to native factor VIII,” Dr. Tiefenbacher said. The half-life extensions that these modifications achieve vary from 1.2-fold for the single chain modification (when compared with a recombinant full-length factor VIII) to 1.5- to 1.6-fold for the pegylated and Fc-fusion modifications.
On the factor IX side, there are three new modified products: rFIX-Fc and CSL654, both of which are approved in the United States; and N9-GP. “Similar to the factor VIII side, modifications to extend the half-life of the IX protein include Fc fusion utilized in factor IX Fc, or pegylation—in this particular case, glycopegylation of recombinant factor IX, which is utilized in N9-GP,” Dr. Tiefenbacher said. Referring to the CSL654 product, he added, “Here we, in addition, have a recombinant factor IX protein that is genetically fused to recombinant albumin, which results in half-life extension due to [the] size and long half-life of the albumin.” That effect is related to albumin’s interaction with the neonatal Fc receptor, “protecting the therapeutic protein from the lysosomal degradation pathway, similar to the mechanism of halfway extension for Fc fusion.”
Whereas factor VIII’s half-life is largely determined by von Willebrand factor, the half-life extension achieved with these modifications is much greater for factor IX. That extension ranges from 2.4-fold for the recombinant factor IX Fc-fusion protein to fivefold or more for the glycopegylated and albumin fusion protein.
Dr. Tiefenbacher presented his own laboratory’s in vitro data to demonstrate the aPTT-reagent dependent recovery that occurs when measuring some of these modified recombinant factor proteins in commonly used IVD approved one-stage factor assays. The laboratory compared the recovery of four recombinant factor IX replacement products, one of which was the established recombinant factor IX product BeneFIX. Recovery was compared over the reportable range of the factor assay between 80 and one percent factor IX activity, and the samples were created by spiking the recombinant factor into congenital factor IX deficient plasma.
The results showed that, consistent with the existing literature, glycopegylated factor IX (N9-GP) is significantly overestimated (recovering at around 1,000 percent from expected) when tested using a silica-based aPTT reagent. In contrast, “the other modified factor IX product recovers appropriately in this reagent,” Dr. Tiefenbacher said. “If a laboratory uses this particular silica-based reagent [to measure N9-GP], it will greatly overestimate the activity, and this would likely result in significant under-dosing and mismanagement of the patient.
“On the other hand,” he continued, “when glycopegylated factor IX is tested in one of the commonly used ellagic acid-based aPTT reagents, the product under-recovers at around 50 percent of expected.” This underestimation, he said, “would likely result in unnecessary use of additional product that is not needed.”
The lesson in all this: The recovery for at least some of the modified recombinant factor IX products can vary greatly according to the aPTT reagent used for factor activity determination, and that can result in both over- and underestimation of factor level, depending on the factor IX replacement product and the particular aPTT reagent used.
“On the other hand,” Dr. Tiefenbacher pointed out, “when we look at the recovery of the same recombinant products in a chromogenic factor IX assay, you can immediately see that the modified and the undisclosed, as well as the established recombinant product [BeneFIX], all recover within about 25 percent of each other.” The two modified recombinant factor IX products recovered within established limits across the entire concentration range tested, while BeneFIX, in accordance with other reports in the literature, “slightly under-recovered” across all the concentrations tested.
Dr. Tiefenbacher mentioned, too, that all of the recombinant factor IX products that the laboratory tested in this study recovered at 100 percent at the one percent factor activity level. “This might actually have been an artifact of the assay setup and protocol for this particular factor IX chromogenic assay on this specific coagulation analyzer,” he said. “Additional testing will have to be performed to determine whether the values at the one percent factor activity levels are valid or not.”
Regarding the recombinant factor VIII product, most products—including the B-domain deleted and some of the modified recombinant factor VIII products—recover within about 25 percent of expected in the silica activated PTT reagent. That said, one of the modified recombinant VIII products under-recovers at 50 percent of expected in the silica activated PTT, but recovers appropriately in the ellagic acid-activated PTT.
He pointed out that the B-domain deleted recombinant factor VIII products in the two aPTT reagents shown did not show reagent dependent under-recovery, as previously reported for Refacto, and thus could be expected to be found for both modified and unmodified recombinant B-domain deleted factor VIII. “Also, the established full-length recombinant factor VIII product slightly over-recovers in the ellagic acid-activated PTT used in our study,” he added.
Meanwhile, recovery of the recombinant factor VIII products in the factor VIII chromogenic assay was more variable, with both of the modified recombinant products demonstrating over-recovery across the factor activity concentration range tested. That’s in contrast to some of the existing published data that suggest all modified recombinant products can be measured adequately in the chromogenic assay.
“I should also point out,” Dr. Tiefenbacher said, “that the over-recovery observed for the two modified products could be related to the over-recovery that was observed for the SSC standard, which is the secondary standard to the WHO 6 international standard that was run as a control to verify the assigned value of the plasma calibrator.”
Dr. Tiefenbacher reviewed the challenges clinical laboratories face when using the existing factor activity assays to measure some of these modified recombinant factor products. One of those challenges pertains to the difference between potency assays (those used to assign potency to a factor product) and the clinical factor activity assay used in the laboratory to measure the product.
Factor potency assays commonly use a product-specific standard, a calibrator, that has been verified against the WHO concentrate international standard, whereas clinical laboratories often use a pooled normal plasma standard that the manufacturer has verified against the WHO plasma international standard. With a product-specific standard—but not with a pooled normal plasma standard—any potential nonlinearities for a modified product in a particular reagent system are likely to be masked.
For factor VIII products, potency assignment in accordance with recommendations of the European Pharmacopoeia is commonly performed using the factor VIII chromogenic assay. To date in the U.S., factor product activity in clinical laboratories is still performed predominantly using a one-stage aPTT-based assay. To account for that potential difference, Dr. Tiefenbacher advises, it’s important to make sure that the factor assay used for post-infusion monitoring aligns with either (or both) the assay used to assign the potency to the product or the assay used to demonstrate clinical efficacy of the product in clinical studies. “This is often easier said than done,” he pointed out, “as it is often not common knowledge what assay system and/or reagent was used during registration of a particular product.”
A second challenge is the inherent variability that exists for one-stage factor VIII and IX activity assays between different clinical laboratories, as demonstrated in CAP Surveys and other proficiency testing. Significant interlaboratory variability (for example, around 30 percent at normal factor levels, with up to 70 percent at factor levels below 20 percent) for both the factor VIII and IX one-stage assay has been observed.
In a recent CAP Survey, he said, “a normal plasma sample with an anticipated value of 100 percent yielded results ranging between 72 and 161 percent,” depending on the aPTT reagent used and the laboratory performing the testing. That inherent variability in the one-stage factor activity assays only makes it more difficult to evaluate and interpret factor activity data for the modified products when generated across different one-stage assay systems and laboratories.
Yet another challenge: Data are limited regarding the behavior of some of the modified recombinant factor replacement products in the one-stage and chromogenic factor assay reagents commonly used in U.S. clinical labs. In fact, such data are currently available for only two of the five modified recombinant factor VIII products, namely, Bax 855 and factor VIII Fc, and for only one of the three modified recombinant factor IX products for factor IX Fc. Ideally, information regarding whether a modified replacement product demonstrates aPTT reagent dependent recovery would be addressed before the product is launched so it can be included on the product label as required.
Finally, although the medical and scientific advisory council of the National Hemophilia Foundation recommends the use of chromogenic factor activity assays for monitoring the modified products, factor VIII and IX chromogenic assays are still infrequently used in clinical laboratories. “Only three of the five available factor VIII chromogenic assays—more specifically the Coatest SP, the Coamatic, and the Siemens factor VIII chromogenic assay—are currently IVD approved for clinical use in the U.S.,” Dr. Tiefenbacher said. “Of these three, only the Siemens [assay] is IVD approved for use on an automated coagulation platform. The remainder of the factor VIII chromogenic kits are currently IVD approved for manual plate-based use only.”
On the factor IX side, only two chromogenic assays are currently marketed in the U.S., neither of which the FDA has evaluated and both of which are thus RUO-labeled. Furthermore, for the factor IX chromogenic assays, only limited validated instrument applications and/or coagulation instrument protocols are currently available, restricting their use to what he called “more expert-level labs.”
Dr. Rajiv Pruthi, director of Mayo Clinic’s Comprehensive Hemophilia Center in Rochester, Minn., used two case examples to illustrate potential issues that laboratories may encounter when monitoring the new modified recombinant factor concentrates. Prophylaxis via scheduled administration of concentrates has become the standard of care for hemophilia management, and patients are generally taught to self-administer factor concentrates at home.
“The half-life of the current generation of unmodified factor concentrates varies,” said Dr. Pruthi, who is also an associate professor, Mayo Clinic College of Medicine, and co-director of Mayo Clinic’s special coagulation laboratory. For factor VIII, the half-life is between eight and 12 hours, whereas the half-life for factor IX is between 18 and 20 hours. “Based on this, the typical practice is to infuse the unmodified factor VIII concentrate about three times weekly, and the factor IX concentrate is typically administered two times weekly.”
The target trough factor level is usually greater than one percent. “Typically, we like to target between one and five percent,” Dr. Pruthi said. “Targeting that level completely changes the frequency of bleeding that severe hemophilia patients experience.” However, there’s wide variability between patients in the half-life of these factors. To provide the most cost-effective therapy, individualized pharmacokinetic studies are usually performed so the dosing can be tailored to each patient.
He shared a slide illustrating the results of a typical pharmacokinetic study for an unmodified and a modified factor VIII concentrate. In this trial, the half-life of the standard factor VIII was compared with that of a modified factor VIII. The data illustrate the time it takes for the factor levels to decrease from a post-infusion level of about 100 percent to a trough of between one and three percent. For the unmodified concentrate, it takes about three days to reach that level; for the modified factor VIII concentrate, it takes about five days. It takes about four days for the standard factor IX concentrate to get down to between one and three percent, but with the modification of the factor IX molecule, the time to a trough level of one to three percent is extended to about 10 days.
“There is a wide inter-individual variability,” Dr. Pruthi reminded the audience. “One of the consequences of inaccurate measurements is that with under-dosing of the factor concentrate, you may increase the risk of bleeding. However, if you over-dose the factor concentrate, you may increase the risk of thrombosis. You certainly will be increasing the cost of care.”
He presented the case of a 20-year-old male with severe hemophilia A who was switched to a modified factor VIII concentrate, and whose pre-infusion baseline factor level was less than one percent (normal range, 55 to 200 percent). “We calculated the dose he would require to target a peak factor VIII level of approximately 60 percent,” Dr. Pruthi explained. “However, when we measured his post-infusion level, it was actually only measured at 30 percent using the one-stage assay. So when this happens, there are several questions one has to address.” For example: Were the sample collection and transportation done correctly? Was the assay the right assay for this concentrate? Did he receive the ordered dose?
“Once the preanalytic and analytic aspects of the assay have been investigated and the assay’s result is not felt to be erroneous, the typical next step is to increase the dose of the recombinant factor concentrate and recheck the pharmacokinetics,” he continued. “Now, if that result was inaccurate and we would be increasing the dose, then definitely we would be increasing the cost of care and potentially putting the patient at a higher risk of thrombosis.”
His team realized the reagents used for the one-stage assay performed on this plasma sample underestimated the true factor level by about 50 percent for this modified factor concentrate. In fact, the package insert for the modified concentrate recommends that the one-stage assay result be multiplied by a factor of two. In other words, the patient was on the right dosage—it was just that the one-stage assay result had to be multiplied by two. The result of a chromogenic factor VIII assay confirmed such.
In the second case, a 12-year-old male with severe hemophilia B was referred to Mayo Clinic’s hemophilia center for help switching to the new modified recombinant factor IX concentrate. His dosing was calculated to achieve a trough level of five percent, and indeed his pre-infusion factor IX was five percent. An hour post-infusion, he reached a peak level of 80 percent.
“So the patient was referred back to his local care provider with the advice that the pharmacokinetics should be rechecked at some point, and between going back to his provider and coming in for a recheck of his pharmacokinetics, the patient experienced no bleeding events since initiation of the prophylaxis,” Dr. Pruthi said.
But when the pharmacokinetics were rechecked at one point, the results—obtained in a local laboratory—demonstrated that his pre-infusion or trough level was less than one percent, while his post-infusion peak level was only 40 percent.
The patient’s primary care provider had planned to increase the dose of the modified factor IX concentrate but contacted the Mayo Clinic hemophilia center for advice. The center determined that the local laboratory was using an aPTT reagent based on a kaolin activator for the one-stage assay, and this kaolin activator was known to underestimate the true factor IX level for this particular product. A sample was mailed to the laboratory affiliated with the hemophilia center, which confirmed the results of the original pharmacokinetic study.
“So the underestimation of the true factor level has a significant consequence,” Dr. Pruthi stressed. “You may be increasing the dose of factor infusion, overdosing the patient, increasing the cost, and putting the patient at risk for thrombotic complications. Whereas if you overestimate the true factor level, the potential consequence is you would reduce the dosage of the factor concentrate and potentially increase the risk of bleeding.”
This is a complex situation with multiple potential solutions, some more practical than others. For example, each laboratory could have an individualized calibrator for each concentrate for which it will potentially perform assays. However, the information regarding which concentrate the patient is on might not be communicated to the laboratory. And maintaining assays with different calibrators poses special challenges to both low- and high-volume laboratories.
“What about chromogenic assays?” he said, referring to Dr. Tiefenbacher’s outline of the available factor VIII kits. “There are no currently FDA-approved factor IX kits. And so each lab would have to validate a kit as a laboratory-developed test, which poses unique regulatory challenges and is very time-consuming and expensive.” Finally, one could multiply the one-stage assay result by a correction factor, as one of the cases showed. “However, each hemophilia care provider would have to be aware of such recommendations to ensure that the correct correction factor is being applied.”
Dr. Pruthi concluded by stressing again that exclusively using one type of assay may lead to misclassification of non-severe hemophilia or even a missed diagnosis, and when monitoring factor concentrates, may lead to over- or underestimating factor levels. “Hemophilia care providers should be made aware of these assay-related issues,” he said, so as to avoid risking incorrect dosage adjustments of the factor concentrates.
Anne Ford is a writer in Evanston, Ill. See the March 2017 issue for the guidance of Dorothy M. Adcock, MD, on the initial evaluation of non-severe hemophilia A.
William Check, PhD
Numerous preanalytical and analytical factors affect the results of these assays.Will she be able to reproduce that activity at the University of Kentucky Medical Center? And how realistic is it to think DMTs can become more commonplace?
April 2017—For decades, Michael Laposata, MD, PhD, chair of pathology at the University of Texas Medical Branch in Galveston, has touted the value of diagnostic management teams, and in February he led the first conference dedicated to such teams, referred to as DMTs. There, Alison Woodworth, PhD, told the story of how and why she created a DMT for primary hyperaldosteronism, what it achieved, and where her DMT focus is now.
“Primary hyperaldosteronism is a complex disorder that is challenging to diagnose,” she said at the conference, held in Galveston. Interpreting the screening test for primary aldosteronism, or PA, is one of the main difficulties. “We in pathology are really needed to assist clinicians in understanding what the laboratory tests mean and in understanding the limitations of laboratory tests,” said Dr. Woodworth, an associate professor of pathology and laboratory medicine and director of the core clinical laboratory and point-of-care testing at the University of Kentucky Medical Center.
A few years ago, when Dr. Woodworth was director of esoteric chemistry at Vanderbilt University Medical Center, she established a diagnostic management team for PA and evaluated its clinical utility. The DMT assisted in the diagnostic workup for PA. “We reduced the number of unnecessary tests and helped with more efficiently diagnosing the patients,” Dr. Woodworth said. Before the DMT, four of 32 patients had unnecessary testing or procedures and eight had potential delayed or missed diagnoses. After the team was implemented, there were no perceived unnecessary tests or procedures and no delayed diagnoses.
At the University of Kentucky, Dr. Woodworth is going through the process of implementing a DMT for PA in a more sophisticated format that includes implementing aldosterone and renin assays with fewer preanalytical interferences. She plans to institute a DMT for yet another challenging endocrine condition: measurement of thyroid function in pregnancy.
Dr. Woodworth embarked on her journey into the world of DMT at Vanderbilt when Dr. Laposata was Vanderbilt’s vice chair of pathology.
“When Mike came to me at Vanderbilt and said, ‘Implement a diagnostic management team in chemistry,’ I think you all can appreciate how overwhelming that seemed at the beginning,” she said at the conference.
Overwhelming, for one, because the breadth and volume of a clinical chemistry and core laboratory make it a huge task to select a condition for which to set up a DMT. “At the University of Kentucky, and probably at most of your hospitals, the clinical core laboratory is the largest laboratory by far, in terms of volume and in terms of employees,” she said. Annual test volume is about five million. “It’s a huge scope and obviously we can’t do a diagnostic management team and interpret the 20,000 laboratory test results that come into the clinical laboratory every day,” Dr. Woodworth said.
The core clinical lab serves the highest acuity patients, and rapid turnaround times are often required. It’s a complex, high-paced, fast-throughput, and automated area with a lot of volume, she said: “How do we determine just what to implement in a diagnostic management team?”
Dr. Woodworth listed three main steps in choosing which area to develop into a DMT: talk to clinical peers, choose an area with a manageable volume, and look for an application with a clinical guideline in which interpretation of laboratory data supplements results.
She began at Vanderbilt by consulting with endocrinologist Andrea Utz, MD. “At the beginning she really wasn’t sure that we in pathology could contribute to the patient care team,” Dr. Woodworth said. “It took some time and negotiation, but we did get to a point where we were able to communicate and have reasonable discussions about what might be important to implement.”
For test volume, “we have to have a test that’s of a manageable volume,” Dr. Woodworth said, “because we only have so many residents and fellows,” who do much of the interpretive work.
Third, “There needs to be a clinical practice guideline or some sort of evidence that we can base our interpretive reports on and not just expert opinions.”
For endocrinologists, a DMT raises concern because their job is to interpret esoteric laboratory test results. “I clarified to Dr. Utz that I wouldn’t be telling her how to interpret lab tests,” Dr. Woodworth tells CAP TODAY. “I told her I would be addressing my interpretations to an audience that has a huge volume of tests to interpret—primary care physicians and nonspecialists.” Dr. Utz eventually embraced the whole process. “She could see there could be a benefit to her service.”
Dr. Woodworth asked Dr. Utz, “How often do you get consults in which the laboratory tests were misinterpreted? How often do you see patients who are walking around out there who are not diagnosed but who have an endocrinopathy you are concerned about? Where do you most experience inappropriate lab testing—underutilization or overutilization?”
Dr. Utz named three areas that fit these criteria: thyroid disease, Cushing syndrome, and primary aldosteronism. In many cases, she said, the primary care physicians will see these patients first and they’re often confused about what tests to order and how to work up these patients. And when the results come back, they are often misinterpreted.
“The good news,” Dr. Woodworth said, “is that all three of these conditions have clinical practice guidelines that help guide the clinician’s workup for potential disease.
“I think what really drove our decision was daily test volume,” she said. “Thyroid function tests in a laboratory, particularly TSH, are about 500 a day. At Vanderbilt that was the volume, and I think that’s typical for academic medical centers of similar size. Cortisols were about 50 to 100 per day. But the screening tests for primary aldosteronism, which are plasma renin activity and aldosterone, were about 10 per day, so that was a manageable test volume that would allow our residents to identify and interpret these test results in a meaningful way.”
Setting up a DMT can be overwhelming not just because of test volume but because of the large number of people in diverse disciplines that it takes to make the team function successfully. In addition to the physicians and other medical personnel, “we also had to have people who knew the business side of things,” Dr. Woodworth said, and for this the dean’s office provided project management support. “We also had support from IT for the different aspects of programming, the EHR and/or the LIS, depending on how we wanted the results to end up in the medical record.”
Also “crucial,” she said, was a knowledge-based management resource called the Center for Knowledge Management, centered in the university library. She found clinical practice guidelines somewhat lacking in references to the primary literature. Center for Knowledge Management staff would fill that gap. “We would say, ‘Well, the guidelines say you shouldn’t measure aldosterone in the presence of this hypertensive med; please go back to the primary literature,’” Dr. Woodworth recounts. “And they would come back with a beautiful evidence-based summary that helped guide our decision-making.”
Finally, “No diagnostic management team can happen without the input of the clinical chemistry fellows and pathology residents.”
To help understand better the value of a DMT for PA, Dr. Woodworth explained the normal physiology of aldosterone and renin in blood pressure regulation and the pathophysiology of PA.
“Blood pressure is regulated in huge part by the renin-angiotensin-aldosterone system [RAAS],” she said. Low blood pressure and low sodium concentration lead to upregulation of renin from the juxtaglomerular membrane cells in the kidney, which signals conversion of angiotensinogen ultimately to angiotensin 2. Angiotensin 2 in turn acts on the adrenal glands to upregulate aldosterone secretion, which then acts on the distal tubule of the kidney to retain sodium at the expense of potassium excretion. Water follows sodium, so blood pressure goes up and sodium concentration in the blood goes up as well.
Autonomous secretion of aldosterone by the adrenal glands that is not suppressed by high blood pressure and high sodium causes dysregulation of the RAAS, which defines primary aldosteronism. “Primary aldosteronism is actually one of the more common forms of secondary hypertension,” Dr. Woodworth said. “It is the most common form of endocrine-mediated hypertension.” It has three main etiologies: aldosterone secreting tumors of the adrenal gland, bilateral adrenal hyperplasia, and, in rare cases, a familial form. Up to 15 percent of hypertensive patients may have PA.
The long-term effects of autonomous secretion of aldosterone are hypokalemia, severe hypertension, and damage to the cardiovascular system, along with sodium retention and suppressed renin activity. Because of its impact on the cardiovascular system, there have been numerous studies on how to work up primary hyperaldosteronism, Dr. Woodworth said. The Endocrine Society published practice guidelines for this workup in 2008 and updated them in 2016.
With aldosterone and renin central to this homeostatic system, it is logical that screening begins with measurement of the aldosterone-to-plasma renin activity ratio. In patients who have two abnormal screening tests, a confirmatory test is done. Typically, a confirmatory test is something that will challenge the RAAS. “The most common is a saline suppression test,” Dr. Woodworth said. “When we infuse saline, it will ultimately result in downregulation of aldosterone. However, in a patient with primary hyperaldosteronism, aldosterone will remain autonomously secreted and elevated.” But among the most important aspects of the workup is a strong screening test.
Who should undergo a screening test for PA? “The Endocrine Society practice guidelines state that we should only screen those at high risk for primary hyperaldosteronism,” Dr. Woodworth said. High-risk candidates include those with sustained high blood pressure on three different measurements over the course of several days; hypertension that is resistant to at least three hypertensive drugs; a patient who has controlled hypertension but only on four or more antihypertensives; or a patient with hypertension plus hypokalemia or hypertension plus sleep apnea. An indication of a genetic component also calls for screening, such as a person with hypertension who has a first-degree relative with primary hyperaldosteronism or a patient with hypertension with a family history of early-onset hypertension or stroke.
The aldosterone-to-plasma renin activity ratio can be measured in two ways. “Typically, in the United States, we use an aldosterone immunoassay and we measure the activity of plasma renin activity through an activity assay,” Dr. Woodworth said. In many of these cases renin activity is suppressed because of the RAAS. (Renin secretion is downregulated in the presence of high blood pressure and/or elevated sodium.) “When you have suppression of renin, the aldosterone-to-renin ratio will be high inherently,” she noted, “and so the new guidelines suggest that we shouldn’t just use the ratio of aldosterone to renin, but we should also use aldosterone concentration.” An aldosterone-to-plasma renin activity ratio, or ARR, greater than 30 with a plasma aldosterone concentration above 15 ng/dL are cutoffs most commonly cited as diagnostic for primary aldosteronism.
Most patients with PA have hypokalemia; low potassium leads to altered results for aldosterone and ARR. Sodium status is critical for maintaining the RAAS. As a result, there will be different results for plasma renin activity, aldosterone, and the ratio, depending on the patient’s diet. Posture is also a factor: Patients who are sitting upright have a higher ratio than those who are supine. And diurnal variation affects aldosterone and plasma renin activity, with both highest in the mid-morning.
Numerous medications affect the RAAS. Most prominent among them are antihypertensive medications, such as direct renin inhibitors and ACE inhibitors.
In the revised 2016 Endocrine Society practice guidelines on diagnosing PA are evidence-based recommendations for how and when to measure aldosterone and plasma renin activity. “They say you should correct the hypokalemia prior to performing these tests,” Dr. Woodworth said. “Also that you should liberalize sodium intake and discontinue many antihypertensive medications for two to four weeks. Specimens should be collected mid-morning and the patient should be awake and sitting upright for a certain amount of time because of diurnal and postural effects on aldosterone and renin.
“I’m sure that you’re sitting there thinking about how difficult it is to take patients off of these medications,” Dr. Woodworth said to the conference audience. “And that’s exactly what my endocrine partner said when I told her we had to take everybody off the medications prior to measuring these things. Sometimes it’s actually not safe for the patients. The side effects associated with going off these antihypertensives are severe, and in some cases it’s not possible. So one of the things we did was to look at how often our clinicians were measuring renin and aldosterone in an appropriate and an inappropriate way.”
Dr. Woodworth and Vanderbilt clinical chemistry fellow, Joesph Wiencek, PhD, studied 200 patients who had been worked up for PA by having aldosterone and plasma renin activity measured and the ratio calculated. “We defined suboptimal sampling conditions as samples with at least one interfering medication, those that were collected at the wrong time of day, those without known potassium status or with abnormal potassium concentration, or specimens with unknown or abnormal renal function,” Dr. Woodworth said. What they found was alarming: 85 percent of specimens were collected in a suboptimal manner. Only 15 percent were collected correctly.
“If you can’t have optimal conditions for collecting these specimens, what should you do?” Dr. Woodworth asked. The 2016 Endocrine Society practice guidelines suggest that laboratory results for aldosterone and renin be interpreted in the context of confounding factors. How can laboratorians ensure that? “The diagnostic management team,” she replied. “We were pleased with our efforts because we had implemented the diagnostic management team about two years prior to the Endocrine Society recommendations.”
Dr. Woodworth showed an example of how the team interprets results in light of the clinical history and confounding factors. “The true definition of a diagnostic management team is one that meets regularly,” she noted. “Our diagnostic management team [at Vanderbilt] met twice a week because we performed testing for renin and aldosterone twice a week. Our residents and fellows looked up clinical histories relevant to all the factors that affect test results and looked for risk factors for primary aldosteronism.”
The interpretations included insight into what these test results might mean in the context of interfering medications, comorbidities, or clinical history. “And then we provided evidence-based recommendations to help the clinicians understand what the test results mean. We included risk factors, uncontrollable hypertension, hypokalemia, and then potassium and renal function status. We talked about the drugs that the patient was taking”—in this case lisinopril and amlodipine—“and we talked about how those are known to decrease the aldosterone-to-renin ratio.” (See “DMT-driven interpretation of high-risk hypertensive patient,” page 18.)
Despite that, the aldosterone-to-renin ratio was 102, and, as mentioned, the cutoff for a potential positive for primary aldosteronism is 30. “So this was probably primary aldosteronism, but because this was a screening test, we advised that the patient seek an endocrine consult for confirmatory testing.” Two links were appended: one for more information on the effects of the different drugs and comorbidities on aldosterone and renin, and the aldosterone-to-renin ratio, and another for information on collection requirements.
Dr. Woodworth and colleagues conducted a study to determine the clinical utility of the endocrine DMT. They studied four primary care practices in two periods—one year before and a little more than one year after implementing the DMT.
“Before, we had 32 patients who had been worked up for suspected primary aldosteronism,” Dr. Woodworth said, “and after we had 27. We reviewed the electronic medical records for how the patients were worked up, the diagnoses, the outcomes, and whether we were able to save unnecessary tests. We looked to see how quickly the diagnosis occurred, whether we thought the diagnosis occurred efficiently, or was delayed.”
Before implementation, four patients had unnecessary procedures, either imaging or lab tests. Potential delayed or missed diagnosis was “quite common,” Dr. Woodworth reported, “because physicians did not understand how to interpret the results of the aldosterone-to-renin ratio in the context of the medications the patients were taking. Eight patients were deemed to have either delayed or missed diagnosis.” Post-DMT, there was close adherence to the Endocrine Society practice guidelines and no perceived unnecessary testing or imaging procedures. Moreover, the five patients who were advised to have an endocrine consult did have the consults and follow-up care was appropriate.
“I got really great feedback” from clinicians about the DMT, Dr. Woodworth said. “In fact, every time Dr. Utz would get a consult as a result of the diagnostic management team, she would call me, very happy that we had provided care for the patient and that they were able to see the endocrinologist quicker.”
PhD scientists can’t bill for these consults. “Why don’t we care about billing?” Dr. Woodworth asked. The answer: Because DMT consults are good for the patient, and they are a value-added practice. “We’re providing a quicker diagnosis and fewer unnecessary tests,” she said, “so we feel like it’s a win-win for the patient.”
“We are instituting DMTs at UK. I just presented the concept of lab utilization bundled with DMT to the CFO, CMO, and CEO. They were overwhelmingly supportive. We have support from the dean’s office and the pathology department.” Her biggest challenge will be working through necessary IT upgrades, “which was also true at Vanderbilt.”
One of Dr. Woodworth’s Vanderbilt colleagues, Jeremy Hart, MD, is also now at UKMC. She and Dr. Hart are on what Dr. Woodworth calls “an evangelical campaign to convert people to DMT.” They are showing data from Vanderbilt to build support among clinicians.
Dr. Woodworth will be moving one step beyond the institutional implementation of DMTs. She will propose a grant looking at how to implement DMTs. It is a targeted NIH proposal that studies the barriers to implementing processes beneficial to patients.
As for wider dissemination of DMTs, Dr. Woodworth said, “A lot of pathologists are doing something like this informally.” Dr. Laposata’s formal definition of a DMT says it must meet regularly and its interpretation must go into the patient’s chart and contain clinical information, be incorporated into the electronic health record, and be specific to that patient and relevant to patient care. “Maybe they don’t have all of these elements,” she said. “A lot of times it’s just about formalizing the process and collecting data showing its benefits.”
Can the DMT concept be extended to higher-volume tests, like the thyroid function test or workup for Cushing syndrome? Dr. Woodworth is optimistic. “In the age of informatics and big data and all the things we’re doing with next-gen sequencing, I feel like we could get to the place where we could provide personalized medicine for some of these higher-volume tests. But it would require powerful informatics tools and algorithms that we had developed ahead of time.”
The next step for the endocrine diagnostic management team is to help physicians understand the context in which they should collect the specimen and measure it. “We can’t fix all of the suboptimal conditions but we can fix many of them,” Dr. Woodworth said. She also wants to expand to other areas of endocrinology that are ripe for developing DMTs, such as thyroid function testing in pregnancy. “This is an area in which the volume would be manageable and there are lots of problems in test ordering and interpretation.”
At Vanderbilt Dr. Woodworth studied ordering patterns for thyroid function testing in pregnancy to see whether clinicians were adhering to clinical practice guidelines. “Guidelines say you should screen pregnant patients at high risk for thyroid dysfunction by measuring TSH. That wasn’t what was happening. Some practices were screening everyone,” she says. Another error was that obstetricians were measuring TSH with free T4. “So they were not screening the right population, and they were not ordering the right test. Also, when results were abnormal, they were not following up correctly.”
She did a root-cause analysis to understand the problem and found that practices doing universal screening had new obstetric patient order sets that included both TSH and T4. So the order set drove universal screening and use of the wrong test. “With regard to follow-up, they couldn’t easily see trimester-specific reference intervals in the EMR,” she said.
Building on these findings, Dr. Woodworth is working at UKMC to improve thyroid function testing ordering in pregnancy. “I am working with the endocrinology fellows here to do a similar study. We are going to put in place a diagnostic management team to mitigate the problems of misordered tests and improper workup.”
William Check is a writer in Ft. Lauderdale, Fla. The second Diagnostic Management Team Conference will take place Feb. 6–7, 2018 in Galveston, Tex.
April 2017—Quarantine, antisepsis, sanitation, vaccination. Over more than a century and a half, as these staples of public health have evolved, they have proved that stunning improvements in general health status can result from adopting broad public policies based on data and statistical analysis.
But just in the past few years, the concept of “population health” has been grabbing attention as a framework for strategizing more tailored improvements in patient care—with laboratory data as one of the linchpins of those strategies. Large health care systems and diagnostics companies, among others, are increasingly seeing the value of a population health approach to process improvement.
As experts in the field explain it, population health is similar to public health but addresses more finely sliced subsets of people receiving health care. Keri Donaldson, MD, founder and chief executive officer of Prescient Medicine, prefers the term “population health management” because it connotes action. Population health management is more targeted than traditional descriptive public health policies, he says, because it “provides for a comprehensive way to classify conditions and stratify risks or underlying health trends across multiple data sources into one analytic stream so we can determine which ones are influencing public health.”
After identifying populations at risk through laboratory and demographic data analysis, population health management makes it possible to focus resources on that subset at risk, he explains. “You’re really drilling down on interrelated conditions that influence health over the course of a life, and what systemic variations may influence those conditions.”
For example, a simple proactive public health approach might say women should be offered or receive age-appropriate breast cancer screening consisting of self-exams, annual physicals, and mammograms. “But the general idea of a population health management approach is recognizing that we are in a capitated environment with limited resources, so let’s focus on where the current system is failing. By determining gaps in the current system, identifying the patients who have a high likelihood of benefiting from additional re-sources—the ones who are at highest risk—we can design interventions that can help change the outcome before it occurs or progresses.”
“A good population health approach really tries to answer the question: ‘So what?’” says Dr. Donaldson, who is also medical director of Penn State Hershey Institute of Personalized Medicine. “You can see you have genetic variation that places you at higher risk for cancer, or you have under-reported diabetes, or you have 50 percent of the population that is not on statin but should be. But those are just facts or statistics. Population health allows us to address these questions, ‘What are you going to do about it? How do you change that?’”
Prescient Medicine is a predictive medicine organization that offers predictive intelligence, Dr. Donaldson says. “We believe that earlier identification of risk and earlier detection of disease leads to more informed decisions.” Early at-risk patient identification and surveillance, reduction in unnecessary procedures, early identification of changes in prescribing practice, and custom, multifactorial decision support are among the services Prescient provides.
A collaborative blood services module, which can overlay or be built within any LIS or EMR, is an early success, he says. “It’s been able to reduce the red cell utilization rate significantly—by 17 to 20 percent just in nonsecular trend analysis. If you take into account secular trends, the number is 30 to 40 percent. In a midsize institution, that’s millions of dollars per year.”
Haemonetics is a competitor of Prescient in blood utilization, but in other areas of population health management, “Prescient has no defined competitors,” Dr. Donaldson says. “We’re sort of a trailblazing kind of organization. If you look at comprehensive opioid solutions or pain management or pain control, not a lot of people are playing in that space. In addition, many people are dropping out of personalized genomics because they can’t figure out how to make it make money. I think 14 or 15 PGx labs closed last year.”
One way pathologists can improve disease outcomes is by looking for opportunities within the hospital or system to implement a rule in the electronic health record to better identify a patient population, Dr. Donaldson says. With its oral anticoagulation module, for instance, his group found that some patients at zero risk who should not have been on an oral anticoagulant were receiving it, while only about 80 percent of those at high risk were receiving it.
“So you ask, should we change how providers are interacting with patients? Send them a letter? Post flags?” The project leaders realized there was an opportunity to improve care. “So we’ve gone through and conditioned decision support on this idea. Providers receive a letter saying: ‘Is this a purposeful action? Are you purposely not giving that patient an oral anticoagulant even though you know they have an overall risk-of-stroke score of six?’”
Some areas in which Prescient has programs, such as the comprehensive metabolic panel, are contained within the lab. At one time, in a more basic laboratory information system, built-in rules would put a hard stop on repetitive ordering of the panel and halt testing at the point of receipt, Dr. Donaldson points out. “The lab would see that the order was for a test with a previously normal result within 24 hours. That violated the rule, and they would throw it out.”
The real source of expense is not in performing extra tests that waste only pennies, however. It’s when one of the tests is abnormal and is followed up with unnecessary workups, he says. In its study at a 1,200-bed hospital system, Prescient moved beyond the old LIS model to cumulative probability analysis. “If I have one normal calcium, how likely is it that the second calcium in a single admission is going to be normal? What about after two normals or three normals?” The algorithm set a time limit on how many comprehensive metabolic panels can be ordered within a day.
The result was a more than 50 percent reduction in the number of glucose and chloride tests ordered, 40 to 50 percent reduction for magnesium, 60 percent for phosphate, and 30 percent for albumin. Prescient is now implementing the next version of this algorithm (linking it to ICD, location, point of order, or indication) in its logic engine. Eliminating standing orders was another application of this same algorithm.
But population health can also relate to an evolution of lab information outside the laboratory, to the systems-based enterprise level, Dr. Donaldson says. “Our original work on areas like urine microanalysis was done at a 550-bed hospital. We modeled it using lab-stored specific data as well as some demographic data, but you don’t have control of decision support within an LIS or at the EHR level.”
“Our type of decision support lives at a data universe that allows application programming interfaces, and those APIs overlay any input or output. So the data may come from the LIS or the EHR, but [for some areas], you’re at a level outside the LIS.” For instance, for drugs of abuse and pain management—an expanding area for Prescient, which has active programs in Pennsylvania, New Jersey, Florida, and Missouri, with Illinois on deck—the customer base tends to be broad with diverse applications.
Closing the quality gap is the key for hospitals as well as insurers, and simply not performing a test is one way to reduce health care dollar outlays, he says. “For example, a lot of people close the quality gap on catheter-associated urinary tract infections [CAUTIs] by just not culturing these patients. We actually prevent CAUTIs from occurring by using high-sensitivity multi-parameter urinalysis. That gives you an opportunity to increase return directly with the insurer, or through partnering with Prescient customers, whether they are small mom-and-pop shops or a very large enterprise. If you chew through their data, you can increase return and decrease costs.” Depending on the desired outcome, that could be identification of diabetic patients, increased compliance with a statin regimen, or decreased length of stay for hysterectomy patients.
Prescient’s ability to address risk factors through population health management connects directly to its business model. One example: “One of the things that’s hot right now in psychiatric hospitals is if they define and treat comorbidities appropriately, they get a higher reimbursement. If they are treating a person for psychiatric illness but the patient also has renal disease, hypermetabolic syndrome, or an infectious disease, they receive more if the comorbidity is classified and treated appropriately. So as an analytics firm, if we help you define testing for that population or to classify disease better with the testing you’re already doing, Prescient’s value to the client can be directly measured with the increase in recoveries.”
As a long-time public health specialist, James Halloran, MSN, RN, CNS, FAAN, deputy chief consultant for strategy and planning in Population Health Services at the U.S. Department of Veterans Affairs, confesses he might be a bit biased. He does see “public health” and “population health” as very similar. “There are certainly tools in the public health armamentarium that we use in population health, especially surveillance and epidemiologic procedures.”
But no one has a copyright on the term, and the VA’s model emphasizes that population health involves attention to nonclinical social determinations.
“Those of us who wear white coats and are very egocentric think that everything that matters is clinical: If it’s not on my chart or not in a field on my computer screen, then it doesn’t matter,” Halloran says. “But population health says there are a lot of [nonclinical] things that do matter.” Socioeconomic status, occupational exposures, geography, access to water, and access to food are examples. The VA measures, monitors, and identifies trends that affect veterans’ health and tries to find patterns that can “turn numbers into knowledge” that will help improve the health of veterans and their families.
Population health is an evolving science, Halloran says, “and the specific models and metrics have been discussed for years,” beginning as classic public health and strongly influenced by disease management models popular in the 1990s. A 2013 Institute of Medicine (now National Academy of Medicine) report proposed a framework for quality measures in population health and used the term “social determinants of health.” At the VA, Halloran says, “Population health goes beyond the model of sickness care to understanding as many of the variables as possible that contribute to the health status of veterans.” Laboratory and pathology data are important, but they’re not the only part of getting to an understanding of veterans’ health. “So they’re necessary, but not sufficient.” Electronic data resources have been key, he adds.
Pamela S. Belperio, PharmD, has been working with the hepatitis C program in the VA for about six years. As a clinical pharmacy specialist for patient care services/population health, Dr. Belperio helps the VA roll out education for national initiatives and policy and works with the pharmacy benefits management group to make the medications available across the VA system. Her responsibilities relating to population health include national reporting on numbers treated and untreated, numbers tested, and numbers cured after treatment, all using the VA’s national clinical case registry and corporate data warehouse, or CDW.
Recently, each of the VA’s 18 VISNs (Veterans Integrated Service Networks, regions of roughly eight to 10 VA facilities each) put together innovation teams to map out a system redesign process, developing processes to improve the current state of care. One of these teams led by Ron B. Schifman, MD, chief of pathology and laboratory medicine at the VA facility in Tucson, Ariz., demonstrated what can be done with population health by reaching out to veteran patients who would benefit from HCV screening.
A patient registry was developed that included all VA-enrolled patients born between 1945 and 1965 who had no record of ever having been tested for HCV infection. This is the high-risk “birth cohort” population that the CDC and VA recommend for targeted screening. Dr. Schifman and his team, in collaboration with the medical staff, developed a patient notification system using letters that could be automatically created and mailed from a central printing facility in Sacramento, Calif.
“Based on the patient registry, a letter is triggered to the appropriate patients explaining why it’s important for them to be screened, and that if they have any questions they can call a certain phone number and talk to a primary care physician. Or if they want to go ahead, the letter can be brought into the various phlebotomy stations we have and they can use it as a requisition form to have their HCV testing performed,” Dr. Schifman explains. The population health team also uses letters because “not all of our patients have information systems where they can get secure messages. Many do, but we can’t count on all of them receiving emails, so we find that old-fashioned mailing system seems to be effective, and it also serves as a lab requisition.”
The laboratory team and primary care physicians collaborated. “We’ve sent out almost 8,000 letters at this point. Notification is automatically documented in the patient record by triggering a note informing the provider that the letter’s been sent,” Dr. Schifman says. Once tested, another automated letter is created and sent to patients with their results and, if needed, instructions for follow-up care. Patients who test positive are immediately contacted and seen by specialists for further management and treatment. About 35 percent of patients who received the letters have been tested so far. “We’ve had a little over one percent of the patients who have been screened test positive for HCV, and all of those patients have had access to care and treatment.”
The Tucson VA is now remotely managing the program to support HCV screening at other VA health care facilities such as San Diego and Albuquerque, with more on the way.
Interestingly, some of the patients who received the letter knew they had HCV (they were diagnosed outside the VA) but were not aware that a new curative treatment was available. “That letter prompted them to then go back and seek retesting and access to care at our VA facility,” Dr. Schifman says.
The initiation of a VA corporate data warehouse—a national, updated repository of data from the VA’s computerized patient records of all VA facilities—helped bring a change to the care of veterans with HCV, Dr. Belperio says. “Originally, our population health care group had developed and maintained a national HCV clinical case registry of everyone with a confirmed laboratory result or ICD-9 diagnosis. Providers at a VA facility can use the registry to generate customized local reports that could be used to assess and manage their population of HCV-infected patients. It can be set up so that every morning an updated report is waiting.” The registry data are used nationally to report metrics and outcomes that guide clinical care, she says.
But until the warehouse came along, there was no good way nationally to look at a particular patient population at higher risk for HCV that had not yet been tested. “The CDW provided a way for us to look for the 1945 to 1965 birth cohort, a group recommended by the CDC to have HCV testing, and see who in that cohort had not been tested.” The data warehouse also made it easier to generate a list and automate the letter mailing.
Automated letters are not new, but in the past they were used to notify people of test results or appointments. The difference here lay in contacting a certain group of veterans to say, “You’re at risk for this disease. We need you to come in and get tested for it,” Dr. Belperio says. “We have the tests already ordered. You just need to come into your local lab with this letter, you don’t have to see the provider, and we’ll notify you of the results.”
“That’s really important for the patient, because it’s one less appointment they need to come in for. I’m not aware of other programs that have been so impressive in identifying people who are at a very high risk for a particular disease, notifying them to get tested, having orders in place for the testing to occur, and then notifying them of the results.”
The VA has seen the highest testing rates for HCV in that birth cohort of any large health care system in the U.S. by far, she says. “We’re at about 75 percent of that birth cohort being tested, and nothing that I’ve seen in the literature is over 50 percent.”
But the approach is not limited to HCV. “Any other disease state where there might be a need to reach out to people who are unaware they have the disease, this approach could be used for.” For example, Dr. Belperio is involved in a pre-exposure prophylaxis program for HIV that will administer medication to people who are at a high risk of developing HIV.
Having new medications that sharply improved HCV treatment gave impetus to this population health project. “That was the thing that transformed HCV, because we had these new medications available and we wanted to get as many people in and cured as we could,” Dr. Belperio says. “If there were some new diabetic medication that would be life-changing for patients meeting specific criteria, you could use the [data warehouse] to identify the markers of patients who would gain the greatest benefit from the new treatment. Several transforming medications are on the horizon and expected to be quite life-changing compared to what we’ve had, so we’re expecting that in the future, that will affect the VA’s choice of other population health projects.”
Unlike breast cancer, lung cancer, and cervical cancer, “liver cancer is rising and the main reason is HCV. It’s also the leading cause for liver transplants,” Dr. Schifman says. So he thinks of the VA’s HCV testing notification program as not just a screening program to help prevent and cure HCV and chronic liver disease, but also as a cancer prevention screening program.
“This is one example of where pathologists can get involved with patient care with regard to population health,” Dr. Schifman says. Traditionally, utilization management has focused on reducing unnecessary tests or removing obsolete testing. “But a widely quoted study has shown that it’s more common to omit testing that needs to be done than to over-test. So in terms of outcomes, that’s where we’re trying to go.”
Dr. Schifman cites three areas of laboratory testing where pathologists can contribute to population health approaches. “One is screening high-risk populations. Another is chronic disease monitoring such as HbA1c for patients with diabetes. Those are patients who might fall through the cracks but should be getting monitoring.” High-risk medications present a third area: “This would include patients on oral anticoagulants, or high-risk medications like amiodarone that require thyroid testing because of the risk of side effects.”
One of the strategies is to try to improve awareness of clinicians or help them use decision support techniques that are built into the ordering process, he notes. “So there will be a pop-up, for example, that will remind the clinician it is time for the patient’s HbA1c test because they are in a population that requires screening.” As decision support systems, however, pop-up menus have two problems, Dr. Schifman cautions. “One is that clinicians are being inundated by alerts.”
“The second issue is the doctor doesn’t necessarily get an alert if they’re not interacting with the patient’s medical record. So if there hasn’t been a patient encounter, then there may not be an opportunity to get the alert, order the test, or make a decision about that patient’s screening or monitoring.”
If the pathologist has access to a patient registry, and it could include HCV, oral anticoagulation, or other similar patient populations that require lab monitoring, then that pathologist could use that information to determine whether the testing has been done. “If it has been done, then that’s fine—move on to the next patient. But if it hasn’t been done, then develop some type of intervention in partnership with the patient’s provider to provide easier access to needed testing.”
An approach similar to the VA’s HCV program would involve taking a registry of patients with diabetes, “to remind them in a primary care clinic of their HbA1c screening, so we can check on patients who have not had their testing performed within the specified period.”
The pharmacist is an important partner, says Dr. Schifman. He or she might have the most knowledge about what testing might be needed for specific medications. “And then you can tie that list into your LIS to see if the patients have had their testing done for potential drug side effects.”
The VA is poised to launch a new population health screening that addresses patients’ opioid use. “There’s a lot of attention, particularly in the VA system, to making sure that pain management is optimized, and one part of that program for patients receiving pain medication is that they get periodic urine drug screening to check for compliance,” Dr. Schifman says.
Ensuring that this occurs will require taking a registry of all patients undergoing pain management, checking to see if they’ve had their periodic urine screen performed, and then sending the same type of letter used for HCV screening, to remind the patients and to provide them with a ready-made requisition for the testing. “So population health goes beyond just screening for chronic disease; it includes compliance with health management programs as well.”
Before the birth-cohort HCV screening program was launched, Tucson had slightly below average compliance on HCV screening. “There was an option in the electronic health care system to remind clinicians about patients who needed HCV testing, and our facility had the auto-alert turned off.” This may have played a role in lowering the compliance level.
The current 75 percent compliance with HCV screening throughout the VA is about twice the national average. In September 2016, a VA database study showed that new drug regimens for HCV have resulted in high cure rates among patients within the VA’s national health care system. Among patients with the most common strain of HCV, 93 percent of veterans receiving treatment were cured.
The VA’s HCV program shows how pathologists can add value to health care by making sure patients have the testing they need, Dr. Schifman believes. “In this particular case, we identified that HCV was a problem, and so we went to GI and our medical staff and said, ‘Here’s a solution that will let us increase our screening by identifying this population that needs screening.’ So this was a pathology-driven process.”
Population health will continue to influence health care systems’ approaches to improving patient care, Dr. Donaldson believes, for two reasons. “No. 1, the complexity of the data within an EHR or patient medical record at this point exceeds the intellectual and analytic capacity of any one person. No. 2, applying that data to determine resource allocation is even more difficult. So when you’re trying to make decisions based on complex data that have an impact on people’s lives, and also reflect a wise use of resources, you’re really out of your depth. You need decision support. Getting people to understand these two points is what population health management is all about.”
Anne Paxton is a writer and attorney in Seattle.
If MSI testing becomes universal, says Dr. Hamilton, “then it needs to be clear that the results of microsatellite instability status are looked at and correctly interpreted by clinicians.” Even a simple positive or negative result can be problematic, “believe it or not.”
April 2017—Molecular testing for colorectal cancer is not for the faint of heart.
While that’s not news to Stan Hamilton, MD—he’s head, Division of Pathology and Laboratory Medicine, and the Frederick F. Becker distinguished chair in cancer research, University of Texas MD Anderson Cancer Center—he was reminded of this fact recently when a friend looked at the multipage molecular pathology report on his own tumor. “He called and basically said, ‘What are you guys doing?’” recalls Dr. Hamilton, noting that his friend, an engineer, is well versed in reading technical reports. “And he was completely befuddled by what he saw.”
Dr. Stan Hamilton (right) at the University of Texas MD Anderson Cancer Center with George Chang, MD, MS, a professor in the Department of Surgical Oncology and chief of the section of colon and rectal surgery. The guideline on molecular biomarkers for the evaluation of colorectal cancer “has brought the quality control aspect [of testing] front and center,” says Dr. Hamilton.
Dr. Hamilton adds, “He asked, ‘Why can’t you make this easier on us patients?’”
And that’s just the report. Left unsaid, but equally valid, is another question: Why can’t molecular testing be easier for clinicians and pathologists, too?
With colorectal cancer, ease is a distant, likely nonexistent, goal. Molecular testing options are complicated to navigate. Even when a molecular portrait of the tumor has emerged, “We don’t have a lot of active agents to choose from,” says Carmen Allegra, MD, chief of oncology and hematology, University of Florida, Gainesville.
Yet the literature continues to grow, and with it come new approaches to using older tests, as well as added data about promising biomarkers. Trying to make sense of it all is a fresh guideline on molecular biomarkers for evaluating CRC, representing the best and the brightest from the CAP, American Society for Clinical Pathology, Association for Molecular Pathology, and American Society of Clinical Oncology (Sepulveda AR, et al. Arch Pathol Lab Med. Epub ahead of print Feb. 6, 2017. doi: 10.5858/arpa.2016-0554-CP).
Unlike previous guidelines from ASCO and the National Comprehensive Cancer Network, says lead author and AMP co-chair Antonia Sepulveda, MD, PhD, that input from four key societies meant unusually heavy emphasis on laboratory testing as well as the more typical guideline coverage of required testing for targeted and conventional therapies. “This has never really been done with such a global scope,” says Dr. Sepulveda, professor and vice chair for translational research, and director, Division of Gastrointestinal Pathology, Department of Pathology and Cell Biology, Columbia University, New York City.
“If you look at the recommendations,” adds Dr. Hamilton, who was the CAP co-chair, “the vast majority of them deal with how to get the testing done. This is not an inconsequential issue. But this is not simply a lab testing guideline. It includes the clinical utility of the tests, and with expert opinion from the medical oncologists who are ordering the tests.”
Another strength, says Dr. Sepulveda, is that the guideline is based on a systematic literature review (with extensive tables to prove it) and levels of evidence, using National Academy of Medicine (formerly Institute of Medicine) standards for developing clinical practice guidelines. This should chase most bias from the recommendations, says Dr. Hamilton. Moreover, even with its 21 statements—“It’s a large and comprehensive guideline,” Dr. Sepulveda says—updates are likely. By following the academy’s standards, the new guideline should remain relevant for some time, she says.
Reflecting the complicated nature of CRC testing, “There was an enormous amount of literature—thousands of papers that we combed through,” says Dr. Allegra, the ASCO co-chair. The major tests for CRC are not new, but their application is evolving—a fact reflected in the guidelines. And in the meantime, researchers continue to find new puzzles in need of solving.
As with the city of Pittsburgh, there are three main rivers to follow in CRC testing: DNA mismatch repair, or MMR, status; BRAF mutation; and RAS mutation.
Testing for MMR, either by immunohistochemistry for the four MMR proteins (MLH1, MSH2, MSH6, and PMS2) or by microsatellite instability DNA-based testing, has evolved from its use in a small group of patients with an inherited disease to a wide variety of clinical decisions, including whether to give postoperative adjuvant therapy and how to treat patients with advanced disease. Oncologists might order that same test for different reasons, says Dr. Hamilton. “That, in fact, is part of the reason we’ve now recommended universal testing in the guideline.”
The first use to emerge was as a marker for Lynch syndrome. MMR is also used as a prognostic marker.
Most recently, researchers have recognized the value of the MSI-high (i.e. high level of microsatellite instability) in patients with advanced disease (about five to six percent of CRC patients) in predicting response to immunotherapy with immune checkpoint inhibiting drugs, specifically pembrolizumab (Le DT, et al. N Engl J Med. 2015;372:2509–2520).
In patients with colorectal cancer, about 20 percent have defects or mutations in one of the DNA repair genes. In about a quarter of those patients, the mutation is based in their germline, the underlying mechanism of Lynch syndrome. As Dr. Hamilton notes, knowing MMR status is crucial not only for managing these patients but also to encourage earlier screening of at-risk family members. For the other 75 percent of patients with mismatch repair deficiency, the mutation is sporadic.
In both groups, MMR mutations carry prognostic information. Those with a deficiency typically, and counterintuitively, have a better outcome, regardless of the stage of their disease. In the case of a stage II patient with an MMR outcome, for example, “They have an extremely good outcome, to the point where we generally don’t consider those patients for any kind of adjuvant therapy after their primary surgery,” says Dr. Allegra.
With other tests, figuring out the next clinical steps often resembles the search for winning lotto numbers.
BRAF mutation (occurring in about eight percent of patients with advanced colorectal cancer) engendered lively discussion when the guideline creators looked at its role as an adverse predictive marker.
“In the report,” Dr. Allegra says, “we said that a BRAF mutation means you don’t do as well with an EGFR inhibitor. But the benefit isn’t zero—that’s what the data showed.” While many clinicians balked at the idea of using EGFR inhibitors in people with BRAF mutations—“They thought it was crazy,” Dr. Allegra says—a hard look at the data suggests some benefit. “So it’s hard to say you shouldn’t use it at all.”
As Dr. Hamilton explains, it’s well known that this gene mutation behaves differently in different subsets of patients. For patients with high levels of microsatellite instability and BRAF mutation, “the BRAF mutation doesn’t seem to matter as much. The outcomes are somewhat worse, but not substantially so.”
In contrast, patients with microsatellite stable or MSI-low tumors and BRAF mutation have a far worse outcome and generally present with more advanced disease, Dr. Hamilton observes. They also seem to be more resistant to chemotherapy. During the guideline discussions, “There was some concern about whether this was related to the fact that the BRAF mutation just conferred a worse prognosis, or whether it really was a predictive marker and could be used to make decisions about therapy.”
Another possible use for BRAF popped up in an abstract presented at ASCO’s 2017 Gastrointestinal Cancers Symposium. Research by Dr. Hamilton’s colleague at MD Anderson, Scott Kopetz, MD, PhD, suggested simultaneous EGFR and BRAF inhibition prolonged progression-free survival in patients with advanced disease. Patients were given a combination of cetuximab and irinotecan, with and without vemurafenib, a BRAF inhibitor. Patients who received the latter drug as part of their regimen “did much, much better than those with the classical chemotherapy,” says Dr. Allegra (median PFS of 4.4 versus 2.2 months; disease control rate of 67 percent versus 22 percent). He considers this a major advance and says, “It was probably the most important paper presented at GI ASCO in January.”
Dr. Hamilton, who has collaborated on a number of papers with Dr. Kopetz, adds, “Scott is an absolutely superb researcher. I think the world of him. And I think he’s right.” But, he adds, it is an abstract.
While that abstract was too newly hatched to influence the guideline, the authors had their hands full trying to assess other possible breakthroughs.
“It took us two years to get this done, because every time we turned around and thought we were getting toward the end, something new, like extended RAS, popped up,” says Dr. Hamilton.
For patients with advanced disease, anti-EGFR drugs such as cetuximab and panitumumab are part of the oncologist’s armamentarium. Less well recognized is that patients who have a KRAS mutation generally will not respond well to those drugs. “There have even been a few studies that have suggested they actually get worse,” says Dr. Hamilton.
In looking at targeting the EGFR pathway, the guideline authors looked for literature for or against BRAF testing. “So far the evidence is insufficient to make a recommendation,” says Dr. Sepulveda. Ditto for markers such as PIK3CA and PTEN. “So while we can test these genes for other reasons, they are not useful at this time for making decisions about anti-EGFR therapy,” says Dr. Sepulveda.
The KRAS discussions thus were relatively tranquil. But while the guideline was being developed, the NRAS story began to be told.
An NRAS mutation should sound an alarm. For these patients, anti-EGFR agents don’t work. “They have zero activity,” says Dr. Allegra. “And they’re toxic. Sparing patients from that therapy is important.”
“This has evolved quickly in the last 18 months to two years,” he continues. Those who had been looking at RAS had mostly confined their search to a couple of hot spots. “But what’s become apparent is that if you have a mutation, probably regardless of where that mutation occurs, it carries with it a negative predictive value.”
About half of patients with colorectal cancer have a KRAS mutation. Another five to eight percent has an NRAS mutation.
“A large meta-analysis, summarizing a number of primary trials, provided additional data that led to recommendation No. 1 in our guideline, for expanded [also called extended] RAS testing,” Dr. Sepulveda says (Sorich MJ, et al. Ann Oncol.2015;26:13–21). Patients being considered for such treatment must receive RAS mutational testing, including analysis of KRAS and NRAS codons 12 and 13 of exon 2; 59 and 61 of exon 3; and 117 and 146 of exon 4.
The authors also had to pause in their discussions about mismatch repair testing.
IHC is relatively easy to do and relatively inexpensive. Turnaround times are rapid, and it can be done with small amounts of tissue. “That’s obviously a terrific screening test,” Dr. Hamilton says.
But it’s now recognized that there are situations where IHC doesn’t work.
One occurs in patients with Lynch syndrome who have a gene mutation that abrogates the function of the gene but doesn’t cause loss of immunoreactivity. In other words, the expression exists in the tumor, but the protein is nonfunctional. “So the patient still has high levels of microsatellite instability and is still generating the phenotype of an MSI-high cancer, but the immunohistochemistry is often not able to pick that up,” says Dr. Hamilton. “There are sometimes subtle differences in the tumors, in the pattern of immunohistochemistry, that can give you a clue that something’s up,” including patchy expression or a peculiarity in the nucleus, where the staining may be less than in a typical case. “It just doesn’t look quite right.”
A more recently identified problem is that in some tumors affected by MSH6 mutations, the IHC will yield an abnormal result—no protein expression—but those cases do not show high levels of MSI. “It’s hard to understand why that occurs, but we see it,” says Dr. Hamilton.
“The other thing now recognized is the biallelic inactivation by somatic mutation,” Dr. Hamilton continues, “where there are point mutations in both copies. One of the mismatch repair genes inactivates them, but again, doesn’t affect the protein.” In this subset of cases, it’s not the methylation mechanism that extinguishes expression; rather, the protein is nonfunctional—the immunoassay sequence is changed by the mutations.
IHC and molecular MSI testing have their pros and cons, clearly. The best choice should reflect patient population and the needs of the ordering physician. “If you’re looking for Lynch syndrome on the basis of a clear-cut family history, it’s probably quite reasonable to start with a molecular test,” says Dr. Hamilton. If that comes back abnormal, “move to one of the family cancer germline mutation panels, and don’t worry about [IHC] in the tumor itself.”
If a patient is older, and methylation of MLH1 is likely, “starting off with the molecular sequencing spends a lot of money and takes up time,” but it may be worth it, Dr. Hamilton says. “The bottom line is, if you want to make certain of what you’re dealing with, you’ve got to do a fair amount of work.”
IHC will tell physicians which genes are involved. If BRAF is mutated, then Lynch syndrome is highly unlikely. “But that’s not perfect,” Dr. Hamilton says. It’s also important to test MLH1 to determine if methylation is present. “But that’s not perfect, either, because methylation does occur in patients who have Lynch syndrome as the underlying cause.” And don’t forget the aforementioned biallelic somatic gene mutations that can lead to abnormal protein—and the need for gene sequencing. “Finally, we now recognize a hypermutable—some refer to it as ultramutated—group with high mutational burden due to abnormalities in the polymerase epsilon and delta genes. Those do not have MSI at all.”
“Fortunately,” says Dr. Hamilton, “we’re beginning to understand much better what we’re dealing with. But unfortunately, it turns out to be very complicated to do the whole workup to get the answer in these individual patients when you get these unusual results.”
Dr. Hamilton pauses, then plunges ahead with a rueful laugh. “I’m still not done. To make things even worse,” he says, studies of germline testing have shown that looking at the phenotype in families has a significant error rate in identifying which genes are abnormal. “Cases that look like Lynch syndrome turn out to be something like PTEN deficiency.”
The guideline can help with even these most complicated cases. Genes are fickle—a fact not always reflected in other guidelines, says Dr. Hamilton. “Frankly, most of the other guidelines looking at results of assays, particularly panel sequencing, are not looking at how you got those results,” Dr. Hamilton says. “This guideline has brought the quality control aspect front and center. I’m not casting aspersions. It’s simply a matter of how they think about that.”
In colorectal cancer, there are few straight lines through the testing process. Even KRAS testing—ostensibly one of the least complicated steps—has its hiccups. Given the exceptions that may turn out to be unexceptional, and the growth of targeted therapies, stepping precisely through CRC testing, with close attention to the quality control directives in the guidelines, becomes even more crucial, says Dr. Hamilton.
Dr. Sepulveda drives home that point when she highlights the predominance of statements devoted to lab-specific issues, such as types of tissue and fixative to use and the benchmarks for choosing them, turnaround times, analytical sensitivity, reporting clarity, quality improvement measures, and the like. “There’s a lot there,” she says. “It’s all important.”
“We tried to cover the waterfront,” Dr. Hamilton adds.
The guideline could add another level of clarification to the MMR discussion as well. Calling for its universal testing should nudge third-party payers. “That’s one of the goals of a national guideline,” says Dr. Allegra. “If you say something ought to be tested, it’s harder for third parties to say no.”
Despite the high stakes, molecular testing results can sometimes fall through the cracks, even when delivered promptly. How can pathologists make sure the results are seen by the right pair of eyes, understood, then acted on?
In the current National Cancer Institute-MATCH trial, for example (a precision medicine trial in which specimens are evaluated for a series of markers to qualify patients for one of 24—soon to be 30—arms), two of the MSI genes are used for determining access to one of the arms. Pathologists are clear on the drill: If a result is positive, that means the gene retains expression; a negative result means loss of expression. And a loss of the protein (i.e. a negative result) is a positive for receiving therapy.
“You would have thought that would have been fairly clear to everyone, but almost on a weekly basis we got a contact from a site: ‘Does that positive [result] mean my patient’s eligible for immunotherapy?’” says Dr. Hamilton.
Counterintuitive reasoning is one problem. Electronic medical records, oddly, are another.
Dr. Hamilton explains: Pathology reports have actually become quite clear. “The CAP has been working on that for years, and the biomarker guidelines are out there [he served on the biomarker reporting committee], and most pathology departments have taken them to heart,” he says. The guidelines, when followed, ensure results are clearly presented—typically in tabular form and thus highlighted in the text.
So far, so good. But when the results become part of the EMR, data from the laboratory information system get converted. Depending on the EMR being used, “You lose that nice visibility when the clinician looks at it,” Dr. Hamilton says.
Dr. Hamilton didn’t recognize the problem until he became involved in the NCI-MATCH trial and saw what happened with certain EMRs. “It can be really tough to find the results in these reports.” The problem extends to reports from the major reference labs. “Their reports are very well laid out,” Dr. Hamilton says. “It’s very easy to get the information at a glance.” When the information hits the EMR, however, all bets are off. The difference, in some cases, “is night and day.”
It’s more than frustrating. “Frankly, it’s a patient safety and quality of care issue,” says Dr. Hamilton. Targeted therapies and immunotherapeutic agents associated with these assays yield good results in a significant proportion of patients, he says. “It’s a real issue that needs to be addressed,” especially given the pressures on already-busy clinicians to see more patients.
Dr. Allegra agrees about the busy part. Even if the results are clear in the EMR (which seems to be the case at his institution), he voices frustration at how test answers often come to him piecemeal. “As docs get busier and busier, it may not get acted on.”
The guideline’s authors—experts all—breezily admit to not following them to the letter in their own practices. It’s to be expected, given their patient populations, which often include those with advanced disease who’ve run out of options elsewhere. As Dr. Allegra puts it, “You go to the university, and for those patients, if they’re lucky enough to have a certain kind of genetic defect, the magic does happen.”
Dr. Hamilton is involved in a large phase one program that is testing tumors in an attempt to develop biomarkers in tandem with identifying toxicity. “We’re requesting testing on a very high percentage of patients with advanced disease with a panel of genes related to that approach. We’re looking at pathways that may be important, not only as targets but also as modifiers of the response and resistance to therapy.”
Dr. Kopetz’s work fits in with those efforts to identify resistance to mutation. Work like this will, it’s hoped, help explain why BRAF inhibitors that work spectacularly in melanomas with a BRAF mutation don’t translate to CRC. “Colon didn’t respond at all,” says Dr. Hamilton. “There were resistant pathways that developed in EGFR and C-meth. When the drug blocked the BRAF pathway, these other pathways were activated, and the tumors kept growing.”
While this deeper understanding is starting to become part of general usage, “We’re not there yet,” says Dr. Hamilton. “In particular, the understanding of which pathways and how many of them can be inhibited without introducing horrible toxicities needs to be answered.” The other problem is that combinations of co-mutations are variable, he says. “So we’re trying to figure out in advance what the most common co-mutations are that you might want to try to inhibit.”
At Columbia, Dr. Sepulveda says, every case of primary CRC undergoes IHC testing for the four MMR proteins, as well as MSI testing. “Some of the immunotherapy clinical trials ask for MSI status of the tumor, so we want that information up front.” They also use a commercial next-generation sequencing panel, do extended RAS testing, and routinely test for BRAF and PIK3CA. Though the guideline does not recommend PIK3CA, compelling retrospective data show that it might be a useful biomarker for patients postsurgically, as well as to qualify patients for a clinical trial. “Because we are an academic center, we decided to go ahead and include this on our reports,” she says.
Dr. Hamilton blithely says there was almost no controversy during the guideline discussions—until he’s asked about turnaround times. The memory of that, like childbirth, was something he managed to forget. “I guess that was a Freudian thing on my part,” he says.
Oncologists, naturally, want test results delivered as if borne by the wing-footed Mercury.
Dr. Hamilton is sympathetic. “Think of it from the patient perspective,” he says. Those with advanced disease understand the gravity of their situation. “Sitting and waiting for lab results to come back is awful. We have a duty to patients to do this as rapidly as possible.”
But real limitations weigh on laboratories as well, such as having sufficient staff to pull a case and review it, in the case of a resection, or sending out a biopsy specimen when that’s the only tissue available from that patient. “These are practical, day-to-day issues that confront us all,” says Dr. Hamilton. “If we had unlimited resources and a guarantee that specimens we’re going to send out are going to be sent back, that obviously would make things much easier.”
Hence, the intense back and forth among physicians. “Some of the pathologists took issue with how fast we were recommending tests and reports got returned,” says Dr. Allegra. Initial suggestions were deemed impractical, he says, given that pathologists can’t always control how quickly they receive tissue for testing.
“There were some areas where there was consternation and handwringing,” says Dr. Allegra. In the end, the guideline says things like, “Laboratories must provide clinically appropriate turnaround times,” “molecular biomarker results should be made available as promptly as feasible,” and “It is suggested that a benchmark of 90 percent of reports be available within 10 working days of tissue receipt in the molecular diagnostics laboratory.”
Says Dr. Allegra: “There was some hesitancy to make things very strict—everyone wanted a little flexibility.”
Apart from some spirited TAT discussions, there was good concordance between the pathologists and oncologists. “That’s a tribute to Antonia Sepulveda as she led the group,” Dr. Hamilton says. What few differences did emerge often had to do with practice styles, he says. “It’s not unexpected. There are some of us who are early adopters, and there are other people who look for a much more advanced level of evidence before they’ll start to take a new approach.”
Karen Titus is CAP TODAY contributing editor and co-managing editor.
Editor: Deborah Sesok-Pizzini, MD, MBA, professor, Department of Clinical Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, and chief, Division of Transfusion Medicine, Children’s Hospital of Philadelphia.
Diagnostic errors, or failure to provide an accurate and timely diagnosis, impact an estimated 12 million outpatient care visits annually in the United States. These errors can often be attributed to the testing process, including test selection, ordering, retrieval, and interpretation. Literature about diagnostic errors has primarily focused on the outpatient setting; study of diagnostic error in the inpatient setting has been limited. The growth of genetic test menus has made the test order process more complex. Furthermore, genetic testing has moved into medical specialties with less experience diagnosing genetic disorders. At many institutions, a substantial proportion of laboratory send-out budgets is committed to genetic testing requests. This has prompted many institutions to establish a utilization management program to decrease and optimize genetic testing. The authors of this study sought to characterize error rates from genetic test orders between medical specialties and in outpatient and inpatient settings. They performed a retrospective analysis of a detailed utilization management database comprising 2.5 years of data and almost 1,400 genetic test orders. Multiple reviewers categorized order modifications and cancellations, qualified rates of positive results and order errors, and compared genetics with nongenetics providers and inpatient with outpatient orders. The results showed that high cost or problems with preauthorization were the most common reasons for modification and cancellation, respectively. Moreover, the cancellation rate for nongenetics providers was three times the rate for geneticists, but abnormal results rates were similar between the two groups. No differences between inpatient and outpatient approval rates were found. Fifteen percent of modified or cancelled orders, or three percent of the genetic test orders overall, were cancelled because the test was not clinically appropriate or modified because the testing was indicated but the wrong test was ordered. In summary, this study demonstrates the high risk for order-entry errors, which may lead to diagnostic errors in genetic testing. A structured utilization committee can help prevent errors associated with genetic testing. Increased laboratory involvement in the diagnostic workup is important in providing the highest value care to patients.
Mathias PC, Conta JH, Konnick EQ, et al. Preventing genetic testing order errors with a laboratory utilization management program. Am J Clin Pathol. 2016;146:221–226.
Correspondence: Dr. Jane A. Dickerson at firstname.lastname@example.org
All obese pregnant women are categorized as being equally high risk for gestational diabetes, even though the majority of them do not develop the disorder. Women with gestational diabetes mellitus (GDM) require more intensive antenatal care to achieve optimal blood glucose control and to identify other common complications, including fetal macrosomia and large-for-gestational-age (LGA) infants. A prediction tool to help stratify disease risk would allow clinicians to identify women at risk for GDM early in pregnancy so they can receive targeted intervention. The authors conducted a study to develop a simple, robust, and easily accessible GDM prediction tool to facilitate early intervention for obese women with the highest risk. They measured 21 biomarkers of biological relevance to GDM and a targeted metabolome of 158 metabolites in early pregnancy from 1,303 obese women as part of their prediction models. This prospective cohort was from the UPBEAT trial (UK Better Eating and Activity Trial), a multi-center trial of a complex dietary and physical intervention strategy designed to prevent GDM in obese women and LGA in their offspring. Twenty-six percent of women in the UPBEAT trial developed GDM. The authors used statistical modeling to combine clinical variables and biomarkers to develop prediction tools. A stepwise logistic regression model based on the clinical and anthropometric variables of age, previous GDM, family history of type 2 diabetes, systolic blood pressure, sum of skinfold thicknesses, and waist:height and neck:thigh ratios, provided an area under the curve of 0.71 (95 percent confidence interval [CI], 0.68–0.74). This increased to 0.77 (95 percent CI, 0.73–0.80) when the authors added the candidate biomarkers HbA1c, random glucose, fructosamine, triglycerides, adiponectin, and sex hormone binding globulin. Of interest, the addition of targeted nuclear magnetic resonance metabolites did not improve the model’s accuracy. The authors concluded that their model will help identify women at low risk for developing GDM and improve intervention in high-risk women most likely to benefit from treatment.
White SL, Lawlor DA, Briley AL, et al. Early antenatal prediction of gestational diabetes in obese women: development of prediction tools for targeted intervention. PLoS ONE. 2016;11(12):e0167846. doi:10.1371/journal.pone.0167846.
Correspondence: Dharmintra Pasupathy at Dharmintra.Pasupathy@kcl.ac.uk
March 2017—Testing for latent Mycobacterium tuberculosis infection and active tuberculosis disease remained relatively unchanged for many years. Screening for latent infection depended on an initial positive tuberculin skin test, and evidence for active TB required a positive culture for M. tuberculosis complex. New tests altered this picture in the past five years. For diagnosis of latent infection, interferon-gamma release assays have taken a major role. And nucleic acid amplification testing is becoming a mainstay for establishing a diagnosis of TB.
These assays took their place as part of the official recommendations for the detection of latent M. tuberculosis infection and diagnosis of TB in a newly published guideline (Lewinsohn DM, et al. Clin Infect Dis. 2017;64:e1–e33). “Development of a new guideline was motivated by the availability of interferon-gamma release assays and some new molecular tests,” says Gail L. Woods, MD, a professor of pathology at the University of Arkansas for Medical Sciences and chief of pediatric pathology at Arkansas Children’s Hospital, Little Rock. She was a member of the guideline committee of the American Thoracic Society, Infectious Diseases Society of America, and the CDC.
The guideline lagged behind laboratory practice to some extent because of the rapidity with which information about these new tests was acquired. “There has been a lot of innovation since the last guideline [published in 2000],” says Charles L. Daley, MD, also a member of the guideline committee, “most notably interferon-gamma release assays and some molecular-based diagnostics for actual TB.” This made it necessary to update the recommendations. “Unfortunately, the update took a long time because so much was happening in the field of diagnostics,” says Dr. Daley, chief of the Division of Mycobacterial and Respiratory Infections at National Jewish Health in Denver. “It has been a moving target. We were hard put to know when to stop and say that’s it, we’re not accepting any more data.”
Between the two reasons to screen—to detect active disease and cure it to stop transmission, and to find latent disease and treat it to prevent progression to active disease—the greater focus in U.S. tuberculosis programs is to find those with latent infection. For this, interferon-gamma release assays have become a major tool. They are in vitro T-cell–based assays that measure interferon gamma release by sensitized T cells in response to highly specific M. tuberculosis antigens.
“There is at least one instance in which IGRAs are better [than tuberculin skin tests],” Dr. Daley says. That is in persons who have received BCG (bacillus Calmette-Guérin) vaccination, in whom a positive tuberculin skin test is not meaningful. “That is a pretty strong area of improvement of IGRAs over tuberculin skin testing,” Dr. Daley says, because most countries outside the U.S. administer BCG vaccination routinely.
Four conditions need to be met to justify primary use of an IGRA: a person age five or older who is likely to be infected with M. tuberculosis, a low or intermediate risk of disease progression, a decision that testing for latent infection is warranted, and a person who has received BCG vaccination or is unlikely to return to have his or her tuberculin skin test read. If even one of these conditions is not met, the tuberculin skin test, or TST, could be used, Dr. Woods says. That is important because IGRAs are much more expensive than TST. At this time, TST is also preferred in children under age five.
Among those who are unlikely to return to have the TST read are undocumented immigrants, who are often mobile, and homeless persons, whom Dr. Daley called “the classic group” for this condition. In addition, jails sometimes release prisoners before their skin tests can be read. For this reason, some jails have gone to chest x-ray (which cannot detect latent infection) to detect active M. tuberculosis disease, since active disease is the main concern. “It doesn’t help a jail to know that an inmate is latently infected,” Dr. Daley says.
Testing is warranted in those who have had a known exposure to a person infected with M. tuberculosis, those entering the U.S. from an area with a high prevalence of TB, HIV-infected patients, and those who are immunocompromised from other conditions, such as chronic renal failure or intravenous drug use. Prisoners could also qualify for testing.
There is an active program to test some who go through the formal process to immigrate to the U.S., including refugees, Dr. Daley says. In this program the IGRA is used because most come from countries where BCG vaccination is administered. For persons entering the U.S. to work for a period, there is no formal testing requirement, though companies can test if they choose. “In Canada they screen all persons staying in the country for six months or more,” Dr. Daley says.
Many health care institutions require staff to be screened for latent M. tuberculosis infection, even though many employees are in a low-risk group. Dr. Woods is required to get tested even though she has minimal, if any, patient contact and does not process patient specimens. In contrast, it is reasonable to screen laboratory personnel who work in a mycobacteriology laboratory.
“Hospitals generally screen health care workers,” Dr. Daley agrees, noting that in some institutions TST is used because health care workers can be relied on to return.
When talking about screening health care workers, inevitably the issue of serial testing arises. “During the time that this document was put together, we obtained data on serial testing with the IGRA assay, mostly in health care workers,” Dr. Daley says. Typically the tuberculin skin test is performed annually in this population. Studies began to show that in this very low-risk population in the U.S., serial testing could lead to false-positive results. This finding was not surprising. “If you take any test and repeatedly screen a low-prevalence population you will get false-positives,” Dr. Daley notes.
“We published data several years ago from serial screening of health care workers with three tests—Quantiferon, T-Spot, and TST,” Dr. Daley says. “We saw conversion in all three groups. But conversion was highest with the IGRA. We don’t know why that is. Usually false-positives on the IGRA revert to negative with repeat testing. Maybe that’s because we don’t have the correct definition of conversion for this test. With the skin test we require a specific change, for instance, an increase in 10 mm of induration. We have to see a certain increase in positivity to call it a conversion. We don’t have that with IGRAs. So maybe we simply don’t have the right definition yet.”
Dr. Daley and his colleagues went one step further: They asked what would happen if they changed the definition of conversion with the IGRA. “In our study,” he explains, “we had to require a very large increase in positivity with the IGRA to get to the same rate of conversion as we saw with TST. That is not a reason not to use IGRAs. They are fairly new and we are still looking for the best way to use them.” As with all tests, there is a tradeoff between specificity and sensitivity. With no gold standard, however, it is not known which results are true.
“The issue for us,” Dr. Daley says, “is what happens after a positive diagnostic test, either an IGRA or TST. We do a chest x-ray, and if that is positive, we collect sputum and isolate the patient. Even if those tests are negative, we treat the patient for months with drugs that have some toxicity. So that is expensive and possibly harmful.” Looked at from the other direction, a false-negative result in a low-risk population is not so bad, in Dr. Daley’s view. “We won’t miss many cases,” he says. “So a false-positive is what we are more concerned about in low-risk populations.”
Because of these concerns, the guideline committee asked the Centers for Disease Control and Prevention to re-evaluate screening practices in the United States.
Screening of health care workers at National Jewish is, paradoxically, less of an issue than it is in some other places. “In this field,” Dr. Daley says, “we have always said that you don’t get TB from the patient you know is infected, but from the patient you don’t know about. And here, where we mostly treat patients who are already diagnosed with multidrug-resistant TB, we know they are coming way ahead of time.” Fortunately, Dr. Daley says, “We don’t really see many cases. There are not many cases of TB in the U.S. anymore.” As a result, they are going through a change in policy to performing less frequent screening of health care workers.
In contrast, “If you go to a place like Denver Health, which treats indigent populations, that is where health care workers are exposed to TB, in the emergency department and on the medical wards,” he says.
A guideline on whom to screen will be out in about a year, Dr. Daley says. “It is moving very slowly, partly because WHO came out with a guideline on this subject, which is the first time they have put out a guideline on latent M. tuberculosis infection. From a global perspective, this was a significant step. They were acknowledging that there are groups everywhere in the world that we should be screening and treating. That was a real change in WHO policy.” It will be difficult to adhere to this guideline in resource-poor countries, he noted.
Although the incidence of active tuberculosis in the U.S. is low, Dr. Woods and Dr. Daley say accurate diagnosis and keeping up with changes in the guideline are important.
“We still do have active TB [in the U.S.],” Dr. Daley says. “It is a complicated and difficult issue. In terms of the diagnostic approach to active TB, we did not make major changes.”
Dr. Woods points out that diagnosing active tuberculosis is entirely different from diagnosing latent infection. “It doesn’t hurt to get an IGRA or do TST, but they won’t make the diagnosis. You have to do culture for M. tuberculosis and a smear and in some cases a nucleic acid amplification test.”
Once a patient has a positive TST or IGRA, the clinician has to rule out active disease by asking about symptoms—cough (particularly if the patient is coughing blood), fever, and weight loss. Next would be a chest x-ray. “If any of these investigations is positive, you need to continue with testing for disease,” Dr. Woods says. “It is crucial to rule out active disease before you treat for infection because the most popular choice [for latent infection] is a one-drug regimen, which you wouldn’t use for active TB.”
There is one change in the workup of active TB. “We did recommend that people use NAAT [nucleic acid amplification tests] to try to more rapidly identify M. tuberculosis in respiratory specimens,” Dr. Daley says. “They were previously recommended to be used but they weren’t used in the U.S. as much as they should. We were quite delayed in adopting rapid molecular tests. I think we are catching up now.” Appropriate NAATs, the guideline says, include the Hologic Amplified Mycobacteria Tuberculosis Direct test and the Cepheid Xpert MTB/RIF test. The Cepheid test detects presence of M. tuberculosis and rifampin resistance mutations in two hours.
Could the policies to identify and deport the undocumented in the U.S. detrimentally affect public health programs to screen those with a risk of having latent infection and TB disease? “I’m pretty sure that’s going to happen,” Dr. Daley says. “What we in public health provide is a safe haven for people who require care. We have used that to find latent infection and TB. We could even discuss with people that treatment will take so many months and ask whether they would be here for that time, and they could answer truthfully. Now I don’t think they will show up.”
William Check is a writer in Ft. Lauderdale, Fla.
March 2017—True, hemophilia is no longer commonly known as the “royal disease” (as it was when several generations of European rulers suffered from it). But in a January webinar, Dorothy M. Adcock, MD, gave some royally important suggestions regarding the laboratory diagnosis of hemophilia A and B.
“In the evaluation of non-severe hemophilia A, it’s important to evaluate both the one-stage clot-based factor activity and the chromogenic [assays],” said Dr. Adcock, who is medical director of Colorado Coagulation, of Englewood, Colo., a member of the LabCorp Specialty Testing Group. “Results should always be confirmed on a new plasma sample, and then if present, you should consider molecular testing to identify the underlying mutation.” Recommendations on the initial evaluation of non-severe hemophilia B are forthcoming, she added; in the meantime, “please do not rely on an abnormal PTT to screen for non-severe hemophilia A or B.”
Hosted by CAP TODAY and sponsored by Novo Nordisk, the webinar—“Laboratory Diagnosis and Therapeutic Monitoring in Hemophilia: Problems, Pitfalls, and Testing Pearls”—saw Dr. Adcock and others discussing issues, challenges, and solutions related to the laboratory assessment of hemophilia A and B. (The webinar is at www.captodayonline.com and additional coverage will be published.)
As Dr. Adcock reminded the audience, there are three methods for measuring the factor deficiencies that define hemophilia A (factor VIII) and B (factor IX): the one-stage clot assay, which is based on activated partial thromboplastin time; the two-stage clot assay, which is rarely performed since it is complex, cannot be automated, and no kit for it is available; and the chromogenic substrate assay, which has limited availability and is often performed as a batched analysis.
Most clinical laboratories use the one-stage method for all factor activity assays. Though the assay is largely standardized, “the many instrument reagent combinations available lead to variability,” Dr. Adcock noted. Chromogenic factor VIII and factor IX activity assays are available. Though the former are available in FDA-approved kits from multiple vendors, few laboratories offer the tests. And few labs offer factor IX activity assays by the chromogenic method, which are not available as FDA-approved kits.
“Well, you’re probably wondering, does assay methodology used to measure factor activity matter?” Dr. Adcock said. “In fact, it does.”
That’s been known since the late 1980s, when discrepant non-severe hemophilia A was recognized and described as a greater than twofold difference in results between the one-stage and chromogenic factor VIII activity assays. As many published studies have confirmed, “in discrepant hemophilia A, the one-stage assay result may be greater than the chromogenic assay or the chromogenic result greater than the one-stage assay, and this may impact both diagnosis as well as classification of disease severity,” she added.
Discrepant hemophilia has been reported to occur in up to 30 percent of mild or moderate hemophilia A, but has only recently been described in abstract form in a very small cohort of hemophilia B patients. Discrepancies in activity based on assay methodology are also reported in the presence of some new recombinant factor VIII and IX replacement products.
“The next important question is: Are these discrepancies in results real?” she said. For non-severe hemophilia A, at least, the one-stage and chromogenic discrepancy has been reported to be consistent between family members and consistent in all individuals bearing the same mutation. “Therefore, this discrepancy has a molecular genetic basis,” she said, with the variability in results depending on the underlying genetic defect. In post-infusion replacement therapy, the discrepancy depends on the modification of the recombinant factor and its effect on the assays.
Dr. Adcock then reviewed the difference in methods, using factor VIII activity as an example (“factor IX assays are very, very similar,” she said). As she noted, in the one-stage factor VIII activity assay, test plasma is mixed with factor VIII deficient plasma. That mixture is combined with the aPTT reagent, which contains phospholipid and a surface or contact activator. To initiate clotting, calcium is added, with the time to clot measured in seconds.
The chromogenic factor activity assay is performed in two stages. First, activated factor X is generated; the amount that’s generated depends on the amount of functional factor VIII in the test plasma. “The reagent components and the incubation times vary a little by manufacturer,” she said. The first stage is incubated for between two and 10 minutes. Second, the amount of activated factor X generated is determined by its ability to hydrolyze a specific chromogenic substrate viewing a colored substance.
“So the factor activity for each assay is then determined off of a standard curve, and this is referenced against an international standard that has a known factor VIII concentration,” Dr. Adcock said. “For the one-stage assay, the result is based on seconds, and for the chromogenic assay, it’s based on optical density.”
What are the critical differences between these assay methods? In the one-stage assay, the reaction proceeds quickly once calcium is added, and the activated form of factor VIII is present for only a very short period. The factors are present at physiologic concentrations. In contrast, in the chromogenic assay the first stage is incubated for a period of time, and activated factor VIII is generated throughout that incubation period. In addition, the factors are often present in quantities greater than are required to optimize the reaction.
“How does this variation in assay methodology play a role in discrepant non-severe hemophilia A?” Dr. Adcock said. “There are mutations, and these are often missense mutations, which tend to be novel. In those circumstances where the one-stage result is greater than the chromogenic, the mutations tend to be localized to the A1-A2-A3 domain interfaces [of the FVIII molecule]. Mutations in these regions tend to cause activated factor VIII to be unstable, and this causes it to lose its activity. This results in less activated factor VIII that is ultimately generated. These mutations are better detected in the chromogenic assay, where activated factor VIII is generated over a period of time in minutes.”
When the one-stage assay result is lower than the chromogenic, she continued, mutations tend to be localized to thrombin cleavage sites or factor IX binding sites. These mutations are thought to be more apparent in the one-stage assay, where the factors are present at physiologic concentrations. “It is also believed that the prolonged incubation time and the excess factor present in the chromogenic assay may, at least partially, overcome these binding defects.”
Most cases of discrepant non-severe hemophilia A have high, often normal, factor VIII antigen levels, and these therefore represent dysfunctional proteins. “I suspect that measuring factor VIII antigen levels may provide assistance in the identification of these cases of discrepant hemophilia,” Dr. Adcock said.
Again, this discrepancy in results between methods may lead to missed diagnosis or misclassification. “Eleven percent of those are reported to have normal factor VIII activity results with the one-stage assay,” she said. “You may also wonder which result is correct. It is generally believed that the lower result correlates better with bleeding tendency and the results of thrombin generation assays, although more study is needed in this area.
“Such discrepancies have recently been described in hemophilia B in a small cohort of patients in abstract form,” she continued. “Also, deviations in one-stage results may be seen in some hemophilia patients, depending on the PTT reagent used. There is limited information about hemophilia B, however, to date.”
As she emphasized to the audience, it’s important not to rely on a normal or an abnormal aPTT to screen for hemophilia: “Depending on the aPTT reagent, the one-stage factor VIII activity may have to fall below 25 percent, for example, and the IX below 15 percent before the PTT prolongs, and this is referred to as reagent responsiveness.” This is defined as the level of factor activity that must occur before the PTT prolongs. “So this is just a reminder that a normal aPTT does not rule out mild deficiency of factor VIII, IX, or XI.”
Anne Ford is a writer in Evanston, Ill.
March 2017—The language of blood banking experts, as they talk about irradiators, transfers easily to a car dealership. How reliable are the newer models? Are you willing to replace it every 10 years or so? Do you keep running it until it dies? What parts are likely to burn out? What will repairs run?
And then the word “terrorism” pops up.
Dr. Jeffrey Jhang (left) and Dr. Jacob Kamen at Mount Sinai Hospital, where the Rad Source RS3400 x-ray irradiator (at right) was installed in January. “We were training, validating, and using the machine in February, and we went live on March 1,” Dr. Jhang says.
Since the Sept. 11 attacks, worries about risks to blood supplies have persisted. Sometimes those fears have burned with intensity; at other times, concern has lingered like a low-grade fever. But they’ve never disappeared. Cesium irradiators have long been used to prevent transfusion-associated graft-versus-host disease as well as in research applications. In the wrong hands, cesium also can be used to make a so-called dirty bomb.
Jeffrey Jhang, MD, associate professor of pathology, Icahn School of Medicine at Mount Sinai, New York City, says he hadn’t given much thought to terrorism scenarios until he spoke about the risks with his institution’s radiation safety officer. He knew about dirty bombs. But other chilling possibilities lurked as well, says Dr. Jhang, who is also director of the blood bank and transfusion services, Mount Sinai Health System.
With ominous visions filling the heads of hospital leaders, it made sense, says Dr. Jhang, to replace Mount Sinai’s cesium irradiators with x-ray irradiators. But as blood bankers at Mount Sinai and other institutions report, doing the “right thing,” as Dr. Jhang puts it, doesn’t mean it’s an easy thing.
For pathologists more used to making decisions based strictly on a cost-benefit analysis, says Dr. Jhang, replacing a cesium irradiator with an x-ray device may not seem like a sensible move. “If you look at my operation, the benefits are not that great,” he says. X-ray irradiators can cost $250,000 to $300,000, with annual service contract costs running $15,000 to $20,000. Moreover, he says, “They are thought historically to have greater downtime, requiring more expensive repairs, and they have heating problems.”
Cesium irradiators, on the other hand, require very little maintenance. “They can be used for many, many years,” Dr. Jhang says, “because the source decays very slowly.” What little maintenance is needed—a rare occurrence, by most accounts—is cheaper.
Advantage, cesium. But factor terrorism into the equation, and perceptions shift.
“I don’t know what the percent risk of it happening is,” Dr. Jhang concedes. “These events are unpredictable. But it could be you.”
That uncertainty led to the decision of Mount Sinai administrators to reduce the risk, despite the cost. “The idea that our hospital could be the center of a dirty bomb attack kept everybody up at night,” he recalls. “So the chief operations officer at our Mount Sinai West facility was very happy to get rid of that cesium irradiator. It would help him sleep at night, help us sleep at night.” The same sentiments coursed through administration at the main hospital, “that if we could do something to reduce our risk, that would definitely be the way to go.”
In fact, says Dr. Jhang, perhaps the hardest person to convince was Dr. Jhang himself.
“I just had to make sure I was comfortable with the notion that a lot of prior problems with x-ray irradiators had been resolved and weren’t going to impact my operations,” he says, noting that older models were known to overheat, “and their x-ray tubes blew frequently, and their power supplies blew frequently.” That meant downtime and unexpected repairs. “That’s something I didn’t want to commit our hospital to, because we are very high volume, and we do rely on irradiating units ourselves, rather than purchasing them.”
Dr. Jhang set his mind at ease by talking to others who had made the switch to newer models. “They seemed much more reliable, with better uptimes and less breakage requiring replacements of key parts, such as tubes and power supplies.”
He cites another advantage: The x-ray irradiator requires less time and labor than the cesium irradiator. While the labor savings aren’t huge, they’re not paltry, either. Dr. Jhang says prior to the replacement, it took about nine minutes to irradiate two units; now, six to eight units can be processed in five minutes.
Mount Sinai’s chief radiation safety and laser officer Jacob Kamen, PhD, CHP, was one of the hospital leaders who saw the advantages of moving radioactive cesium out of the facilities. Mount Sinai recently installed two x-ray irradiators, one for the blood bank and one for research.
Dr. Kamen, who is also senior director of Mount Sinai’s Radiation Safety Department and an associate professor of radiology, recalls the long road to making these changes. While worries spiked after 9/11, simply removing cesium irradiators—as some in the federal government initially demanded—is no quick task.
A renewed push came in 2010, Dr. Kamen says, with the 10-year anniversary of the attacks approaching. Al-Qaeda had been making threats in advance of the anniversary, and administrators were worried about the possible use of radioactive cesium in a dirty bomb to contaminate a large area. “A dirty bomb could cause long-term economic damage,” says Dr. Kamen. Mount Sinai (which at the time had not yet merged with other area hospitals and was simply Mount Sinai Medical Center) seemed like a likely soft target, as did other New York City hospitals, he says.
The first step was to prepare for a worst-case scenario with cesium still in place. The hospital purchased sophisticated equipment to monitor radiation levels, for example, as well as other equipment used by the police department, to make sure both used the same terminology and equipment in an emergency situation, Dr. Kamen says. The hospital set up decontamination facilities and trained security staff how to use them in the event that a large number of contaminated people were to come to the hospital. “We had a lot of drills with the fire and police departments,” he says.
Mount Sinai also collaborated with the federal government, specifically the National Nuclear Security Administration, and the subsection now called the ORS, or Office of Radiological Security. Among other actions, the hospital drastically reduced access to the cesium irradiator used for research. At the time, 144 people used the research device, Dr. Kamen says. It made more sense to have one person perform irradiation tasks for everyone; that person underwent FBI background checks.
Securing the blood bank irradiator was harder, given the need for 24/7 access. More staff needed to undergo FBI background checks. And the machines were “hardened”—security speak for making the cesium irradiators unassailable—with measures such as monitoring systems with multiple alarms. “Mount Sinai was the first hospital in New York City to be connected directly to the police department in case any of these alarms goes off,” Dr. Kamen says.
But the risk, while reduced, had not been removed. Given Mount Sinai’s size and status, it didn’t make sense to keep the cesium irradiators. “And at the 2016 Nuclear Security Summit, radiological risk was the key issue,” Dr. Kamen says, with more than 50 world leaders agreeing the highest threat is nuclear and radiological terrorism. Alternative technology is one way to reduce the threat. “The x-ray irradiators are FDA approved,” Dr. Kamen says, “and there’s no need to worry about liability if a radiological event were to occur.” As an added incentive, the health system’s leaders hoped Mount Sinai would inspire other institutions to remove their cesium irradiators if they hadn’t done so already.
The research group was somewhat difficult to convince, since the irradiation tasks its members perform are diverse. “Some researchers perform whole body irradiation on rodents, others perform targeted irradiation, and some perform irradiation on cells,” Dr. Kamen explains.
In response, Dr. Kamen and his colleagues spoke the blunt language of money, explaining that the federal government currently covers the six figures it costs to decommission a cesium irradiator. If the hospital doesn’t migrate to alternative technology now, and in a few years if the U.S. government doesn’t help, grant and other monies could be at risk.
“The researchers at Mount Sinai have come to the conclusion that they will help any way they can,” he says. A handful of researchers did the necessary comparison studies and were reassured that an x-ray irradiator could perform just as well; ongoing studies have since proved that point with the new machine. “We think we’re getting even better results than we were before,” Dr. Kamen says, noting that the x-ray device has 320 kVp—twice the energy of the old machine.
Federal involvement remains a key factor in the equation, with some administrations assigning a higher priority than others, Dr. Kamen says.
Jed Gorlin, MD, vice president of medical and quality, Innovative Blood Resources, St. Paul, Minn., jokingly refers to “the whole sordid history” of the U.S. government’s interest in removing cesium irradiators, before laying out the issues involved.
“I certainly sympathize with the Department of Homeland Security, whose job it is to minimize risks and opportunities for malfeasance,” he says. While the risks from radioactive sources is not direct harm, “One simply needs to look at the circle drawn around Chernobyl or Fukushima to recognize there are large radii in which people will no longer be able to live for a hundred years, and understand the economic and personal impact. It does need to be addressed.”
On the other hand, cesium irradiators can’t be wished away. Decommissioning a cesium irradiator costs $100,000 or more, Dr. Gorlin says, with a significant portion now paid by the federal government.
“That’s why government support is such an important factor,” says Stephen Wagner, PhD. And even if the government continues to fund disposal of cesium irradiators through its Off-Site Source Recovery Program, the process can be slow, he says. As senior director of the American Red Cross, Holland Laboratory, Transfusion Innovation Department, Rockville, Md., Dr. Wagner is familiar with how that process has played out at multiple Red Cross sites as they switched to x-ray irradiators. “You may have to wait a year or two before you’re able to arrange a pickup for an old gamma irradiator,” he says. “It requires a lot of planning.”
Whether that will continue with the new administration is anyone’s guess. While some in Washington see an event like the Paris attacks as ample reason to view cesium irradiators as a target, others may view the devices through a different lens, arguing that over-regulation is the bigger problem. That could create a “let-people-deal-with-it-themselves” approach, as Dr. Jhang puts it.
In recent years, compliance related to the security of existing cesium irradiators has only grown more onerous, Dr. Gorlin says. Given that difficulty, if a blood bank is ready to purchase a new irradiator—for whatever reason—“I can’t see anybody buying a new cesium irradiator.” This is a point of bafflement for Dr. Gorlin, actually. “If the government really is intent on assisting us in that direction [to remove cesium irradiators], wouldn’t the logical first policy be not allowing new instruments to be sold in the U.S.? Which is not the case.”
Nevertheless, Dr. Gorlin is quick to praise the work of those who regulate radioactivity in the United States through the National Research Council. “When certain overenthusiastic government officials wanted to ban cesium irradiators overnight [post-9/11], with no plans for whether there were available replacements, they did an amazing job of gathering subject matter experts” and laying out a more thoughtful response. The government’s part in assisting with decommissioning and “hardening” cesium devices “was a tribute to government at its best,” he says.
X-ray devices have their own monitoring requirements, but Dr. Gorlin says they’re far less onerous—comparable, he quips, to the requirements used to oversee dental x-rays.
Drs. Jhang and Kamen also predict that the regulation of cesium devices will only become tighter in the years ahead. For staff, that will likely mean added requirements in terms of training, qualifications, and background checks. For institutions, that could spell higher security and insurance costs. “So the cost-benefit analysis must include future regulation,” Dr. Jhang says.
The regulatory requirements were already daunting in 2007, when Children’s Health in Dallas took over the transfusion service from its blood provider, says Daniel K. Noland, MD, an assistant professor of pathology at the University of Texas Southwestern Medical Center, Dallas, and medical director of the transfusion and tissue service for Children’s. Looking at the background checks, locked doors, and radiation badge monitoring required for a gamma irradiation source, “We chose to go with an x-ray irradiator. Looking at all the costs, we thought it was much more effective for us,” Dr. Noland says. “You have to look at it the same way as you look at purchasing any other instrument. You look at footprint. We don’t have to have this behind a locked door—we can have it right there in the blood bank.”
After that initial purchase, Children’s bought a new x-ray irradiator in 2014. The older-generation device had its problems, particularly with the power supply, Dr. Noland reports, though he adds that the center could always meet its throughput demand. The newer instrument has had no such issues, although “We did have an issue getting it through customs [from Canada] initially,” he says, which led to a delay of a week or two. The problem was dealt with over the phone, and Children’s used alternative sources of irradiated blood products in the interim. “I got the impression that customs was a relatively unusual but not unheard-of problem.”
Lengthen the time frame by a few more years, and blood centers might be able to add another variable to the mix: It’s possible the need for irradiators of any type may disappear if pathogen inactivation technologies continue to take root. “I’m not holding my breath,” says Dr. Gorlin, but he adds that some might say it’s reasonable to hold off on purchasing an x-ray irradiator in the hope that red cell pathogen inactivation will be viable at some point, alongside platelets. The field has advanced, he concedes, and he suggests this has even led to stagnation in the x-ray irradiator market.
The x-ray devices have already been through two rounds of development, which further clouds the cesium versus x-ray debate. The unreliability of earlier x-ray models helped cast a gauzy light around the cesium devices.
Cesium irradiators “never break down, and they last forever,” says Dr. Gorlin. He knows of one cesium irradiator, a Nordion serial No. 1 machine, that “probably has the longest irradiation cycle on the planet, but it still works.” And with few moving parts—“other than changing a motorcycle battery every now and then”—the ongoing maintenance cost, he’s heard, is “bupkis.”
Based on his own experiences of making the switch, x-ray irradiators are far less reliable, burning out with regular frequency. Backup plans are essential. “Companies are reasonably good at making repairs,” he says, but it can take 24 hours or more to get a device back online.
His blood system was an early adopter of an x-ray irradiator. “The good part about being early is you get a discount,” he says. “The bad part is you don’t generally want to buy a new car the first year of the model, because the manufacturer is still working out the kinks.”
Echoing Dr. Jhang, Dr. Gorlin does see progress in the x-ray irradiators, however. “My understanding is that the reliability has improved significantly,” though he still sounds a bit battered from his early-adopter experiences. He also credits the vendor for promptly servicing the machine when it required repairs, which was often. Reflecting further, Dr. Gorlin says that making the switch “was a very different experience, moving from a machine that never needed repairs or replacement” to one that did. Another x-ray machine at a different site—this one without external cooling requirements—had what Dr. Gorlin calls a tenuous first year, but since then has been “pretty well behaved.”
It’s worth noting that earlier model x-ray irradiators required external water cooling, which added space and infrastructure complexities; the newer machines do not. When one of Innovative Blood Resources’ blood centers replaced its x-ray irradiator several years ago, after more than 10 years, it purchased one that still required external cooling, Dr. Gorlin says, since the infrastructure was already in place. “It was the path of least resistance.”
Unfortunately, he says, there are not enough data to provide Consumer Reports-type (or CAP TODAY product guide, for that matter) comparisons and guidance on different models.
Dr. Wagner agrees. The Red Cross has a number of x-ray irradiators that are more than 10 years old. “But there is not enough good data to know exactly what the lifetime of an x-ray device is in a blood bank. And we know even less about the new devices, although I would suspect that with their newer designs, they might last a little longer.”
Dr. Kamen suggests that the x-ray irradiators have not only improved but also that users are becoming savvier about their operation. Not all his colleagues share his affability. Speaking of one institution that became unhappy with an x-ray device purchased nearly a decade ago, Dr. Kamen notes that it was one of the older devices, which were deemed difficult for, among other things, their lack of self-cooling. “They probably used the machine too much during a short period, which caused the x-ray tube to overheat and break,” Dr. Kamen says. He compares it, appropriately enough, to a car. “Let’s say I give you a brand-new car with a five-year warranty, in perfect condition. If you drive it for five months without stop, what do you think is going to happen?”
But other colleagues tell more successful stories, he says. As for his own system’s newer machines, he says, he’s been told by the manufacturer that they will handle about 2,000 hours of use, or roughly eight years. “And it’s not that you throw the machine away after eight years; you just change the tube.”
Looking back, Dr. Kamen suggests that blood centers still grappling with the issue learn from Mount Sinai’s experience and switch directly to x-ray irradiators. Enhanced security, working with the police department, and FBI background checks were expensive and time-consuming, he says.
And for those who have decided, Dr. Kamen offers another bit of hard-won experience: Don’t underestimate the amount of planning and time it takes to dispose of and replace and validate a new device. “You can’t just leave it to one department and assume you can switch it out in a month or so.” Six to nine months, depending on available personnel, is more reasonable.
Training on the new irradiator was fairly seamless, Dr. Jhang says. Mount Sinai sent a couple of members from its radiation safety office as well as from the blood bank to undergo intensive operations training at the company’s headquarters. In addition, the company did onsite training for the rest of the blood bank staff. “It took about five days to train the 30 staff,” he says.
Anticipating downtime, Dr. Jhang says the blood bank has created a log to document throughput and better understand uptime operations. “If it breaks down, we want to know what will be triggering it—how many units in a given amount of time would cause it to overheat?” Mount Sinai would have to purchase units if an extended repair time depleted its inventory. “It’s doable, but obviously it’s something we have to think about in our calculus—what would be the cost impact if there’s a prolonged downtime?” he asks.
(That’s less of an issue at the Red Cross. With its nationwide blood bank network, Dr. Wagner says, “We’re able to ship blood where it’s needed in emergencies. So we can react to an instrument going down.” And, he notes, cesium irradiators also experience downtimes, despite many glowing reminiscences to the contrary.)
Dr. Jhang also recommends that anyone installing an x-ray irradiator consider the work environment. Is ventilation adequate? What is the temperature range in the area? “If the machine overheats, you can’t run it,” Dr. Jhang says. He and his colleagues neglected to make robust calculations regarding the heat output of the x-ray irradiator. “We found the area warmed up much more than we thought it would, so we had to go back and install additional air conditioning.”
At Children’s Health, Dr. Noland was told that since Dallas has “hard” water, the x-ray tube shelf life might be shorter. To eliminate that possibility, the center changes the water filter more frequently than is typically recommended. “We haven’t experienced any decrease in the longevity of the tube,” he reports.
Among these reassuring, almost tame observations, it’s easy to forget the concerns that first launched the debate over removing cesium irradiators. But as several observers suggest, there’s much to ponder beyond immediate economic or safety returns.
Says Dr. Jhang: “I think you have to be forward-looking and say, ‘OK, maybe this is not 100 percent benefit to my institution, but there is benefit to the community and protecting citizens in the surrounding areas.’ ”
Adds Dr. Gorlin: “I think it’s the right thing to do.”
The Protecting Access to Medicare Act (PAMA) requires certain laboratories to submit private payor rates for clinical laboratory tests. Private payor data is due to the CMS by March 31, 2017. To help you with the submission process, the CMS created a PAMA DATA COLLECTION USER GUIDE with stepbystep instructions and screen shots. The CAP has added this invaluable tool to our pathologyspecific PAMA RESOURCES, including an INFORMATIVE INFOGRAPHIC and PODCAST, to help laboratories understand regulatory requirements and upcoming deadlines. These resources and additional tools can be found on the CAP'S PAMA RESOURCES WEBPAGE.
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