From the coalface

Sponsored by the the National Institutes of Health and published in the latest CID Journal is an article by Susan Dorman (John Hopkins). This article takes a good look at New Diagnostic Tests for Tuberculosis.

What’s new in TB diagnostics? A lot, but not enough. The future is brighter as several promising new tools enter the demonstration and late evaluation stages. But the need is great, and important barriers remain in translating technical advances into meaningful and sustainable improvements in individual and public health in settings hardest hit by TB.

So the challenge, to accept change, is now set before public and private health providers and policy makers.

Ms Dorman identifies one of those barriers, that of ignorance

lack of knowledge about the types of tests that are most needed and likely to be relevant

Withholding or delaying knowledge is one barrier to which public health officials can make a positive contribution - the inherent slowness of bureaucracy should no longer be a valid reason for delay.

And what of QuantiFERON?

To date, in the United States, use of these tests as replacements for or adjuncts to the tuberculin skin test has not been widespread, but momentum appears to be growing.

This is something that we have been seeing more of lately, changes to existing testing policies incorporating or favouring QuantiFERON.

current strategy in dialysis patients should use these tests (IGRA) instead of TST for LTBI screening and as an aid for the diagnosis of active TB.

More on the 'skin test is cheaper' meme

From Italy; note that this recently published study deals with those who are at a very high risk of latent TB

Screening for M. tuberculosis infection in immigrants at very high risk of latent infection, high rate even if underreported BCG vaccination and poor health care system access (especially in undocumented or illegal immigrants) could take advantage of the ‘‘ex vivo’’ one shot blood assay reducing the rate of drop-outs, the false positive results and the overload of the health care system for the second level assessment thus exceeding the bias of the higher cost for a single test.

Destroying the skin test cost myth

During an online discussion based on the latest Cellestis newsletter 'Puzzled' says

The final piece of the puzzle is affordability, that is we need to know whether these oil-rich countries can afford QFT-TB testing for these workers?

The comment was in reference to the growing demand for QFT in the Middle East.

What people need to understand is that it is the TST that is the more costly eg in the very latest study from France

Our objective was to evaluate the cost-effectiveness of replacing TST with QFT or TST+QFT (i.e., QFT performed only when TST-positive) in the diagnosis of LTBI in close contacts of tuberculosis (TB) in France, where patients are BCG-vaccinated

..In conclusion, our analysis provides evidence that using QFT to diagnose LTBI is less costly and more efficient than using the TST. QFT was more expensive but also more efficient and more cost-effective than TST+QFT.

A picture is worth a thousand words

In his article A 100 year update on diagnosis of tuberculosis infection Ajit Lalvani says

The ELISA has been assessed in larger numbers of individuals in such studies than the ELISpot. In a recent systematic review the specificity of the ELISA ranged from 89 to 100% with a pooled specificity of 99% for the second-generation ELISA and 96% for the latest generation, in-tube ELISA. The pooled specificity of the ELISpot was also high: 93% (range 85–100%).

It is better explained thus

Link

Note that the two meta studies did not use the FDA approved criteria for T-Spot TB which fails counts of 5,6 or 7 spots.

Nebraska get it right

Link

Lets grab this bull by the horns

Over on Hotcopper,  an internet forum for chatterboxes, poster 'Alexanders' makes the following observations 

I have seen a couple of your posts where you talk about the impact of 3G in Japan coming through this half.
I do not think this will have a big impact. There was a lot of negative feeling about 3G in Japan when the first batch of tubes had endotoxin contamination and were recalled. Now the Research Institute of TB in Japan thinks the gel in the tube gets soft in hot weather, breaks off, stimulates the blood cells and gives false positive results. They are openly saying this in Japan.
All of this will delay new customers moving to QFT.
Existing 2G customers will have to move to 3G when 2G is stopped in a couple of months but this will just be substitution so will not affect total revenue.

Normally comments on HC are treated with a very large pinch of salt however as 'Alexanders' somewhat infrequent posts appear to be considered and knowledgeable they did attract some attention.

The reality is that Cellestis advised of a product recall due to endotoxin contamination in August 2009 and further advised of problems with excessive shaking in November 2009. Furthermore, in their 2010 half yearly presentation Cellestis advised of the lag in uptake in Japan for that period and that this lag was in the process of being resolved (those who attended the broker presentation were also in). This was also confirmed by their agent who said that these two issues had caused them to suspend deliveries of Quantiferon, a suspension that was lifted in January 2010.

So I think that on the evidence available it is reasonable to conclude that the anonymous 'Alexanders' is simply dressing up old news as new with a bit of hyperbole thrown in to spice things up.

.

When no no no means yes*

A story about a prison visitor whose TB skin test suddenly turned positive

He had broken one of the rules. Volunteers must present a clean bill of health, and Joe's annual prison tuberculin skin test had turned out positive. That meant he was out.

Joe took his plight to a specialist who

redid the skin test -- which he described as notoriously unreliable. Then for another kind of test, he took a blood sample. 

After the third visit

the results of the blood test were in -- negative!

The author of the story continues

it all ended well. But it got me thinking that it's not too often that one of our MedPage Today stories personally hits home.

The story TB Blood Tests Outperform Skin Test was one of them.

It's a report of two new blood tests for tuberculosis -- one was the test Joe received from the pulmonologist, the QuantiFERON-TB Gold (QFT-IT) -- that are less likely to lie to you. When they say you're positive for TB, you're actually more likely to really have it.

Always worth reading the comments

Because I live and work in a border town (and Mexico has TB) our hospital has already switched to the blood test - on the hospital's dime.

-- Posted by linda m hamilton

As an employee of a medical center, I am required to undergo annual TB testing and I would be far happier with a blood test than the injection of foreign substances into my body on principle. Unfortunately, if we want the blood testing instead of the skin test, we have to pay for it out of pocket and travel to a distant location. Hopefully the blood tests will become standard of care in very short order!

-- Posted by Cyndi Rosenblatt

-------

*For those not familiar with the TV show Vicar of Dibley, the above character was reknown for his stutter "no no no no no..." before almost everything he says, which was usually "yes"

Spin cycle

Oxford Immunotec must be in need of good PR, here they milk this study for what it's worth

278 individuals categorized as being low risk for TB infection were tested, only 3 were positive for TB according to the T-SPOT.TB test.

But that is not what the November 2009 abstract says

Of 326 subjects, 8 (2.5%) had a positive T-SPOT.TB result, six of which occurred in the absence of a positive TST.

It is possible that of the 326 only 278 were judged as being low risk for TB infection; it will be interesting to read the full study, when it comes through.

Now that I have learned how to spell syto...

It appears that Cytomegalovirus is more than just a problem for transplants; it may well be the major contributor to the decline of the immune system with age

...the effect of CMV infection on the risk of frailty, a common geriatric syndrome, and mortality in older women.

...CMV antibody concentration in the highest quartile independently increased the risk of 5-year mortality

CMV is also a danger for those at the other end of life, the newborns

hearing loss was detected in 4 (80%) of the 5 congenitally infected children who were infected after a primary maternal infection in the first trimester of pregnancy and in 1 (8%) of the 12 children when the maternal infection occurred in the second trimester of pregnancy

Global marketing

Skorpian links to the following article; it deals with TB, IGRA and dialysis patients and gets straight to the point

current strategy in dialysis patients should use these tests instead of TST for LTBI screening and as an aid for the diagnosis of active TB.

The article was printed by the American Society of Nephrology which, according to sources, is

the world’s largest professional society devoted to the study of kidney disease. Composed of 11,000 physicians and scientists, ASN promotes expert patient care, advances medical research, and educates the renal community. ASN also informs policymakers about issues of importance to kidney doctors and their patients.

It is worth reflecting on what Lodge Partners said back in February 2010

The company has also developed an impressive network of global key opinion leaders, who have not only been able to assist in the design and evaluation of the test but will also be critical in building demand for the product

What exactly is Cytomegalovirus?

From Medical news

Cytomegalovirus (from the Greek ''cyto-'', "cell", and ''-megalo-'', "large") is a herpes viral genus of the Herpesviruses group: in humans it is commonly known as HCMV or Human Herpesvirus 5 (HHV-5).

Elsewhere HCMV is

A virus that infects 50-85% of adults in the US by age 40 and is also the virus most frequently transmitted to a child before birth. 

Primary (or the initial) CMV infection in the immunocompromised patient can cause serious disease. However, the more common problem is the reactivation of the dormant virus. Infection with CMV is a major cause of disease and death in immunocompromised patients, including organ transplant recipients, patients undergoing hemodialysis, patients with cancer, patients receiving immunosuppressive drugs, and HIV-infected patients. 

That is probably as much as I want to know, before I get overloaded.

The consensus statement  by the International Transplantation Society recommends numerous testing of both donor and recipient prior to operation and the use of prophylaxis over preemptive therapy for highest risk recipients. Generally treatment can be between 3 and 6 months and it is recommended that recipients be tested once a week during the treatment, to monitor treatment progress and check for drug resistance. From the consensus statement

Unlike the ELISPOT assay, ICS (and QuantiFERON) can provide both quantitative and qualitative characteristics of CMV-specific T cells.

And unlike the QuantiFERON assay, which is simple to use, the ICS (intracellular cytokine staining) requires access to a flow cytometer

Why I hate forrest gump

well not really, but he did beat me to the post for the latest win for Cellestis

"For transplant recipients whose immune systems are already compromised by anti-rejection medications, the emergence of immune monitoring of CMV-specific T-cell responses in transplant medicine is an exciting development," said Assoc Prof Atul Humar, Director of Transplant Infectious Diseases, Department of Medicine, University of Alberta, Canada. "Immune monitoring may potentially allow physicians not only to gauge a patient's risk of developing post-transplant CMV disease, but also to assist in determining the most appropriate management pathway on an individual, patient-by-patient basis."

It's all to do with Quantiferon and cytomegalovirus, which is important to those that have transplants.

Uptight at Upstate

Upstate Medical University lists the following requirements for students;

Q: Will QuantiFERON-TB Gold (interferon-gamma release assay) testing be accepted as an alternative to the tuberculin skin test.
A: No, not under usual circumstances. QFT is not used for routine TB surveillance at Upstate. A TST must be placed to establish a baseline for future testing.

New York DOH rules specify only TST

ppd (Mantoux) skin test for tuberculosis prior to employment or affiliation and no less than every year thereafter for negative findings.

Considering that these rules were formed in 1996, prior to the approval of QuantiFERON, the exclusion is reasonable. However since the approval of QuantiFERON the DOH generated the following letter

The purpose of this letter is to clarify changes in requirements for employee tuberculosis (TB) screening in hospitals and diagnostic and treatment centers in New York State. The New York State Department of Health (NYSDOH) requires a medical evaluation of all health care workers prior to employment in these facilities, which must include tuberculosis screening. TB screening may be done with any approved test to detect M. tuberculosis infection, such as the tuberculin skin test (TST), or one of the whole blood interferon-gamma release assays (IGRAs) approved by the Food and Drug Administration (FDA).

At this time, approved IGRAs include QuantiFERON-TB Gold, 2005; QuantiFERON-TB Gold In-Tube, 2007; and TSpot.TB, 2008. NYSDOH regulations, including 405.3(b)(10)(iv) for hospitals and 751.6(d)(4) for Diagnostic and Treatment Centers, will be amended to allow the use of these tests as an acceptable alternative to the tuberculin skin test, when used in accordance with the product insert. However, health care employers may incorporate these tests into employee screening protocols effective immediately

It appears that it is now under review

WHO treatment guidelines - revised

It's nice to see any revised guidelines, this lot being from WHO and dealing primarily with treating active TB. At a quick glance the big change seems to be in the recommended drug regime,

to discontinue the regimen based on just 2 months of rifampicin (2HRZE/6HE) and change to the regimen based on a full 6 months of rifampicin (2HRZE/4HR) will reduce the number of relapses and failures.

In longhand that is two months of INH, Rifampin, Pyrazinmid and Ethambutol followed by four months of INH and Rifampin

It appears that Ethambutol carries a risk of blindness.

There are also various drug combinations dependent on levels of resistance and patient health - invariably TB patients are sick.

Treating active TB can be a complex business and it would be easier to treat the initial infection before it progresses to a disease state.

Contact investigation of HCWs

Here is the study that preceded the book, all good stories have nice endings;

The QFT-GIT proved to be a feasible method in this large scale, in-hospital contact investigation

...IGRAs have the potential to profoundly change our clinical practice

...The high frequency of discordant results observed in our study argues against a two-step screening procedure in a low-incidence country with a substantial proportion of BCG vaccinated subjects

...the substantially lower frequency of positive QFT-GIT results may provide the opportunity to target preventive therapy and thus contribute to enhanced TB control in health care.

.

First the book, then maybe a movie..?

Dr Felix RingHausen, senior physician of internal medicine and a lecturer at the University of Zurich, has written a book with the arresting title

Tuberkulose-Kontaktuntersuchung im Gesundheitswesen

Stellenwert des Interferon-¿ Release Assays QuantiFERON®-TB Gold In-Tube nach Exposition gegenüber einem mikroskopisch negativen Indexfall

Tuberculosis contact investigation in health care
Importance of the interferon-release assays, 

QuantiFERON ®-TB Gold In-Tube after exposure 

to a microscopically negative index case

Inside flap, roughly translated...

Chest article draws fire

Writing in the latest issue of Thoracic (Quantiferon-TB Gold test versus tuberculin skin test) Viroj Wiwanitkit says

it is interesting to compare cost effective of the new approach to classical tuberculin skin test. Recently, Ito et al. reported that 'estimated costs of annual QFT tests among general female nurses in Japan to prevent tuberculosis disease is very high, and annual QFT tests could not be recommended'

Firstly, the Ito et al study was an estimate made on models and does not offer any alternatives or comparisons - the comment that costs were 'very high' is subjective.

Secondly, the presentation by Akiko Kowada compared QFT with TST and X-ray separately and in various combinations and with HCWs Kowada found that

The QFT alone strategy is the most cost effective in BCG vaccinated healthcare workers in Japan.

.

The Socratic method

The Greek army appear to have just made a discovery

BCG received after infancy produces false-positive TST reactions

To most of us that is ancient history.

TST, the great pretender

From Korea,

With the introduction of IGRA for diagnosing LTBI in middle- and high-school students, approximately 47% of students who show a TST induration with a 10 mm diameter and over can avoid taking unnecessary preventive chemotherapy.

Fairly standard stuff nowadays, perhaps the CDC should update their guidelines on TST

There's a Girl in My Soup

Another rheumatoid arthritis patient (WarmSocks) plays with her alphabet soup;

The DTBE of the CDC established the TBESC for purposes of TB research.  How accurate is PPD in people who’ve had prior BCG?  Is IGRA more accurate than TST?  What is the difference between T-SPOT.TB and QFT-G?

Anyway, WarmSocks' doctor said that you should make sure that you don’t have TB before prescribing medication and so off she goes

Even though my doctor said I needed a TB test, and wrote TB on the lab slip (in addition to all the regular tests ordered), a skin test wasn’t done.

... I discovered that there is a blood test for tuberculosis.  I’d only known of the skin test. 

These changes in latitudes, changes in attitudes; Nothing remains quite the same*

More info from the Southeastern National Tuberculosis Center Webinar, this time from Dr. Thomas Dobbs and deals with the integration of QuantiFERON TB Gold In Tube (QFT-GIT) into the public health of Mississippi.

Without the explanatory text it is a little difficult to get a handle on what they were doing. At first they appear to be using QFT-GIT for those that have prior BCG, poor rate of return, TB suspects and HIV positive. This is in keeping with provisional CDC guidelines, which is to be expected as the SNTC is funded by the CDC.

However, they then use QFT-GIT to confirm a TST+ which is contrary to the same provisional CDC guidelines;

It's possible that the confirmation of TST+ was limited to 56 individuals

Costs do not seem to be an ongoing issue - the savings from not treating TST false positives appear to balance out the increased cost of QFT-GIT supplies

They seemed to have worked out the logisitics OK, the extended storage time of QFT-GIT allowed them to centralise processing

Confidence in QFT-GIT was worth noting

Confidence is critical - when you face 9 months of medication which has the potential to ruin your liver you want to very sure that you are doing the right thing. This confidence applies to both patients and doctors with health care workers often being both.

* it just seemed appropriate to borrow a few lines from that Mississippian, Jimmy Buffett

Following the rifampicin trail..

Following on from studies into short course therapy with rifampicin, with the added benefit of being able to track the success of the treatment using QuantiFERON-TB Gold In-Tube, we have this study into previously treated TB patients

Specific T (EM or effector memory) cells persist even in subjects treated for TB decades ago with modern anti-tuberculosis chemotherapy

Clearly to eradicate TB there is a need to monitor TB therapy which makes the following trials more compelling

In this trial, 3 months rifampin had somewhat better efficacy than either 3 months of isoniazid and rifampin (3HR) or 6 months isoniazid.

Two large scale trials are ongoing; one is comparing efficacy and effectiveness of 9H with 4 months rifampin (both daily and self-administered), while the second, which is nearing completion, compares daily self-administered 9H with 3 months directly observed once weekly INH combined with rifapentine.

The results of these two trials will likely shape future recommendations substantially.

Should the trials prove that a short course of rifampin (or rifampicin) is preferred there are the following benefits;

• reduced risk of hepatoxicity to the patient
• shortened treatment period which is more acceptable to the patient
• ability to determine if the infection has been fully eradicated.
• an opportunity to eradicate TB entirely

All this and more, made possible by QuantiFERON.

Too easy

New Jersey Medical School (UMDNJ) have this reference card for latent TB diagnosis and treatment

Using IGRA alone makes the decision to treat easier.

Two step TB testing just another silly chicken dance.

Another aspect of the about-to-be-announced CDC guidelines was this

IGRAs may be used in place of (and not in addition to) TST in all situations

The CDC are quite clearly against using an IGRA to confirm a TST. There could be any number of reasons for this but the one that I most like was put forward by CDC Field Medical Officer Dr Christine Ho

Training, quality assurance and maintaining proficiency of laboratory personnel performing IGRAs are feasible, achievable and preferable over maintaining TST proficiency of thousands of clinic personnel.

It is illogical to run two systems side-by-side when IGRA alone would do a better job. If the CDC prefer that IGRA be used on BCG vaccinated and or those that find it difficult to return then it would be commonsense to just use the one system, the one that the CDC prefer

Rates of return - an overarching clause

The provisional CDC guidelines say

Populations/situations in which IGRAs are preferred
– testing persons from groups that historically have poor rates of return for TST reading

Which populations might that be? Bothamley et al, from the East London Tuberculosis Service, looked at their data of screening new entrants in a hospital based new entrants' clinic, general practice and centres for the homeless and found that

Attendance for screening was 17% of the port of arrival notifications (63% had registered with a GP), 54% in primary care, and 67% in the homeless (42% registered with a GP)

On the other side of the pond Dewan et al, from both the the CDC and California, found that the return rate to be 79% and noted

the reported return rate for TST reading in similar patient populations in other cities, including 84% at a needle-exchange program in Baltimore, 64% at a public health program in Atlanta, and 47% in a street outreach program for drug users in Long Beach

So it seems that for migrants, general practice, homeless, public health and drug users the rates of return are historically poor and the CDC would prefer IGRA to all these groups.

LoBue, Menzies and Rifampin

From the latest issue of Respirology;

-----

Isoniazid (INH) has been the mainstay of treatment of latent tuberculosis infection for almost 50 years. The currently recommended preferred regimen is 9 months daily self-administered INH (9H); this has efficacy of more than 90% if completed properly. Unfortunately, INH is associated with serious adverse events, including hepatotoxicity.

Although risk factors for this complication are well established, allowing for better selection of candidates for therapy, this complication still occurs, and is occasionally fatal. Hence close follow up of patients is necessary, increasing the cost and complexity of treatment.

This problem, plus the lengthy duration, results in poor acceptance by patients and providers, and poor adherence by patients.

As a result, many preventable cases of tuberculosis continue to occur, and the public health impact of latent tuberculosis infection treatment is suboptimal. These problems have spurred interest in finding shorter, safer and cheaper alternative regimens, with similar efficacy.

Of the many regimens that have been examined, 2 months of rifampin and pyrazinamide has excellent efficacy—in experimental studies in mice and randomized trials, largely in HIV-infected persons. However, while the safety of 2 months of rifampin and pyrazinamide appears acceptable in HIV-infected persons and children, in non-HIV-infected adults this regimen is associated with an unacceptably high rate of severe liver toxicity.

Three to four months of INH and rifampin has had equivalent effectiveness as 6 months INH in several randomized trials. However, completion of therapy and toxicity has been the same as with INH—possibly because two drugs are taken rather than one.

The fourth commonly studied regimen is 4 months rifampin. This has been found to have significantly better completion than 9H, with significantly less toxicity, especially hepatotoxicity. However, only one trial has evaluated efficacy and effectiveness of mono-rifampin therapy.

In this trial, 3 months rifampin had somewhat better efficacy than either 3 months of isoniazid and rifampin (3HR) or 6 months isoniazid.

Two large scale trials are ongoing; one is comparing efficacy and effectiveness of 9H with 4 months rifampin (both daily and self-administered), while the second, which is nearing completion, compares daily self-administered 9H with 3 months directly observed once weekly INH combined with rifapentine.

The results of these two trials will likely shape future recommendations substantially.

-----

Philip LOBUE 1 AND Dick MENZIES 2
1 Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia, USA, and 2 Montreal Chest Institute, McGill University, Montreal, Canada

Updated CDC Guidelines..

..well sort of - you can read Dr. Philip LoBue's presentation slides here.  I think that we can safely assume that Dr. Philip LoBue's comments are those of the CDC - if you look at the CDC orgchart he is well placed

One of the nice subtleties of the LoBue presentation is on slide 25

Populations/situations in which IGRAs are preferred
– testing persons from groups that historically have poor rates of return for TST reading
– testing persons who have received BCG (as a vaccine or for cancer therapy)

This indicates a departure from previous CDC advice which stated that

the TB skin test is not contraindicated for persons who have been vaccinated with BCG. 

It would now seem that for BCG vaccinated persons the CDC would prefer that you used an IGRA.

Also on slide 27 Dr LoBue put the skids under the two step process

Routine testing with both TST and an IGRA is not recommended

It doesnt leave testers with too many options?

Collapse of the denialist camp

The Canadian TB control program has been used as a model by other bodies, such as those within Australia. Regarding the use of IGRA the then South Australian Minister for Health, John Hill, did advise me that

Expert opinion in South Australia is that the NTAC recommendations are in keeping with Canadian guidelines, which are probably the most balanced given the current level of knowledge.

The NTAC that Minister Hill referred to is the National Tuberculosis Advisory Committee. The Australian Medical Association also report similar views

We are advised that the Australian Tuberculosis Advisory Council does not recommend these tests at this stage due to issues of validation. Their position is similar to that of the Canadian TB Advisory Committee

The National guidance has permeated its way through the various health bodies; here is the view held in Queensland

Tuberculin skin test readings are interpreted after considering the clinical and epidemiological setting rather than defining a specific positive or negative cut-off. Skin testing by trained staff is done in conjunction with patient education, counselling, and screening for symptoms of tuberculosis.

..With trained staff, tuberculin skin testing lends itself to community screening and in populations at high risk for tuberculosis and it may be more sensitive for detecting remote (rather than recent) tuberculosis infections.

It is worth reviewing the effectiveness of these much quoted guidelines - and according to a recent report TB control in Canada has failed in a spectacular fashion

Manitoba's former tuberculosis control director will testify in front of a federal health committee to push for action to eliminate a disease critics call a national embarrassment.

Longtime TB control director Dr. Earl Hershfield will appear alongside other TB experts and First Nations representatives at a health committee hearing in Ottawa on April 20. Recommendations stemming from the testimony will be debated in Parliament, raising hopes the Harper government will address the poverty, poor housing and lack of access to medical care that help TB spread.

Hershfield spent 37 years at the helm of Manitoba's TB control program and recently blasted provincial health officials for losing track of sick TB patients, saying the system is "falling apart."

Let the facts speak for themselves

Some northern First Nations communities have recorded more than 600 cases of TB per 100,000 people...the rate in Bangladesh is slightly below 400 cases per 100,000.

Whatever Health Canada are doing they are doing it wrong

Health Canada Advisory Statement Recommendations
IGRAs are not currently recommended :
1. For the diagnosis of active TB in adults (Sensitivity=rule out, specificity = rule in)
2. For serial testing such as in health care workers or prison staff and inmates.
3. In an immunocompromised person, TST is the preferred test.

The time for change is now

The Canadian Tuberculosis Committee (CTC) recommends that all provincial and territorial governments fund the use of IGRAs for use according to the current CTC recommendation

Australia should take their advice.

.

The TST, a prick of a test

In 2002 the CDC ran an article about a study published in the Pediatric Infectious Disease Journal called Interpretation of the Tuberculin Skin Test Reaction by Pediatric Providers. The study said

The tuberculin (TB) skin test is widely used, but it is not easy to read...Many providers, regardless of professional training and experience, read a 15-mm TB skin test reaction as >10 mm, but a significant minority interpreted it as negative.

Khan and Starke, Texas Children’s Hospital, claim that for the skin test

most of even 15-mm reactions in children at low risk are false-positive results

which prompted them to call for better diagnosis of TB in children.

Ironically the PediatricSuperSite.com are running the "Blood assays outperform skin test in TB diagnosis" story.

Whilst Dr John Bradley continues to favour the skin test he does recommend IGRAs for some situations eg;

for a child with a positive skin test with no known exposures (these are presumed to be false-positive tuberculin skin tests, he said).

The problem, for Dr Bradley and others, is providing sufficient evidence that skin test reactions can be interpreted correctly and accurately. He maintains that for IGRA

There are insufficient data at present to recommend switching from tuberculin skin testing to an IGRA blood test for all kids

Employing the same argument there is now insufficient data to recommend using the TST.

Dutch military confirm TST false positives with QFT-GIT

Another test of Quantiferon over time and it will be interesting to read the full study once it becomes available. Essentially QFT-GIT was performed at inclusion and repeated after 2, 6, 12 and 18 or 24 months.

This study confirmed a low rate of positive QFT-Git results among military personnel with a positive TST after deployment, supporting the hypothesis of NTM exposure.

TST produces false positive due to NTM, something in which the US military also have experience

These false positives tests have become more than a mere institutional inconvenience or a momentary medical scare for Soldiers being tested. They are a real financial and medical burden because they inappropriately diverting limited funds and resources.

NTM (Nontuberculous mycobacteria) are everywhere

NTM are widely distributed in the environment, particularly in wet soil, marshland, streams, rivers and estuaries. Different species of NTM prefer different types of environment.  Human disease is believed to be acquired from environmental exposures

...NTM is estimated by some experts in the field to be at least ten times more common than TB in the U.S

The evidence just keeps on piling up

Interferon-Gamma TB Tests Are Not Yet Ready for Widespread Use

So they say, the final verdict from Dr. John Bradley was

“We believe the IGRA is a more sensitive test,” Dr. Bradley said. However, “they cost a lot more, so we’re not ready to recommend them for widespread use.”

Apparently Dr Bradley is more concerned with costs and less concerned with the good of the patient.

The final countdown

From the Texas Department of Health Services

Webinar "Interferon Gamma Release Assays (IGRAs): Yesterday, Today, and Tomorrow"

On April 14 from 10:00 a.m. to 12 noon Central, the Southeastern National Tuberculosis Center will present the webinar "Interferon Gamma Release Assays (IGRAs): Yesterday, Today, and Tomorrow." This webinar will include a presentation by Dr. Philip LoBue providing background on the development of IGRAs and a review of relevant IGRA studies performed to date. Special emphasis will be placed on recommendations and utilization of IGRAs following the new CDC guidelines for IGRAs (expected to be released in the first quarter of 2010) and the future of IGRAs. This session will also include details on the practical public health applications of both available IGRA tests: QuantiFERON presented by Dr. Thomas Dobbs and T-SPOT presented by Dr. Michael Stacey.

Question: will the CDC guidelines be published in time for the CDC to discuss them?

.

The Diel meta analysis

A response to the Chest article from medpage today

Action Points 

• Explain to interested patients that this meta-analysis found that two newer blood tests for TB are each more sensitive than the old tuberculin skin test, especially when the tests were performed in the developed world. 

• Note that the new tests evaluate the amount of interferon-gamma that is released by infected T cells after in vitro stimulation by specific Mycobacterium tuberculosis antigens.

You can shout it out from the roof tops..

CHEST Analysis: Blood Tests Demonstrate Superior Accuracy in Diagnosing Tuberculosis

Newswise - New data from a meta-analysis of existing literature published today in CHEST, the official journal of the American College of Chest Physicians, demonstrate that Interferon Gamma Release Assays (IGRAs) are superior to the previous standard in diagnostics, the 100+-year-old tuberculin skin test (TST), for detecting confirmed active Tuberculosis (TB) disease. This was especially true when the IGRAs, both QuantiFERON®-TB Gold (QFT), which is manufactured by Cellestis Limited, as well as the T-SPOT®-TB (T-Spot), were administered in developed countries.

In the United States (U.S.), TB remains a public health threat, with as many as 14 million Americans infected with TB bacteria. At any given time, members from this large pool of infected people can develop full-blown, highly contagious TB. This new meta-analysis provides further evidence supporting a new, scientifically-proven standard for detecting tuberculosis infection.

"Tuberculosis remains a global public health threat and as such, should be regarded with a corresponding level of urgency," said lead study author Roland Diel, MD, MPH, Assistant Professor, Department of Pulmonary Medicine, Medical School (MHH) Hannover. "The study results support IGRAs as modern advances in diagnosing a very old disease that is just as significant today as it was in the 1700s."

The authors critically reviewed and analyzed 124 studies investigating the commercial QFT and T-Spot blood tests and TST for sensitivity (the percentage of infected persons who return a positive test result) in confirmed active TB cases and specificity (the percentage of uninfected persons who return a negative test result) in individuals with no risk factors for infection. Researchers found that the newer blood tests provide significant improvements in sensitivity over TST. The authors reviewed studies from developed countries and found the TST had only 71.5 percent sensitivity compared with QFT at 84.5 percent and the T-Spot at 88.5 percent.

In a country with a relatively low rate of TB disease, such as the U.S., specificity is more important because poor specificity leads to greater numbers of false positives. QFT is highly specific at 99.2 percent versus 86.3 percent for T-Spot. By comparison, TST specificity may be as low as 59 percent in persons who are BCG-vaccinated and only 97 percent in non-vaccinated populations. To highlight the importance of specificity in low prevalence settings, in testing 1,000 persons without TB, the TST would return between 30 and 410 false-positives, T-Spot would return 157 false-positive test results; QFT only eight.

"In addition to aiding the prevention of future outbreaks, improved tuberculosis diagnostics reduce the costs associated with TB control," said Tony Radford, Chief Executive Officer, Cellestis Limited. "With QFT virtually eliminating false-positive readings that are common with TST, TB control and treatment can now be more accurately targeted to those persons who truly are infected, minimizing unnecessary further testing and treatment."

Additional Meta-Analysis Results
This new analysis was conducted to establish performance benchmarks, and to this end, only took into account work based on accepted "gold standards" of diagnostic confirmation of active TB disease. The analysis highlights an added benefit that IGRAs offer over TST -- built-in control for measuring immune status of persons tested. This reduces the risk of false-negative results in those with compromised immune systems. IGRAs flag such individuals with a result of "Indeterminate". The pooled rate for all populations of indeterminate results was low, 2.1 percent for the QFT and 3.8 percent for T-Spot.

About Tuberculosis
Tuberculosis (TB) is a contagious disease caused by a bacterium called Mycobacterium tuberculosis. TB bacteria usually attack the lungs, but can affect any part of the body such as the kidney, spine, and brain. If not treated properly, TB can be fatal. TB bacteria is spread through the air when a person with TB disease of the lungs or throat coughs, sneezes, speaks, or sings, which may lead people in close proximity to become infected.

According to the World Health Organization, about one person dies of TB every 17 seconds, causing nearly 2 million deaths annually. TB continues to be a contagious scourge in developing countries, and with the world shrinking rapidly due to global migration, it is a major public health threat in developed nations as well, including the United States. Each infected person represents a potential yet preventable future outbreak. Convenient and trustworthy testing for TB infection is necessary in order to quickly identify the appropriate persons for treatment and thereby prevent its spread.

About QuantiFERON®-TB Gold (QFT)
QuantiFERON®-TB Gold (QFT) is a simple blood test that accurately identifies people infected with Mycobacterium tuberculosis, the causative agent of Tuberculosis (TB). As a modern alternative to the 110 year old Tuberculin Skin Test (TST), also known as the Mantoux, QFT offers unmatched specificity, high sensitivity and simplicity. QFT enables focused TB therapy by providing clinicians with an accurate, reliable and convenient TB diagnostic tool. QFT is unaffected by previous BCG vaccination and most other environmental mycobacteria. Unlike the TST, it requires only one patient visit, is a controlled laboratory test and provides an objective, reproducible result that is unaffected by subjective interpretation. Results can be available within 24 hours.

QFT® is available for use in all clinical settings in which TST is commonly used. Examples include contact tracing, regular employee testing, for example for health care workers, as well as screening programs for prisoners and immigrants. QFT's application in the screening of immunosuppressed patients prior to anti-TNF-alpha therapy initiation and in patients with HIV, cancer or organ transplants offers distinct advantages over the TST.

QFT® is sold directly in the U.S. by Cellestis Inc; in Europe by Cellestis GmbH (Germany); and in Australia and Asia by Cellestis International Pty. Ltd. (Australia). QFT is also available through Cellestis Commercial Partners in Japan, Europe, the Middle East and other countries around the world.

About Cellestis Limited
Cellestis Limited, a listed Australian biotechnology company founded in 2000 in Melbourne, Australia, develops and manufactures the QuantiFERON-TB Gold In-Tube (QFT) test, a breakthrough blood test for the detection and control of tuberculosis. The QuantiFERON technology is a patented method for detecting cell mediated immune (CMI) responses of T-cell lymphocytes using whole blood samples. In comparison to existing methods of measuring CMI, this unique technology provides accuracy and sensitivity along with major savings in operator time, labor and reagents. Using its patented QuantiFERON technology, Cellestis develops diagnostics tests that measure immune function for diseases with an unmet medical need.

Cellestis is proud to be exploring opportunities to enhance the global effort to eliminate TB. Cellestis is an industry partner of FIND (the Foundation for Innovative New Diagnostics) and the Stop-TB Partnership.

For more information, please visit www.cellestis.com.

TB and diabetes - a deadly combination

From India an article on diabetes and TB

-------------------------------

High risk: Diabetes has a strong association with TB.

Tuberculosis (TB) is an ancient disease and the earliest archaeological evidence of spinal TB was found in Egyptian mummies dating back to 2000.BC. The great Indian Physician Susruta was the earliest to note and comment on the association between diabetes and TB.

Before the discovery of insulin, a diagnosis of diabetes was like a death sentence within five years; and the most common cause of death was tuberculosis.

With the advent of insulin in early part of 20th century and with the availability of complete cure for TB, the association between the two was forgotten or perhaps grossly neglected.

But today, due to the diabetes pandemic, there is a “re-emergence” of the forgotten link. India has the largest number of people with diabetes in the world.

Rapid increase

The prevalence of Type2 diabetes has increased rapidly over the years especially in urban areas due to social and cultural changes, dietary changes, reduced physical activity, ageing population and other unhealthy behavioural patterns. Tuberculosis, on the other hand, is an infectious or communicable disease, and has been declared as the single largest killer by the WHO.

Sujatha, 34 years, was employed in a private firm and was supporting her family of four. She had been ill for some time and had rapid weight loss, fever and severe cough. She was diagnosed with tuberculosis and began anti-tuberculosis treatment through the DOTS programme. However she continued to feel tired with frequent urination and increased thirst. She was also not gaining weight, which made the physicians suspect concomitant underlying illness.

Investigations confirmed the diagnosis of diabetes. Sujatha was put on insulin to control her blood sugar levels and all her symptoms disappeared and she was able to attend to her routine work. There are many such people in the community who even succumb to the disease even before they are diagnosed with the deadly duo.

Patients with TB, who also have diabetes, may be more seriously ill and run the risk of relapse and treatment failure and may even pose a higher risk of spreading TB in the community.

Uncontrolled blood sugar levels have an adverse impact on TB treatment and leads to poor prognosis.

A systematic review of international research publications found that diabetes has strong association with TB. Studies among diabetes patients show a higher risk of developing TB due to impaired immunity. Sometimes there may be a reversal of the association, i.e. patients with TB may have increased insulin resistance and thereby run the risk of impaired glucose tolerance and diabetes is increased, in addition to the effect of some anti-TB drugs increasing blood sugar levels.

Dangerous impact

Whatever the pathway, the diabetes-tuberculosis duo will have a dangerous impact on public health.

The risk from HIV is well known, while HIV contributes to 3.4 per cent of adult TB incidence, in comparison, diabetes accounts for about 20.2 per cent of infectious TB incidence and 14.8 per cent of adult pulmonary TB incidence.

Today, there is more convincing epidemiologic evidence about the duo, and yet it is being largely ignored. None of the established guidelines/policies considers the relationship between the two diseases. It is high time that the double burden of diabetes and TB in developing country is recognised and given the utmost attention that it deserves.

Diary of latent TB patient

Darcy keeps us up to date with the INH journey

I hope to chronicle my 9-month journey of Isoniazid (or INH) for Latent Tuberculosis Infection (LTBI). I'll share my paranoia, my diet, side-effects and the process. My focus will be to strengthen and protect my liver, as this is a major component of INH side-effects. Please keep in mind that this is my journey, and I am in no way qualified as a doctor or profess to have any authority in that area. I am simply a traveler who freaked out at the thought of having to take this, and wanted to share my process for others like me.

Darcy's story starts here and her logic is sound however I did wonder if her diagnosis was reliable

In late 2001, I was given a PPD test and lo and behold I reacted! I was told I had latent TB and given a pill bottle full of INH to take to isolate the tuberculin bacteria...I stowed the bottle in the bottom of a box of books in my shed and forgot about taking it

...Here I am with a beautiful five year old and a cough that started in late 2009. No, I don't have active TB, but had bronchitis and just finished a round of azithromyacin. What spurred me to follow up on my latent TB was the unknown factor: could I have active TB? I spent a week in panic thinking that I could possibly expose my family to TB. I spent a week wondering what would happen if I were to be contagious...what would happen to my family, co-workers, friends if I had to be quarantined? Thank goodness none of that happened...

...For me, the instant I made the decision to take this drug I had peace of mind.

Armed with the facts Darcy develops a strategy

INH could mess me up big time but I can do a few things to help lessen potential effects. At this point, I'm working with just two things: Diet and Supplementation. We'll see what crops up as I go along.

Darcy's account is compelling and well worth taking the time out to read.

Spot the difference..

..between this

"It’s very hard to have a population policy if you haven’t got a border protection policy."

and this

It is now critical to develop a population policy for Australia in order to decide immigration numbers rationally and in the best interest of Australians.

and this

Answer: there is no difference, they are all sounds made by humans to attract dogs.

The worst is behind us..

..says US President Obama

"Today is an encouraging day. We learned that the economy actually produced a substantial number of jobs instead of losing a substantial number of jobs. We are beginning to turn the corner," Obama told workers at a battery components plant in North Carolina, a key battleground state he won in the 2008 presidential election.

Whilst job growth was evenly distributed healthcare remains one of the strongest sectors

Private-sector job growth was biggest in health care and temporary help services. Since September 2009, temporary help services have added 313,000 jobs, including 40,000 last month. Health care, which grew steadily even during the depths of the recession, has added 588,000 jobs since the start of the downturn over two years ago, including 27,000 jobs in March.

The Bureau of Labor Statistics has the numbers;

• As one of the largest industries in 2008, healthcare provided 14.3 million jobs for wage and salary workers.
• Ten of the 20 fastest growing occupations are healthcare related.
• Healthcare will generate 3.2 million new wage and salary jobs between 2008 and 2018, more than any other industry, largely in response to rapid growth in the elderly population.
• Most workers have jobs that require less than 4 years of college education, but health diagnosing and treating practitioners are highly educated.

 .

Association of Public Health Laboratories - IGRA teleconference 2010

APHL are offering a range of continuing education and professional development programs and this one is all about IGRAs.

Note that the convenor is Matthew Binnicker from the Mayo Clinic, Rochester.