Introduction and implementation of QuantiFERON

The Southeastern National Tuberculosis Center (SNTC) Webinar Interferon Gamma Release Assays (IGRAs): Yesterday, Today, and Tomorrow now has a transcript available; the following is a portion of it.

"..I’ll try to talk faster so you can understand it. I’m Thomas Dobbs from Mississippi State Department of Health and I’d like to thank the Southeastern National TB Center for having me. It’s been great and I’m going to talk really about our experience with QuantiFERON and how we’ve integrated QuantiFERON testing into public health practice in Mississippi.

Let’s get started and so just a quick background. Mississippi has a population of about three million so we’re a lot smaller than New York City for the whole state. We had a TB case rate of approximately four per 100,000, 118 in 2008. We rank 15 overall in case rate. We rank number 2 in native-born case rate. We don’t have much foreign-born disease. We have an additional four and five suspects in 2008 and the majority of our acid fast that come through our state lab likes to (atypicals) so we have a lot of NTM in our area and we follow about 1800 LTBIs for that year.

There we go. We have 68% TB above African-Americans, 93.2% of cases are U.S.-born, 14% are homeless and 15% are HIV-positive within this age range.

We have two different diagnostic tests we use for diagnosing latent tuberculosis. Of course we’re using tuberculin skin testing but also too we’ve incorporated QuantiFERON and right now we’re using the QuantiFERON Gold In-tube assay for certain groups routinely through our state protocol for actually for TB suspects who are using preferentially QuantiFERON testing.

We use it for HIV-positive individuals and a lot of that is because we’re a rural state. We actually have a regionalization of HIV care and most people don’t actually live in the town where they’re seen. We had a very low rate of return for reading TB skin tests and so we’ve instituted QuantiFERON testing for HIV-positives and we’ve had a marked increase in getting results back. Also too we use QuantiFERON for those who may not return for a reading and also those with prior BCG exposure.

Basically we used In-tube assay using the tube system. Each tube will automatically fill to one cc. It has a preloaded vacuum so if you draw it, it will draw to one cc without a problem. Basically we have our nil tube, our positive control and our TB antigen and basically, if we have appropriate controls and a negative TB antigen, it’s interpreted as a no TB exposure. And then if we have the same appropriate controls and then a positive TB antigen tube which contains three different antigens mentioned above, we took that as a positive TB exposure and then if we have inappropriate controls, we can interpret either as an overactive immune system or underactive immune system in a real basic sort of model.

However, the interpretation’s a little bit more complicated. There is a relatively thorough algorithm that was designed to optimize performance characteristics of the assay. And so it’s not quite so simple, but it’s become quite apparent that it’s very important for us to have the actual ELISA values available to us when interpreting this test, and some of this will be relevant and you’ll understand why it’s important because a TB antigen of .8 or 4 is very different and it may have severe implications for your management of the patient.

So in 2008, we started using QuantiFERON Gold In-tube assay. We had tried with QuantiFERON Gold initially but there were a lot of logistic problems that really prevented us from implementing it, so our first year we did 554 specimens of which 20% were positive. Now a lot of these were actually TB suspects and TB cases so that’s why you have such a large number, 77% negative. We had 18 indeterminates, about half of which were known to be HIV-negative and two were HIV-positive and the 14 culture-confirmed TB cases that we did have QuantiFERON performed, 11 were QuantiFERON-positive, three were QuantiFERON-negative, consistent with published studies.

One of the things that really good about Mississippi is we have a centralized public health infrastructure. Each county has a county clinic and they all answer to the state health department in Jackson.

We also have an incubator in each county clinic and so each county can incubate QuantiFERON through the In-tube assay on-site. They draw the blood on-site. They incubate it overnight and then they will transport through an in-state courier system that goes through every day and does night deliveries into Jackson where they do two to three runs per week on an automated ELISA platform.

The other thing that’s been good about the state is we have an automated platform that minimizes human error and the In-tube assay really is critical to keep folks from not having to process the specimen for analysis.

The other thing is with the In-tube assay because of the new design, after it is actually drawn, it can sit for 16 hours prior to incubation. But assay incubation actually can sit for several days before you actually have to get it to the central lab and I think I’ve got some things in here so we collect them at the county health department, incubate them overnight, actually can centrifuge them on-site or we can centrifuge them at the central lab, you have three days.

We have an overnight courier and then after the specimens are processed, they’re basically good for three days at room temperature, up to four weeks refrigerated and maybe even up to eight weeks according to the package insert and then for four months or longer if frozen to low temperatures.

So one of the rationale that we use either in Mississippi, well similar, and probably not improved sensitivity versus TST, we also would like to use it for its enhanced specificity versus NTM exposure and also too for BCG-vaccinated folks. We don’t have a lot of BCG-vaccinated folks but we have some. Single site visit is required which has been very important, objectivity of readings. This is actually fairly important because most of our positive TST reports that we get are from communities, not from people who are TB nurses  or TB experts, but from people who do it periodically maybe at healthcare screenings or for infection control at small hospitals maybe because there may be some better correlations, exposure and risk of developing active disease and also too, it may be cost-effective and we’ll look at some of the details of that in our experience.

So clearly we have enhanced specificity versus TST for NTMs, particularly MAC. We have a lot of MAC in our area. BCG, although we have few foreign-born cases in Mississippi, we do have a large immigrant presence in certain local industries and also too we have some military bases. We’ve had some folks from Afghanistan and Iraq.

There’s kind of a soft body of evidence that supports the possibility that a lot of your positive TB skin tests in the south may be due to MAC and NTMs in low-risk folks, and this is just a study from a group that has actually a small body of work using MAC sensitin which one of the things that MAC sensitin is, it’s not standardized and so you have to take it with a grain of salt. But basically one of the conclusions you can find is that the majority of folks, healthcare workers who had a 5 to 14-millimeter PPD reaction were actually not due to exposure to tuberculosis but were more likely due to MAC exposures. And in our area, we do have a lot of MAC, and even in the state we had a lot of Non-Tuberculosis Mycobacteria, but in my area specifically, we actually have probably twice as much as the state overall as far as clinical isolates of AFB’s.

And so what disadvantages do we have to worry about? Well, there’s a cost to the lab program. We’ve tried to minimize that but it is considerably more expensive to the lab compared to TST. There’s a logistics with blood draw, transportation infrastructure but we’ve actually overcome a lot of those barriers just because of the way our state is organized and also too, lack of  experience with IGRAs actually has been quite a problem because it’s taken awhile particularly for local physicians to get used to the proper way of using it. But also too we have to worry about our judicious application of resources. These are some of the county clinics in one of my districts and they’re relatively small clinics and on some days, there’s only one nurse there, particularly if one has been told to do something else. And they have a lot of responsibilities from immunizations to helping pregnant women to a whole lot of things and if they’re having to track down a bunch of LTBIs, which is really the vast burden of work for our health department, they can’t get done what they need to do specific to fit the community and their needs so we really need to use our resources very judiciously.

So this whole next section entitled Primum Non Nocere, which we all know means First Do No Harm and Bayes’ Theorem, because we’re in a low incidence area for tuberculosis, you know, we’re testing a lot of people who really are not going to have disease.

I take Isoniazid toxicity very seriously. I know it’s rare and it’s probably very safe and certainly is effective. Real hepatitis is perhaps 20 per 1,000 persons treated and rarely we see fatal hepatitis. But in Mississippi, we’ve had one death in one liver transplant over the past four years from Isoniazid and so it’s something that we take very seriously and I really don’t want to treat, as a clinician, treat someone for latent tuberculosis if they really don’t have it.

So we want to take good care of these people not just from a population perspective but also from an individual perspective. So one of the things that we’ve done in my area is we’ve tried to use QuantiFERON in a limited way to look at people who were low risk for actually having latent tuberculosis. And a lot of these people as Dr. LoBue had mentioned before, people that we shouldn’t have checked in the first place or maybe we checked because we’ve got a system in place that automatically checks folks who really would not have otherwise been assessed. As an example, we have seen several people who would go in to volunteer in a hospital to work in the gift shop and they would all be tested and they would have positive skin tests. Based on a state policy and other states have similar policies, anything over 10 millimeters is a positive. Well, these are people that would not normally have been tested and now they’re sent to our system to be treated for latent tuberculosis infection.

And we’ve identified quite a number of people who kind of fall into this category so we wanted to look at folks who were TST-positive, low risk for tuberculosis, were not at risk or increased risk for progression to disease and we’ve performed QuantiFERON Gold In-tube testing on them and if they were positive, we would treat them for latent tuberculosis infection. If they were negative, then we would not treat them and we would monitor them so at this point, we’ve identified 56 low-risk individuals in our area thus far with an age range of 13 to 82 years of age, the majority African-Americans. Majority were females and the female predominant tested mostly with healthcare and nursing and people going into that field in our area. The TST range was five to 20 millimeters so there were some people who came out of that 10 to 14-millimeter range that we were considering and most of them were health sector screenings. There were some who were screened for adoption and foster care. If you want to adopt a foster child at one of developmentally disabled schools, you actually have to get a skin test, for nursing home admissions and special circumstances, military, congregate settings, child care, nursing school, etc.

And so one of the things that we discovered when we checked these folks, of the 56, only seven were positive by QuantiFERON which was a lot lower than I had anticipated, but really I’m cherry-picking a population that’s going to be naturally low-risk for having a positive test. So we did treat these folks for latent tuberculosis and I felt very good about it. I felt like I was doing the best thing for the patient and then we also identified another 48 who were negative by QuantiFERON and then we had one who was indeterminate.

Not surprisingly when you broke it down by TB skin test, there was some difference that actually is statistically significant that in the low range 10 to 14 millimeters, there were only 8% of people actually had a positive QuantiFERON. In the higher TB skin test range which we think really is the more specific skin test range, it was higher at 21% but still was not even half of the folks who came in and we did have one person had a five-millimeter skin test actually had a positive QuantiFERON and we did treat that person.

Funding issues, these are the cost breakdowns that we’ve done on internal analysis of what it costs for us to treat folks for latent tuberculosis. TB skin testing is about $4 including materials and applications. QuantiFERON is $21. That’s pretty low when I talked to other folks but one of the things is through volume and automation and we incorporated it into an ELISA platform that we used for other things, it’s $21 a test so it’s really not that bad and we batch them, too. This includes lab tech time, materials, transportation and everything. The most expensive parts are X-rays which we did on all of these folks, just based on the way that we do our TB controls. Isoniazid treatment is not very expensive. Lab, actually our lab would be more than that because I’m more compulsive about LFT orderings and our nursing time actually $190 per nine months. Actually this is a little bit low because this doesn’t account for people who have problems, people who have nausea or elevated liver function.

And so when we look at that, the cost that it would have taken if we had just followed the TST would have been about $24,000 for this cohort of folks. Our cost was $14,000 but if you exclude the cost of the chest X-ray, actually which primarily is placed on the patient or on their insurance provider, the total cost for QuantiFERON testing for this whole thing for all these patients was about $2800 and saved us about $2000. I asked for that $10,000 in a raise but they turned me down. But also too, when we follow these folks, in about 60 patient-years of follow-up so far, we haven’t had any development of that disease. I’m going to knock on wood right here.

Also too we’ve used it in some outbreak settings. We’ve had periodic chicken plant outbreaks or exposure in contact investigations we have to do in our area. We recently had a 54-year-old gentleman who worked in a chicken plant had cavitary pulmonary disease, 49 employment rated contacts. Instead of using TB skin testing which we traditionally had done, we used QuantiFERON. Chest Xrays were performed on those who had symptoms or positive QuantiFERON. Of initial screening. It took a total of two days which was very good. Usually it takes us a lot longer to get hold of everyone so it’s a lot of shifts. We had people who had to work shift. We got all the employees in a two days. Three nurses were required. One thing that we were surprised about is 12 of the tubes did overdraw when we hooked it up on the automatic vacuum. The Celestis folks told me that that was impossible but I told them to bring extra tubes anyway in case it happened again so that was one thing we just had to kind of watch out for. And so of the 49 folks, we had 8% positive by QuantiFERON, 19 were foreign-born, a total of QuantiFERON cost was $931 and our LTBI treatment costs were about $1000.

In comparison, we compared it to a 2005 chicken plant contact investigation with the 21-year-old gentlemen with cavitary disease, 229 employees and they used TB skin testing. Now these are a little bit apples and oranges. This earlier chicken plant outbreak actually had more foreign-born individuals so you can’t make dread comparisons and also obviously you can’t say one person was particularly more infectious than the other but there were 229 screened. Twenty-seven percent were TST-positive, 52 were treated for latent tuberculosis infection that was either holdouts. 209, the majority were foreign-born and total LTBI treatment costs were about $11,000. We broke it down by individual. You can see QuantiFERON we had an 8% positive rate in the recent outbreak, 32% in the other but when you look at the cost, we tried to break it down and see what was the cost to us for QuantiFERON versus TST screening and final results and basically it was cost-neutral.

For the U.S.-born, it was about $19 a piece total cost and for the foreign-born, it was slightly more for QuantiFERON but again, we’re talking apples and oranges.

Also too we’ve had some anecdotal issues come through. We do have some folks with BCG. Our experience is that in most of our foreign-born folks, BCG have a very strong distrust of TST and the majority of them actually refused LTBI treatment.

Two a one, the people that we’ve done QuantiFERON on that were positives that had a positive TB skin test, they all agreed and were anxious to take LTBI treatment because they believed it. They didn’t believe the TB skin test.

Also too we have seen some false positive QuantiFERONs in healthcare screenings. We do have a large hospital that does about 3000 screening QuantiFERONs in their health system every year.

We did have a pseudo-outbreak one summer where they had a baseline rate of 1% and this includes people who previously were known TST-positives and also had a 9% one month. We went back and looked at them. A lot of them were low-risk. We went back and repeated the QuantiFERON on a recollect draw. Almost all of them were negative and we’re monitoring them but we did not treat them.

This is another situation where looking at the actual values was very important because when we looked at the TB antigen result, we would see that it actually was very low. They would just be barely above the cutoff value for positive interpretation and so we’ve kind of noticed anyone who has TB total antigen readout of less than one, these were folks that were questionable. And all of these folks actually on recheck were negative and we’re talking about people who have a positive mitogen of greater than 10 and maybe a null control of 0.35 and then a TB antigen of 0.7 so they’re really close to the nil and just above the cutoff. We also had some initial skepticism by our public health nurses. In TB control we’re kind of wedded to tradition a little bit and can be kind of slow to embrace technology but we’ve had rapid acceptance from our nursing staffs and our professionals and now there’s a lot of preference because they’re seeing some of the benefits. It’s not a panacea. It’s a useful tool. You got to take it with a grain of salt because some of the things - it’s just a test. It’s not perfect and if it doesn’t make sense, we don’t need to kind of hang all of our decisions on it.

And that is all that I have and I would like to thank you all very much for letting me be here and share our experience in Mississippi..."