A Qualitative Study to Explore Influences on Tuberculosis (TB) Clinicians’ Decisions when Choosing an Interferon Gamma Release Assay (IGRA)





Evonne O. Harding

Former Lead TB Nurse (Borough Lead), Lambeth PCT


INTRODUCTION

Mycobacterium Tuberculosis (MTB) is the single leading microbial killer and a major cause of morbidity and mortality, causing an estimated three million deaths per year (Maher & Raviglione 2005, ATS 2000). It is estimated there are nine million people from the large pool of individuals with latent TB infection (LTBI) developing active and infectious TB disease every year worldwide (WHO 2004). The treatment of LTBI to prevent progression to active disease is said to play an essential part of global TB epidemic control and elimination (ATS & CDCP 2000, Geiter 2000, Broekmans et al 2002, Jasmer et al 2002, NICE 2006). Interestingly, the treatment of LTBI is not part of the Stop TB strategy (WHO 2004, WHO, 2006) but has become a major goal and interest for wealthy low prevalence countries (Horsburgh 2004). Raising the question on whether treating LTBI is of interest for those with the luxury of not seeing too much active transmission.


An accurate and reliable diagnostic tool, enhanced treatment strategies and efficacy markers to compare them is needed to help combat and reduce the TB load. Until now, the tuberculin skin test (TST) has been the only method of identifying infected contacts. It cannot be trusted as a “gold standard” because it is long known to be unreliable with numerous problems. A relatively new method of using immune-based rapid blood tests for detecting LTBI offers an upgrade with distinct differences from the traditional TST. These diagnostic blood tests were developed based on a specific elevation in the interferon gamma (IFN-y) concentration that occurs as T-cells respond to early secreted antigens target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10), both of which are specifically expressed by MTB but absent from bacille Calmette-Guerin (BCG) and most environmental mycobacterium (Hotta et al 2007, Mori et al 2004).


The two commercially available interferon gamma release assay (IGRAs) differ from each other based on the technique of IFN-y detection, either by enzyme linked immunoassay (ELISA: utilises whole blood: Quantiferon-TB Gold {QFT-G}) or enzyme linked immunospot (ELISPOT: utilises peripheral blood mononuclear cells: T-SPOT TB {T-SPOT}) (Mori et al 2004, Adetifa et al 2007, Pai et al 2004, Kang et al 2005, Barnes 2004, Lalvani et al 2001).


To date, there has been no evidence of any study providing data on the opinions and/or views of the growing number of IGRA users regarding its introduction into their practice or about how they choose the most appropriate IGRA. Current IGRA studies have either compared its effectiveness with the TST, its cost effectiveness, reviewed its role in diagnosing both LTBI and active TB or its effectiveness in certain groups (Lalvani et al 2001, Dinnes et al 2007, Mori et al 2004, Pai et al 2004, Mazurek et al 2005, Menzies et al 2007, Kang et al 2005).


This current study was designed and aimed to qualitatively explore and determine the views of TB clinicians about the influences on their decisions when choosing to use IGRA in a routine clinical setting. The study also sought to identify what they saw as their opinions on the National Institute for Clinical Excellence’s (NICE) published guidelines of the introduction of IGRA (NICE 2006).




METHODS


Sample

A purposive sampling method was used, ensuring only TB consultants with training and expertise in the management of TB was included in the study.

The inclusion criteria for this study were:

  1. Current practising TB clinician,

  2. TB clinics based in the London area and recognised on the London TB register (LTBR),

  3. TB clinicians aware of the introduction of IGRA in the NICE guidelines.

Each TB service as recognized on LTBR were contacted to identify the clinic’s Lead TB clinician and an email of invitation to participate in the study was sent out. Eleven was successfully interviewed after four cancelled due to their work load. Email and telephone responses indicated willingness to participate and arrangements were then made for the interview.


Data Collection

Each participant had a tape recorded face-to-face semi-structured interview, lasting no longer than thirty minutes. Signed consent was obtained from each participant. Interviews took place between 20th February 2008 and 1st April 2008 with all participants being interviewed once within two weeks of receiving their email approval.

At the time of the interview, a reminder of the aims of the research, further explanation on the researcher’s interest in the topic, reassurance about confidentiality and anonymity were given.

Interviews were transcribed word-for-word within twenty-four hours of the interview. During transcription, voice intonations for joking or irony, laughter, relevant facial expressions or gestures in order to put remarks into perspective were recalled.


Ethical Consideration

Ethical approval was granted from the Guys Ethics Committee (REC no: 07/H0804/97). Research and development approval was also sought from the St Thomas’ Hospital research and development department


Analysis

Data analysis in this project followed the steps below (Hancock 2002, Zhang 2006, Seidel 1998, Taylor-Powell & Renner 2003, Pope et al 2000, Maying 2000).

Step 1: Knowing the data

The data was transcribed and then organised by question in order to understand the data. The transcriptions were read several times.

Step 2: Categorisation

During the reading, similarities in question response were highlighted and then summarising categories were drawn from these sentences. The containing sentence or phrase was then listed under the appropriate category or, in some cases, listed under multiple categories where the sentence was relevant to more than one category.

Step 3: Research Focus

The primary categories determined were then analysed for similarities and common themes in an iterative process and more specific or generic super-categories emerged. The initial categories were refined under super-category headings. The super-categories were grouped under a final 8 key themes.

Step 4: Interpretation

The data was then discussed using the final 8 key themes and super-categories. Using these classifiers, major lessons, new meanings and the potential interests of future readers of the research were extracted from the raw data, discussed and presented as the research results. Quotes were also used to illustrate points and bring the data to life.










RESULTS

The analysis is presented under the following key themes:

  1. Knowledge of available brands of IGRAs

  2. Specialists who made the decision about using IGRA

  3. Circumstances in which IGRA could be used and the IGRA mostly appropriate for these circumstances

  4. Views on the different commercially available brands of IGRAs

  5. Views on IGRA’s use and usefulness

  6. Opinions on NICE TB Guidelines of IGRA,

  7. Current and Future research, and

  8. Factors which could improve more wide-spread use.



1. Knowledge of available brands of IGRAs

The two commercially available brands of IGRA identified were T-SPOT using ELISPOT (Oxford Immunotec, UK) and QFT-G using ELISA (Cellestis, Australia).


All participants were aware of both the aforementioned brands of IGRA, even if they had not used them. This response was pre-empted through the interview question. However, one particular participant’s response was not pre-empted, regarding a third test that is under research based on flow cytometry and not currently commercially available:


‘Our research in this area is largely looking at flow cytometry rather than ELISA, or ELISPOT technology, although we have done some of that as well. In terms of the research, we do not really use blood that much because we feel that it is not as sensitive and as helpful as we are finding when we look in the lungs. The research now has moved into doing induced sputum. So, we are looking at other sites outside of blood which we think gives us a lot more information.’


Frequency of use: A few of the participants explained IGRAs were not routinely used because they are not yet established in everyday practice. A particular participant was sceptical about the existing TST and so was even more sceptical of the IGRAs:


‘I think I would only use it relatively occasionally, I am not a great enthusiast for the TST, so I don’t see why I should be a great enthusiast for the IGRAs.’


For those already using IGRA in practice, usage ranged from fairly-routine to routine, with a few having in-house services and a budget agreement for 200 – 300 tests a year:


‘Where as the HIV patients have a budget or have agreements to send 250 – 300 tests a year’


2. Specialists who made the decision about using IGRA

It was evident the decision as to when and which brand of IGRA should be used was an individual thing in the different trusts. This decision had been based on the patient or patient group being investigated. The specialists identified as having either independently or jointly made that decision were Lead TB Clinician, TB Commissioning Board, Immunologist, TB Network (New), Laboratory Technician, Health Protection Unit (HPU), Primary Care Trust (PCT), Multi-Disciplinary Team and Research Group:


‘It was vital, and we were careful in ensuring, that people in the network were involved at every step of the process. We have a network here, which is unlike any others in that all the TB nurses are under one employer. The clinicians at the different hospitals are employed by the acute trust, so there is a network of hospitals. What we didn’t want to do is say, fine, we are going to introduce IGRA right across the sector which would have caused all sorts of upset in what’s a very new network.’


A few participants also felt after the decision was made they were able to use it because the manufacturers approached and provided the test. Some sensed that in view of current TB commissioning, this could be the best time for IGRA to be taken up.


3. Circumstances in which IGRA could be used and the IGRA mostly appropriate for these circumstances

A minority of participants were unsure as to the situations IGRAs would be most valuable, preferring to wait and keep an open mind. However, shown below are the identified main areas for IGRAs.


Contact Tracing: All participants felt happy IGRAs’ position, value and good performance was in contact screening immunocompetent persons, especially those who had prior BCG vaccine or were unclear about having had the BCG vaccination. They felt it made screening much easier, although a particular participant explained it wouldn’t be used on contacts of sputum smear-positive pulmonary TB. Participants identified QFT-G as being appropriate for this circumstance:

‘I wouldn’t use IGRA in patients who are contacts of smear positive pulmonary TB because the risk is high and therefore if according to NICE the TST is positive I would treat the patient, as I don’t feel adding IGRA in the way NICE had recommended will change my policy on that’


‘QFT-G is good for non-immunosuppressed when you are trying to confound or confirm latent disease from our point of view’


Paediatrics: Participants deemed IGRA useful in paediatric TB diagnosis especially for school outbreak screening. They felt it was already difficult diagnosing TB in children particularly when acutely unwell or when their immune response did not generate the T-cell response needed.


They felt an area that could be problematic was when used according to NICE’s algorithm for screening children below two-years who are contacts with infectious TB and have not received the BCG vaccination. NICE suggests such children are “started on Isoniazid 5mg/kg and perform initial TST, if this is negative ≤6mm then continue on Isoniazid and repeat the TST in six weeks, if the TST is positive ≥6mm and increase on initial test ≥5mm then use IGRA” (NICE 2006, pg 146). Participants believed IGRA needed to be done prior to giving preventative therapy because it can affect the test and a negative test cannot be interpreted. Therefore, they are interested to know what the effect on paediatrics would be. They are unsure what Paediatricians think of it, what difference or use it could make to their diagnosis and how much they would want to use it. Even though participants felt unsure of the use of IGRA in children, some felt maybe T-SPOT was appropriate within this group:

‘Paediatrics where you would give chemoprophylaxis and then re-check in six weeks you cannot use IGRA because IGRA may be negative because of the drugs, while TST would still be positive and so people have to be careful. The test can go negative particularly low level ones. I think you would still have to do TST. I am interested to see how much the Paediatricians want to use IGRA because I don’t think its going to be as much use to them as they think its going to be.’


‘The data on children obviously on the current published literature is reasonable to use the T-SPOT in addition for instance to the TST’


Human Immunodeficiency Virus (HIV) & Immunocompromised: All participants believed IGRA could be routinely used in identifying LTBI in HIV patients thereby preventing active TB; they felt it was the best available for this group. Majority of participants felt T-SPOT’s use in this group was appropriate:


‘For HIV positives there is recently published very good data which shows that the T-SPOT performs extremely well, even at low CD4 counts.’


‘For HIV, clearly there is very good data that the T-SPOT performs extremely well’


Its use in the HIV service in one trust allowed for them to roll it out to all other users. A particular participant expressed dissatisfaction that newly diagnosed HIV positive patients were not being screened for TB, especially when TB accelerates the course of the disease, but all new TB patients were offered an HIV test:

‘It is sort of disappointing because in the UK although we are happy that every TB patient should have a HIV test we are still 15 years behind the states where every HIV positive patient has a TST or at least some tests relating to TB’


High risk groups: Participants suggested IGRA would be valuable in doing targeted screening in the community on high risk hard-to-reach groups such as drug and alcohol abusers, and the homeless (who could be coughing and have night sweats for a whole host of reasons). They believed they were the groups that might have difficulty returning for follow-up visits for TST reading and that doing the blood test would help free nurses’ time by removing the need to chase patients. The time saved could be spent on ensuring patients complete treatment therapy as this is as important as the diagnosis itself. Therefore, they felt this could help combat one of the numerous challenges when dealing with this group. Within the data, participants did not identify which IGRA they thought was best used within this group:

‘It can be useful certainly if you have got a group of drug addicts who coughs, they could be coughing for a whole host of reasons and it may be very useful in them’


‘We are hoping to use it at some point on high risk people in the community, people who are on drugs and alcohol group’


New entrant screening: IGRA was identified by participants as an initiative screening tool for new entrants and UK born citizens who frequently travel to high incidence countries. They felt IGRA could help identify LTBI in those new entrants with exposure in last five years, thereby reducing risk of activation. Even though the topic of immigration was thought to be controversial, a few participants thought IGRA could change the way new entrants are currently screened at port of arrival. A few participants questioned the use of an expensive test like IGRA in western countries when the real burden and need is in parts of the world that cannot afford the test. Some participants felt QFT-G could be suitably used in this group:

‘migration and immigration are not the sort of things to talk about but IGRA could be used at port of arrival rather than the current CXR procedure, which is not working, making the process potentially easier and simplified.’


‘Basically, this could be QFT-G’s niche area, because it is cheaper you can do bulk, you can freeze and then analyze it later. It lends itself to that kind of issue, so for latent disease, contact tracing, new entrant screening potentially that’s its niche area’


Immunosuppressed: Another area IGRA was said to be useful was in the immunosuppressed as interpreting their TST result could be difficult. Participants believed it could be used effectively as a risk assessment screening tool prior to patients going onto anti-TNF agents, or for patients on moderately advanced or other various forms of immunosuppression. T-SPOT was identified by majority of participants as being appropriate for this circumstance:

‘In theory could be used for individuals who have various forms of immune-disregulations or immunosuppression. So as I say screening people who are going to go onto anti-TNF agents.’


‘we reasoned that the ELISPOT test is probably the more sensitive in individuals with advanced immunosuppression than the whole blood Elisa QFT-G assay’


Occupational health screening: IGRA was considered to be good in occupational health pre-employment screening in order to identify and treat LTBI. QFT-G was identified as being appropriate for this circumstance:

‘In London there are lots of staff coming from high risk areas and IGRA’s confirmatory use gives us clarity, plus we know where we are, plus allowing us to be a bit more aggressive in offering and insisting on the use of preventive therapy.’


‘Occupational health screening we should be using QFT on the positive TST for convenience because one doesn’t want to keep giving more chemoprophylaxis than one has too’


Active TB rule out/rule in: Some participants identified IGRA could be accurate as a good aid in the investigation of possible suspected diagnosis of active TB, mainly as a rule-in or rule-out test, but others disagreed expressing they were unsure of its role in this area of use. Participants felt IGRA could give extra information to help make a decision and exclude TB, but at the same time, felt it needed great consideration especially in knowing what negative or positive meant. Within this area, a few participants felt they would use it infrequently because it is only licensed for use in contact screening, which they are not directly involved with, also IGRA and/or the TST does not distinguish between active TB and LTBI. For these reasons participants expressed they discouraged other users within their trusts from using either test in diagnosing active TB. Participants believed IGRA should be part of clinical risk assessment in this area and not used on its own. They preferred to get samples such as sputum as the test doesn’t give culture and sensitivities. Even though some participants questioned the use of IGRA within this area, majority of participants felt T-SPOT is the better test to use:

‘if I have done all my usual screening tests and I couldn’t make a decision based on the result of that as well as my clinical finding and I am reliant on a further test to make a diagnosis. I would add IGRA in addition to the information I already had. So, I’m looking to see what extra information this gives me.’


‘Our view is the T-SPOT is more sensitive but its more fiddly and therefore the capacity issue is an issue for labs. Therefore for active TB rule out we use the T-SPOT’


LTBI: IGRA has been used for diagnosing and/or confirming LTBI especially as a target screening tool. It was deemed as efficient and better in this area because it confirms whether the patient has LTBI. Most participants felt QFT-G was an appropriate test in diagnosing LTBI:

‘What it is there for now which is basically looking for latent TB. I think its incredibly useful’


‘Well for investigation for LTBI in the immunocompetent population predominately. I have used QGT-G’


4. Views on the different commercially available brands of IGRAs

T-SPOT: According to the participants, T-SPOT seemed to offer more accurate results and was said to be better than QFT-G. Participants felt it had better reliability and was fairly conclusive, giving off fewer indeterminate results as well as lower false positive and negative rates than QFT-G. As a result T-SPOT was used as a confirmatory test to check whether QFT-G indeterminate results are real discordant. T-SPOT was deemed to be more sensitive and specific than both QFT-G and the TST. Participants mainly using T-SPOT felt they would monitor usage and if demand increased they would change how they were using it:

‘T-SPOT is probably the more accurate test, well, it has a lower false positive and lower false negative rate I believe than quantiferon.’


Participants criticised T-SPOT for being more complex, labour intensive, having capacity issues for the laboratories and being less accessible. They felt it was technically more difficult because there is an important need for blood samples to be sent to the laboratory fresh and on time for immediate analysis, creating logistical problems with transporting the samples:

‘I think the T-SPOT is more reliable but less accessible.’


‘The T-SPOT test is more complex and it has to be analysed immediately which creates logistical problems.’


Participants expressed that T-SPOT was more expensive, needing special equipment. It could be cost effective and cheaper than QFT-G if performed in large amounts continuously and if participants had access to in-house services. If only two or three tests used weekly, clinicians did not want to use a whole plate due to the expense. In addition, the laboratories were paying for re-agent, which is not factored into overall cost:

‘The way a plate is done means its technically a difficult test to do, where as if you put it in a coulter counter which they do the full blood count with, that can make it much easier.’


QFT-G: Participants identified this brand as having operating advantages, such as needing less volume of blood, which may be important in children. It was considered easier to implement and process by batching samples together for later bulk analysis, reducing equipment investment:

‘And the great advantage of the QFT-G is you can actually batch, you can store the sample once you have done some steps of it, and then run all of the analysis in one go.’


‘I understand that QFT-G is a bit easier in that it’s just easier to handle the specimen, etc, so that it can be sent away more easily’


Most participants felt QFT-G was cheaper, more easily accessed, less complex than T-SPOT, logistically better, practically better and technically easier to perform as antigen stimulation begins within the tubes used to collect the blood sample. These characteristics gave the impression it was superior to T-SPOT especially in the current financial climate. This was also, why technicians recommended it in preference to the T-SPOT, instead of employing a biomedical scientist to do the extra work on T-SPOT. Participants believed because QFT-G was a simpler cheaper test to do, routine screening could go straight to it, with contacts that have had prior BCG vaccination:

‘It’s actually a logistically simpler test to do for the laboratory; it’s also cheaper as well which is quite important. So we have tended to use QFT-G’


Participants were not satisfied by the amount of indeterminate results they were getting from QFT-G which then needed to be checked with T-SPOT, which meant it was less reliable:

‘With the QFT-G, it is very accessible but less reliable’


5. Views on IGRA’s use and usefulness

Both brands: Most participants have had the opportunity of using both brands of IGRA, but only a few currently have continuous access to both and this is unlikely to change due to financial constraints. For this reason participants tended to use the easiest brand available locally. When asked to compare brands, participants felt both tests had different ways of measuring IFN-y:

‘If we took an individual and we ran a T-SPOT and QFT-G on the same individual we saw very similar results.’


Comparison of IGRAs and TST: Some participants believed IGRA and the TST to be similar tests, looking at the same phenomenon, except measuring different criteria. Because of this, a few participants were unsure and found it difficult to say if IGRA was superior and/or better than the TST and if there was a big difference in the efficacy between them. They also felt both tests had the same kind of mythology surrounding them, as being instant tests to diagnose TB. Some were curiously surprised to find as many IGRA positives as there were TST positives, but felt they would believe the IGRA result over the TST because it was not affected by the BCG and EM. This also meant IGRA was better used when screening people who had or possibly had been BCG vaccinated. They felt there was a difference of neonatal BCG makes from thirteen-year-old BCG:

‘In children, the evidence is that, I mean the difference is now based on whether you have had neonatal BCG. Prior to BCG there is no difference between IGRA and TST. With neonatal BCG its slightly more difficult, but actually neonatal BCG doesn’t interfere as much with TST as thirteen-year BCG did.’


The TST was felt to be just as good as IGRA on people not BCG vaccinated but favoured over IGRA because it was well known and clinicians felt comfortable with its long track record, while IGRA was new and unfamiliar. Like the TST, participants felt IGRA was a continuum with cut off. Those who had routine access felt that reservations were due to unfamiliarity with IGRA and with gradual introduction, they would be able to build their own experience irrespective of the literature.


Some participants felt the TST should not be abandoned or replaced by IGRA, but they complement each other, work well together, add to the information, and are both reasonable tests giving greater certainty and the biggest predictive value. Nevertheless, a few others felt IGRA was just another test for diagnosing TB and an up-graded version of the TST. However, they did still believe both test had a role in diagnosing TB:

‘ I think the TST and IGRA are two reasonable tests if you put them together and you get a positive overall then you are going to believe that result, but with a positive mantoux and a negative IGRA, in general terms I am going to believe the IGRA on someone who has been BCG vaccinated.’


Participants also felt IGRA offered a number of clear cut technical, practical and operational advantages for facilitating TB screening clinics over the TST, such as:

  1. IGRA results being available as quickly as 24 hours after blood collection, as opposed to 48-72 hours for TST,

  2. IGRA allows for a “one-stop shop” by the requirement of only a single visit for a blood test, with a negative result meaning the TB nurses can simply give results and discharge by telephone,

  3. IGRA procedures are performed in a consistent manner in immunology laboratories where they are familiar with routinely analyzing such tests, rather than reader biases with the TST which could push a patient into positive by being 2/3 millimetres (mm) out,

  4. IGRA gives an immediate win situation to those with TST 6-14mm, who are positive but not strongly positive and currently nothing is done with them,

  5. Replacing difficulties when resources such as skilled TB nurses are unavailable to perform TST,

  6. Replacing uncertainty about the BCG and immune-status of the person tested by distinguishing whether positive TST was due to false positive,

  7. Reducing boosting effect due to repeated TST:

‘It requires the single blood draw, it’s relatively easy to interpret and it means that the patient doesn’t need to come back for follow up visits and therefore should facilitate TB screening and finally it isn’t influenced by prior BCG vaccination or cross reactivity with environmental mycobacteria’


Method of Approach: The two-step-process through the NICE guidelines, where IGRA was used as a confirmatory test in contacts with TST of above 15mm with the aim of offering preventative therapy, was sometimes used by a majority of the participants, but not always. These participants thought that it worked well and gave them the highest negative predictive value when used for contacts. This approach was criticised by a few as they felt the method was driven by economics, rather than by the scientific value and benefits behind the test. However, they were aware that the NICE two-step-approach would need to be considered in order to gain the funding to use IGRA at all:

‘But in fact it was not backed by science, the study wasn’t done to say this is best model it was “if we do so many tests and we factor in the finance bit, what do we come out with” and from my perspective that’s not as satisfying as knowing what the correct scientific answer is and then costing it.’


In another approach for research purposes, IGRA was used first and if it was positive and preventative therapy was the aim, and then the TST would be used as the confirmatory test. This is not quite as per the NICE guidelines, but still uses the two-step-approach:

‘But the way the PCT have funded it, is that they want to do the IGRA test first and then only give chemoprophylaxis if we do a TST afterwards. So it’s not quite the way NICE guidelines recommended.’


A single-step-approach not consistent with NICE was also used where participants went straight to IGRA without using the TST. This was as a result of staff shortages and for active TB rule out. Those who had used this approach questioned the two-step-approach feeling it did not offer any benefit to nursing time but rather gave them an additional step to deal with. They felt NICE ended up with this approach because they were being cautious.


A particular participant explained that they had used a three-step-approach, regarding it as an interactive approach rather than a simple tick-box exercise. It used both brands of IGRA and the TST, so there had to be very specific reasons why IGRA was used. It also depended on where the clinician entered the algorithm:

‘In this trust we are going Supra-NICE, so we have what we call a three-step-approach. You start off with QFT-G because it is the cheaper more pragmatically easy test. We will use both QFT-G and TST, we don’t do one followed by the other, we do them both up front because there is good data to show there is priming. For instance of your QFT-G test by doing a TST first. And if we have a concordant result that’s easy, they obviously have preventative therapy, but if we have a discordant result, i.e. TST positive and QFT-G negative then we take a policy of a radiology follow up. If however the clinical data is very strong that the person does in fact have LTBI and you are getting a false negative then we will judge it based on the imaging and the strength of the TST. In fact what we have in the three-step-approach is that we put a T-SPOT if there is a discordant between the TST and the QFT-G. So if you have double negative at the first hurdle that’s easy. If you have single positive they get radiology follow up unless the clinical criteria are very high. In other words, the TST of fairly high millimetres of blistering, well we will assume the QFT-G is a false negative.


Work load: Participants believed the role of TB clinicians was in reducing the disease and infection load in the community and IGRA could be a good way to do this, but they were interested to see what would happen to their work load once they started using IGRA routinely. Would it significantly reduce screening exercises, could it allow for fewer numbers of patients needing to be treated with preventative therapy or would clinicians be seeing more people in the sense that once they found LTBI they would have to screen them further for active TB before offering preventative therapy? Some felt that IGRAs could help them streamline TB services making nurses’ working lives more interesting rather than just screening. The transfer of work from the TB clinics into the immunology laboratories was another area participants felt would need reviewing. Even though it would free up TB nurses’ time to be more effective, the laboratories would be the ones providing the technical support:

‘We are providing the technical support so I don’t think it’s appreciated enough that there will be a transfer of work from the TB nurse into the lab.’


Sensitivity and Specificity: Majority of participants felt IGRA was more accurate and offered better sensitivity and specificity. This helped them to only give preventative therapy to those genuinely sensitised to TB. They also felt its sensitivity was viable depending on the population and generation being screened. Some expressed IGRA showed higher sensitivity and specificity than the TST especially in HIV patients but not in patients with active TB. Others felt unsure of IGRAs’ sensitivity and specificity and that it may not be what the manufacturers say it is:

‘I think that IGRA is useful because it is of greater sensitivity as far as we can tell than the TST in immunocompromised individuals.’


Interpretations and Results: Participants felt the interpretation of IGRA results was important, needing caution applied to how the result should be used as it could have different meanings. Other factors such as past LTBI (treated or not), active infection or maybe a false positive for another reason needed to be taken into account.


In their opinion, before any test, not just IGRA is performed, a clear goal regarding the result should be established and if the answer is the same with or without the result, then the test should not be done. They believed it was irresponsible to do the test unless the results would be acted on and this assessment should be done before doing the test, and maybe such a rule should be applied to other tests available within hospitals. Some participants believed not all IGRA positive results meant an individual would need preventative therapy, that it would depend on the individual’s situation, and that they would act on the result based on the algorithm and enough clinical data:

‘I think in any test you have to say you do the test, If this is positive what am I going to do, if this is negative what am I going to do, and if the answer is the same then you don’t do the test. Not, unless you are doing a research study’


They also believed IGRA gave them clarity about what they were doing and a supporting reason for being active about giving preventative therapy. Some participants expressed lack of understanding, low confidence and frustration at the way the results were presented as negative or positive. They felt there was a range of cut offs and knowing what this was would help towards interpretation. This highlighted the importance of correct interpretations:

‘A combination of information gives you greater certainty of what you were doing. You just have to be sensible in the interpretation’


Methodology: IGRA was thought to be a simple procedure for the immunology laboratories to interpret, as they were familiar with routinely handling, storing and analyzing such tests. Participants felt if IGRA was established in their local hospital’s laboratory and ordering system, it would make accessing and ordering a lot easier and allow for more routine usage.


Participants criticised the methodology of both brands of IGRAs for being labour intensive tying one technician for days just to do a small number of tests. Both brands would not be used at the weekend as the laboratories were not open and they also required the samples the same day before 4pm. Beyond this time, the laboratories were unable to handle the sample on that same day due to the sample processing time. They understood each brand differed mainly with respect to the technique of IFN-y detection and the types of samples used (peripheral blood mononuclear cells vs. whole blood):

‘it has inconvenient cut off-times for specimen collection as well as the use of courier services, the need for the blood to be processed within 12 hours. From specimen collection to actual testing often exceeds the 12 hour limit.’


Cost Price and Resources: All participants agreed the price of both IGRAs was too expensive making users reluctant to use it. They also believed it was unlikely for most trusts to have both brands available for routine use especially under the current NHS financial climate, but this should also make clinicians think before ordering the test as they felt usually NHS staff were not good at spending money on investigative tests. They felt it provided benefit to trusts in terms of reduction in patients’ hospital length of stay, reduction in number and use of unnecessary treatment, and rapid diagnosis of smear negative TB within hospital in-patients.


A few participants felt T-SPOT was only financially viable when carried out in bulk (at least twenty tests) by freezing samples for later batch analysis. For fewer than twenty tests only QFT-G was viable. However, they felt both brands could be cheaper overall than the TST when the cost of a patient returning to another clinic for TST reading was factored in.

Participants felt the cost price did not take into account transporting the samples, but that this could be dealt with by having in-house IGRA services. Only a few participants had in-house IGRA services and those few also did work for other trusts:

‘It’s like anything that comes with a price tag, and is perceived as been more expensive. Actually if you work it out, pound for pound, somebody having to come back to another clinic to have their skin test read can work out more expensive’


IGRA Protocol: Most participants had written local IGRA protocols and policy for its routine use with different approaches aiming to streamline the system and services. Only a few had no protocol in place because their usage was adhoc. There were specific algorithms for all the different circumstances identified in key theme three as the niche areas for IGRA, (including laboratory related policies). There was also a policy of using the more sensitive and/or cheaper IGRA first in some circumstances:

‘I am going to use the cheaper, more pragmatic test up front in combination with the mantoux for most of the categories of Immunocompetent, latent TB. Run them through the algorithm, if they are discordant you then use your second IGRA – the more sensitive one’


Concerns raised: Participants voiced their concerns around IGRA being made readily available and used in the wider hospital. Once it was available on hospitals’ computer ordering systems it could potentially be over-used, used recklessly, open for abuse and misinterpreted as a confirmed test to diagnose active TB. This might result in patients being inappropriately placed on TB treatment due to non-TB clinicians’ lack of understanding:

‘This has caused problems in that clinicians don’t quite understand what they were requesting. They were placing individuals inappropriately on TB treatment without liaising with the TB clinic’


Their concerns came from their experiences of the way non-TB specialists currently use the TST for diagnosing active TB within some trusts, when there are other methods to establish this. Participants felt educating non-TB colleagues to understand the TST is not meant to be used for diagnosing active TB had being difficult enough and that this would be even more difficult with IGRA, it being a blood test that could be easily ordered along with other blood tests:

‘Lots of colleagues, including someone on the phone just before you came up said “can’t you do that fancy blood test please” to look for active TB, You have to say to people that’s not what its licensed for. It’s not been proven as a test to look for active TB, that’s not the thinking behind it. It can take a lot of convincing, in some respect that’s the same as the TST. The TST is never there to diagnose active TB and we have had to really try and educate people in the hospital’


The other concern raised by some participants was that they believed they did not know enough about IGRA to feel confident yet they would be called by non-TB colleagues to interpret the results. They also believed there was a lot of “hype” around the tests and that non-TB clinicians did not know that the development of the NICE two-step-approach was predicated on cost, not clinical efficacy:

‘We should not feel compelled or get pushed by non-respiratory colleagues into using it willy-nilly which would be a shame. It’s easier with blood tests than with skin test to use it inappropriately, to just request for a blood test along with other blood tests and everything else.’


‘Such careless usage would be irritating, because they would expect us to interpret the results when I wouldn’t have used the test initially’


6. Opinions on NICE TB Guidelines of IGRA

When participants were asked what they thought of the introduction of IGRA by NICE guidelines there were of mixed feelings.


Negative: Some participants felt NICE rushed the inclusion especially when the evidence was still weak in most areas. They criticised them for been predicated on cost and not clinical efficacy, their lack of awareness regarding availability of funding being readily available and having faulty cost benefit analysis. They did not approve of the analysis as it did not take into account different populations being screened:

‘well, I think the NICE guidelines were a little bit naïve in that, there was a bit of an assumption that the funding was already out there’


A small number of participants also believed NICE were being cautious by stipulating IGRA could be used where available and only for LTBI diagnosis. They felt this limited them, as they were too vague in not explaining to non-TB specialists that IGRA does not distinguish between active and LTBI. A few believed lack of clinical evidence meant they themselves were unable to incorporate it into their personal practice:

‘There was no explanation to non-respiratory clinicians that IGRA wasn’t readily available or could not be used to screen for active TB but only for LTBI. Non-TB specialist, Joe-public, who doesn’t look at it day-in-day-out does not understand how NICE reached its conclusion. So I think from that point of view, the science message is wrong.’


Positive: Others were in favour with NICEs’ introduction because they believed it gave clinicians the opportunity to test IGRA out and that the introduction allowed them to try different approaches, making written business cases for its use and retrieve their own data. In their view, NICE should not be criticised for its vagueness because they were reasonable about how they reached a consensus on their approach:

‘Now of course, everyone castigates them for having been so vague about it and I don’t think that’s fair. I think that they responded to a situation with hind sight sensibly’


They also felt NICE had no choice, because IGRA was already “out there”, licensed and had been an important new technological development in TB for many years, therefore NICE had to mention it to allow for it to be assessed and tested for reliability and appropriateness. They felt NICE was honest about how they reached consensus and responded sensibly, giving clinicians the push to approach PCT and local authorities to provide funding:

‘NICE pushed clinicians to try and get funding, persuading PCTs and local authorities and that’s a good thing.’


7. Current and Future Research

IGRA was used by a few participants in this study as part of research studies based on the research questions being investigated such as a review of its benefits, usefulness and effectiveness in contact tracing, HIV positive population, occupational health, evaluation of its sensitivity and specificity and NIH trial in evaluating its position i.e. does it change the probability of the diagnosis significantly. Participants felt some of the literature and evidence supported IGRA, but there were lots of questions they would like answered, so research teams need to be encouraged to carry out more research on IGRA. All participants expressed an interest in seeing further research studies on IGRA in the following areas:

    1. Evaluating its effectiveness and most appropriate brand in children,

    2. Its value in the immunosuppressed,

    3. Better evidence showing its usefulness in the context of active TB diagnosis,

    4. The difference neonatal and thirteen-year-old BCG makes to IGRA,

    5. Does the use of IGRA lead to a reduction in the amount and need for preventative therapy,

    6. Does the use of IGRA help address whether preventative therapy works,

    7. Support or refute of the NICE two-step-approach,

    8. Benefits in terms of the TB clinic,

    9. Costing analysis based on IGRAs scientific value,

    10. The response of IGRA post TB medication – does the result revert to negative?

    11. What paediatricians think of IGRA,

    12. What IGRA does to their work load,

    13. Evidence IGRA is able to distinguish between active TB and LTBI,

    14. More head to head studies with mixed patients, comparing both brands of IGRA versus the TST and versus each other,

    15. What proportion of mycobacterial kansasii would interact with IGRA

    16. Follow up of IGRA positive and TST negative patients to see the value of IGRA:

‘We used Elispot as part of NIH Trial for the diagnosis of TB, in trying to work out its position. Where did the test actually fit in? Did it is actually change your probability of diagnosis significantly.’


8. Factors which could improve more wide-spread use

Participants felt IGRA was a small and interesting development but not what is needed. What they would like to see is a test that rapidly and easily allowed them access to making firm diagnosis of active TB, especially in difficult diagnostic situations and poor resource setting.


Funding: Lack of funding has resulted in participants having limited access and usage. Its not being available on the NHS has meant that NHS patients are paying privately for testing, challenging clinicians diagnosis of LTBI without the use of IGRA as NICE recommends when offering preventative therapy, thus reducing user autonomy and confidence. A few participants were currently going through the negotiation process of agreeing budget, reviewing financial limitations, writing business plans and arranging funding, while others have had IGRA funding ruled out:

‘I advise patients on my NHS TB contact clinic with suspected latent TB that a blood test exists which I don’t have access to, which they may want to pay for privately’


Some participants felt if IGRA was introduced, cuts would have to be made elsewhere and, as a result, some have responded by dropping their TST. This could potentially be problematic, because it means they are going to completely replace one test with another test, which is as yet uncertain. A few participants felt NICE should remove the IGRA opt out from the guidelines, as this would give PCT and local authorities the supporting incentives to fund it:

‘I personally think if NICE removed the TST from the guidelines then it would allow me to use it more because then the PCT would have to pay for it as NICE deems it the better test. So at present there are little incentive because NICE gives them an-opt-out.’


‘Without funding if this means, for example, you can have IGRAs but that means that you can’t therefore have nucleic acid amplification tests, ( PCR molecular probes looking for Rifampicin resistance) then I will say, well, I probably would rather have the Rifampicin resistance test because I feel that they are more useful in certain contexts’


Methodology: If the methodology was easier and simpler with regard to restrictions, type of sample, courier services, timing, etc, participants felt it would encourage them to use the test more. They would like T-SPOT methodology to be re-formulated and made easily accessible with the test being available on their local hospital computer investigation ordering system just like other tests. A reduction in the need for laboratory equipment was also recommended by the participants:

‘It would be nice to have the ELISPOT re-formulated so it is easier to use because we are still not using it with HIV positive and the problem is the way a plate is done it means that it’s technically difficult’


A few participants would also like to see if the IGRA technique could be used in samples other than blood such as bronch-alveo-lavage and pleural fluids, facilitating testing of samples cells from meningitis and pleural effusion patients:

‘I look forward to its use being a single approach for clinical assessment in diagnosis of active TB.’


‘From our point of view we use a lot of IGRA in peripheral blood but we would be interested in looking at it in broncho-alveo-lavage and other pleural fluids.’


Unit cost: Another limiting factor discouraging routine use and an issue recognised by participants is the relatively high cost price which is twelve times the cost of the TST. Participants would like to be able to offer both brands of IGRA, depending on the most appropriate brand suitable for the population being screened, again if the price was reduced and became reasonable:

‘If it got down to being as cheap as tuberculin it would make a tremendous amount of difference. It’s about 12 times the cost at the moment.’


Those using the test fairly routinely were reviewing whether the requests were increasing, which would mean the current approach would have to change. They felt money saved from patients not needing to return for TST readings could be put back into the services to cover the cost of IGRA.


Any cost analysis should include practicalities such as couriering the samples to far away laboratories, the cost of laboratory equipment and staff and the extra work load for phlebotomy departments and/or TB nurses. The cost and accessibility could make clinicians choose one particular brand over the other:

‘Would use this assay far more but it’s interestingly cost that is an issue.’


Predictive value: Participants would like to see whether IGRA shows predictive value for progression to active disease, once an individual is infected with MTB, and also indications that it differs from the TST in that once a patient has had a positive TST, they are always going to have a positive TST. They felt IGRA would be used more if there was confirmation that it revert back to normal once the patient had received treatment as currently the information available is unclear:

‘and the other thing I am not sure of, and I am not sure that researchers are sure of, is does it revert to normal when people have been treated for TB and how useful is it in using it in those patients. I think there is some information out there about that but I don’t think anybody is really sure.’


DISCUSSION

The interviewees come from a diverse sample of TB clinicians ranging from Lead Consultants, Consultant Physician, Paediatrician and Immunologist across different areas in London. In maintaining confidentiality and anonymity, the demographic details were not recorded, as they would be easily identified. To ensure that a good balance of views was collected, TB clinicians who had not used IGRA as yet were included in the study.


Joint Collaborative Involvement: This study suggests it is important to have joint collaborative involvement of specialists such as TB physicians, paediatricians, immunologists, TB nurses, rheumatologists, dermatologists, phlebotomists, HPU, members of the sector, PCT representatives and/or sectors when deciding to choose and/or implement the use of IGRA. Such joint involvement is relevant when developing and setting IGRA policies and protocol, plus also in view of commissioning.


Main Groups for the use of IGRA. Various different studies have identified IGRAs’ use in the following groups listed below, supporting this study’s’ finding:




Unanswered Questions and Future Research.

The results within this study highlighted several areas where research would help to clarify IGRAs’ role in all the different settings identified above. The findings from further research clinicians have expressed an interest in seeing would increase their confidence in the test and in turn increase their usage.

One of the main areas needing further investigative work and research-based clarification is around the best approach for IGRAs’ use. This study highlighted three other different approaches other than NICE’s two-step-approach. The mentioning of these other approach other than NICE’s supports the relevance of having different protocol algorithms for each circumstance, including laboratory related issues. Clinicians used the two-step-process through the NICE guidelines not because it is the right and best option but because it was NICE’s recommendations. If clinicians were to gain funding from Trust, they would need to have implemented and adhered to NICE guidelines. This then questions if the recommended approach by NICE are based on the best scientific practice or whether based on the best economically practice.

The research findings were raised several times as contributing towards knowledge and increased usage:


Concerns. There are concerns rise regarding IGRAs being made readily available within hospitals for routine use. This means that healthcare professionals without the experience and expertise of caring for TB patients could use it in the wrong way. This has potential implications resulting in actions such as the test being over-used, used recklessly; open for abuse and misinterpretation of the result as a confirmed test to diagnose active TB.

Such concerns stems from the lack of understanding, and difference in current practice use of the TST as a diagnostic tool for active TB within some Trusts as expressed by participants. Even though a lot of education is being undertaken in trying to stop non-TB clinicians from using the TST as a diagnostic tool for active TB, this is yet to be achieved and so therefore worry that IGRA could be misused in the same way.

TB services in London follow 4 different models as identified by NICE 2006. The differing and decentralised nature of these TB services structure makes it all the more challenging in trying to coordinate a system, therefore making it difficult in monitoring the use of IGRA. IGRA being a blood test makes it easily accessible on hospital-computerised system as it could be ordered along with other blood tests.

Some TB clinicians feel they do not know enough about IGRA for them to be confident regarding the interpretations. Yet they would be asked by their non-TB colleagues to interpret the results, especially when they would not have initially used the test as a diagnostic tool for active TB. Caution needs to be applied to the result and interpretations of IGRAs as it could have different meaning depending on what the contributing factors are. These factors should be reviewed very closely before TB treatment is given, if not, such lack of understanding could potentially result in patients being inappropriately placed on TB treatment.

In order to reduce some of the potential negative implications as highlighted above. IGRA could be established in hospitals’ computerised ordering system but with strict policies, procedures and algorithms applied to it. This would promote increased routine usage but at the same time used by professionals with experience and better understanding of it.


Both Brands of IGRA. The use of both brands of IGRA could be encouraged by a reduction in the cost price as the current price makes it ten times more expensive than the TST and availability of funding without cuts being made elsewhere. It would allow for an IGRA or both brands of IGRA to be used depending on the clinical circumstance and patient group it fits instead of being chosen for ease and/or cost price. Given the views of the participants through the available research, they have accessed and in applying best practice there is room for both tests to be used together by someone with increased knowledge about the test. Such increased usage would allow TB clinicians experience and confidence in the test, just as over the years they have built their confidence and experience in the TST.


The TST and IGRAs. There was consistent comparison of IGRA with the TST, probably because the TST has established a long track record and clinicians felt that IGRA is intended to replace it. Overall, the majority of participants agreed IGRA should not replace the TST but should be used alongside it, just as NICE guidelines 2006 had recommended. Although, using IGRA the way NICE had recommended might change once clinicians have as much experience and confidence in it as they have with the TST.

With increased usage, research comparison and experience clinicians would be able to clarify the difference between the TST and IGRA a bit more. Even though some participants clearly felt that IGRA offers an immediate win in those patients with TST results between 6 – 14mm who currently nothing is done with.

The identified advantages of IGRA over the TST within this study are the same as identified in various studies such as Ewer et al 2003, Kang et al 2005, Zellweger et al 2005, Mazurek & Villariona 2003, Arend et al 2000, Munk et al 2001, Wu-Hsieh et al 2001.


QFT-G. QFT-G was regarded as the:

It was deemed appropriate for diagnosing:

Participants could see from a logistic point of view how QFT-G could work well within the above identified settings.


T-SPOT. T-SPOT was said to be:

It seemed to be used as a confirmatory test check when QFT-G gives indeterminate results. It was identified as being appropriate for diagnosing TB in :

Participants’ opinion was that T-SPOT offered:


Early Discharge. The use of IGRA was identified within this study as promoting speedy discharge from the clinic during contact and occupational health screening by allowing for only one day visits to the clinic, with results being given over the phone. It was said to also reduce the number of patients that already do not return for their TST results to be read and measured, in turn resulting in wasted resources.

It was said to allow for the nurses’ time to be spent on active case management than spending it in clinic doing contact tracing screening for patients who do not show up for the readings. It would be interesting through research to see whether the use of IGRA has any relations to early discharge from the hospital’s clinic.


Opinion regarding NICE TB guidelines. Interestingly there were mixed feelings around the NICE guidelines introduction of IGRA. The negative opinion about the introduction were around the fact that NICE may have rushed the inclusion of IGRA especially when the evidence at the time appear to still be weak, and there appeared to be lack of awareness or input regarding the cost of the test. The inclusion of IGRA in the guidelines appears to have being cautiously added by stipulating that the test can be used where available. Such stipulations in the guidelines give PCTs and local authorities no supporting incentives but the option to opt out of providing IGRAs within TB clinics.

It also fails to address that the test does not distinguish between active or latent TB. Having said that the test was already licensed and used in other countries and really was an important development in TB for many years. Therefore, by NICE introducing the test into practice through the guidelines it allowed clinicians to assess the reliability and appropriateness of the test.

It also gave clinicians the push to approach their local authorities and PCT in trying to use it within different patient group and clinical circumstances. NICE guidelines has now prompted the increased amount of research being carried out about the test with more research to come.



False-positive and false-negative reactions to TST can make identification and decisions about preventive therapy problematic, and resources are wasted on treating individuals incorrectly identified with LTBI (Lalvani 2003, Lalvani et al 2001, Mori et al 2004, Barnes 2001, Liebeschuetz et al 2004) . Despite these limitations, the TST is routinely used in screening (Broekmans et al 2002) even entering the diagnostic algorithm of patients with clinical signs suggestive of active TB (Ferrara et al 2005, Ferrara et al 2006). The decentralised nature of the TST makes collection of valid LTBI surveillance data very challenging, plus it is not a reportable medical condition in most areas.



Strengths and Limitations of the study

By recruiting TB clinicians with differing roles such as consultant physicians, immunologists and paediatricians, this reflected the broad range of specialists frequently using IGRA. This was not quantitatively tested however due to the lack of exact data about the users of IGRA across London before the study was conducted, and because some clinicians are maybe, using IGRA but they are not TB specialists.


One of the main advantages is that the interview type and qualitative method did not allow for further exploration of certain issues coming up. For example a particular participant mentioned about a third IGRA based on flow cytometry which is under research and not commercially available and also no further probing was done into how IGRA contributes towards the reduction in patients’ hospital stay. Apart from the interviewer being present there is nothing else that hindered the study from portraying the truth. The clinicians were very confident and had their own opinion about the subject, so it was not difficult for them to talk openly.


This was a small, qualitative study carried out within the London area, which confirmed some findings from previous literature. It presented a number of additional conclusions, but was too small to decisively confirm them.























CONCLUSION

TB will probably not be eradicated completely until we effectively identify and treat those with LTBI. How much priority this is given in a country’s national programme depends on how much active transmission of disease occurs.


It is exciting for TB as their have been no new developments for many years. It would be of great interest to see IGRAs’ reviewed in ten years time. The need for education for TB specialists as well as non-TB colleagues as to what the test means was highlighted in this study as they are currently lacking the understanding. Clarification of the confusion about the test was identified as important with the need for increased usage to gain experience.


The use of qualitative methodology process netted rich data, and, by choosing the cohort carefully, this research has being relevant, and stimulating further research.


The aim of the study was achieved through the participants positively and negatively exploring and identifying the influences when choosing to use IGRA in a routine clinical setting. They were able to give their opinions on:


As clinicians become more skilled and comfortable with IGRA, they might perceive greater benefits, thus encouraging greater implementation in practice. A larger study including more TB specialists in and out of London could enhance future research studies and a review of this current study in eighteen months time to see how many changes have occurred would be interesting.


The research findings should be useful to practising TB clinicians who are thinking of implementing the use of IGRA as it should give them some insight into how their peers’ opinions and concerns.


Some of the comments and findings from future research studies could contribute towards a change in how IGRA is being used, becoming a test that rapidly confirms a diagnosis of active TB especially in different diagnostic situations and poor resource settings.


This study found more research opportunities are required to enhance clinicians’ understanding, which would then give them more confidence in this new test. There were varying opinions among the participants about its use in diagnosing active TB which they highlighted as needing clarity and various other ranges of issues were identified as relevant to using IGRA in practice. The most appropriate choice of IGRA to use may depend on the clinical setting.


IGRA would be used widely and play an important role in the diagnosis of TB once increased knowledge and experience and confidence has been achieved and its use has being strongly established like the TST


Further research is needed into the effect of IGRA post preventative therapy as in the case of paediatric patients when seen according to how the NICE guidelines recommended. Because such research would increase confidence in its usefulness in this group


The study highlighted IGRA is a good test which could be useful if used in the right people at highest risk of developing TB and not in populations with less TB, but it is important everyone is also aware it has limitations.





ACKNOWLEDGEMENTS

I gratefully acknowledge the emotional support and encouragement of David Nugent. This work was partly sponsored by The Worshipful Company of Curriers Millennium Bursary 2005.


The researcher independently completed the research with comments from Gail South, Karen Eden (TB Nurse), Dr Ronan Breen (Respiratory Consultant: Guys and St Thomas’ Hospital), Dr Jack Baker (Respiratory Consultant: Kings College Hospital).



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