Quantiferon and active TB

Too often amongst the list of pro's and con's of QFT you read the line

It cannot easily distinguish between latent infection and active disease.

However, research has shown that variations in the response to antigens changes between latent and active TB

we have shown for the first time that multiple biomarkers measured in QFT test supernatants have high ability to discriminate between active TB and the absence of active disease

This could be good for researchers but the demands for further lengthy study and assessment and regulatory approval would make such a diagnostic difficult to make available for general use in the foreseeable future.

By employing available diagnostics researchers from Chung-Ang University School of Medicine, Seoul, Korea were successful in diagnosing active TB in false negative polymerase chain reaction (PCR) patients. They found that the combination of high-resolution computed tomography (CT scan) and QuantiFERON Gold was the most effective

the current findings support that the combination of HRCT and QFT-G allow for a rapid diagnosis of PTB in patients who are sputum smear negative or have no sputum production at all.

Note that the study did not use the TB skin test.

Fear the Boom and Bust

QuantiFERON Gold InTube in haemodialysis patients

Swiss Medical Weekly have just published the results of a study into the efficacy of QFT-GIT in haemodialysis patients.

The inside story

For some reason Oxford Immunotec feel compelled to publicly unburden themselves; here is their SWOT analysis (Strengths, Weaknesses, Opportunities, and Threats) for marketing their product in the UK

(click on image for FULL SIZE)

Saudi Arabia - latent TB guidelines

This statement provides the first set of national recommendations for targeted tuberculin testing and treatment regimens for persons with latent tuberculosis infection.

Full guide below the fold

TST gets a bad rap

The TST uses a relatively crude mix of antigens from MTB.
...many practitioners remain reluctant to use the TST, and therefore, do not give therapy for latent TB infection even to patients at high risk of reactivation.

whilst the IGRA recommendation appear to be cautious

1. IGRAs should not be used to diagnose active TB in adults. In children, they may be used as an adjunct test, in combination with TST, chest x-ray, and microbiological investigations. A negative IGRA alone should not be used to rule out active TB.
2. In BCG-vaccinated individuals (adults and children), IGRAs may be used to confirm a positive TST result (i.e., to check if the TST result is a false positive). If a positive TST result is confirmed by a positive IGRA result, LTBI treatment should be initiated after ruling out active TB.
3. In immunocompromised patients, if a false-negative TST result is suspected, IGRAs may be used to rule out LTBI.
   

bear in mind BCG vaccination is endemic in Saudi

BCG vaccination was started in 1964 in Saudi Arabia and a 95.9% coverage rate was achieved by 2007

and rates of TB infection are considered to be in the intermediate category

Al Kassimi et al in 1993 conducted the first comprehensive and nationwide tuberculin survey in the Saudi Arabian general population with urban/rural stratification. Using a definition of a positive tuberculin test of 10 mm or more, 33% of the subjects had a positive TST, and 56% were aged 45 years and older.

They also address the known problem of TST boosting by suggesting that both the TST and IGRA test be done concurrently which begs the question - why bother with the TST?

..it may be best to collect blood for IGRA at the time the TST is read (i.e., within three days of placing PPD).

Spot watch

UMDNJ have also got the T-Spot timing very wrong;

Blood must be stored at room temperature (do not refrigerate or freeze) and shipped to the laboratory to arrive within 24 hours of blood draw.

The UMDNJ stuff reads a bit like an advertorial;

T-SPOT.TB has proven to be the most accurate TB screening test available with 95% sensitivity in culture positive TB patients and 97% specificity in low risk healthy individuals (2).

The study referred to (2) was partly authored by the CEO from the manufacturer, Oxford Immunotec Limited.

Quoted specificity and sensitivity roughly matches those in the FDA approved package insert however to add to the confusion is Oxford's "International" site which has a slightly different version

Specificity of 99%*

The * refers to the US package insert in which borderline results are excluded. The US package insert insists that if borderline results persists

other diagnostic tests and/or epidemiologic information should be used to help determine TB infection status of the patient

In addition the US package insert gives a further two equal estimates for specificity

If all the borderline (equivocal) results are considered all positive or all negative, the estimated specificity of T-SPOT.TB was either 94.8% or 99.0% respectively.

Similarly with sensitivity

If all the borderline (equivocal) results are considered all positive or all negative, the estimated sensitivity of T-SPOT.TB was either 96.2% or 90.7%, respectively.

Oxford are offering various values for specificity and sensitivity with at least one being the most accurate. It is interesting to compare their approach to that of the QFT-GIT insert

As there is no definitive standard for confirming or excluding the diagnosis of LTBI, an estimate of sensitivity and specificity for QuantiFERON®-TB Gold IT cannot be practically evaluated

Spotted dick

The Oxford Diagnostic Laboratory  FAQs are worthy of closer examination; they claim that

A blood specimens would be rejected if:
* Received more than 32 hours from the time of collection

This is inconsistent with the FDA approved Package Insert

Blood samples should be processed within 8 hours.

and the T-Spot.TB  FAQ

Blood samples should be processed within 8 hours.

Perhaps they have mixed up the T-Spot North American site with the International site where 32 hours is given as the time.

Addition of the T-Cell Xtend reagent (available from Oxford Immunotec) to the sample immediately prior to processing allows samples to be run in the T-SPOT.TB assay up to 32 hours after they have been collected.

Not only is T-Cell Xtend not approved for use in the USA the performance specifications are quite different.

T-Spot in the US

In the US the only publicly known place to have T-Spot TB processed is here, Oxford Diagnostic Laboratories. It all sounds quite straightforward, until you reach the bit about packaging

Conversions and reversions

More from Madhukar Pai. Here he discusses reproducibility

Serial IGRA testing shows that IGRAs are highly dynamic, with high rates of conversions and reversions. Although some of the dynamic changes may be due to test reproducibility some of the kinetics might signal the underlying transitions that occur in the TB spectrum.

For example, rapid reversion of a positive IGRA after exposure is well documented and could imply that infection was eliminated in association with transient T cell priming.

All sorts of theories are challenged - perhaps one third of the world isn't infected with TB and perhaps there is greater progression to active from those who remain infected.

Some individuals convert their IGRA result from negative to positive and then revert again. Others convert their IGRA result and stay converted, at least in the short term. Certain individuals are repeatedly IGRA-positive for a long time, and others remain IGRA-negative for years, despite ongoing TB exposure. Although no data exist to link these trajectories of test results with disease progression, it is inconceivable that all of these phenotypes will have the same prognosis.

Reversions and conversions can cause heartburn to some diagnosticians - the skin test was so easy!

Those with a transiently positive IGRA result (‘unstable conversions’) may have a low likelihood of disease progression, possibly similar to the persistently negative group. Without serial testing, the underlying phenotypes are not separable, and this will undermine the predictive value of a single test result.

However, without large amounts of data made available progress towards eliminating TB will be limited if not stalled.

Without more predictive biomarkers or combinations of biomarkers, or novel serial testing strategies, we may not be able to translate biological advances into clinical interventions that can eliminate TB.

Changing the way the world looks at TB.

In the highy acclaimed journal Nature C E Barry et al write that infection by MtB can

result in the formation of physiologically distinct granulomatous lesions that provide microenvironments with differential ability to support or suppress the persistence of viable bacteria.

This prompted a response from Madhukar Pai

QuantiFERON-CMV Irish study

Abstract available here,

A total of 271 QuantiFERON-CMV samples were collected from 72 patients between January 2007 and November 2008. These patients were either hospitalized in St. James’s Hospital or attending the hospital as outpatients for monitoring after stem cell transplantation.

QuantiFERON-CMV was compared with the flow cytometric intracellular cytokine (ICC) assay

results of the QuantiFERON-CMV assay correlated well with the ICC assay, which is considered the gold standard in analysis of HCMV specific immune responses.

A word of warning on drug resistant TB

Professor Loddenkemper and Dr Hauer take a global look at TB, drug resistant strains of TB and HIV and warn

Only rapid and internationally concerted action, combined with intensified research efforts and the support of the affected nations, will be able to prevent the development of a situation that will no longer be manageable even with 21^st-century technology.

Another happy customer

Washinton State said that the switch over to QuantiFERON saved both time and money, what was the next question?

We decided to use the QuantiFERON®- TB- Gold Test (QFT-G ), exclusively, on all eligible TB patients, due to the large foreign-born population the TB Program serves. We are very fortunate that the Spokane Regional Health District has an onsite laboratory that has pioneered this endeavor. Making the switch from TST’s to QFT’s was a smooth transition which has helped the TB Program be more efficient and conserve our resources. No longer treating false positive TST’s or having patients come back for TST readings has saved both time and money and increased quality of patient care. This was a huge change that has had a very positive outcome.

Many thanks to doc-gt

Switzerland Tells of TB

You would think that with all that fresh air and scenery Switzerland would be relatively disease free. This is true to an extent however disease continues to be an unwelcome visitor imported from other countries. After mining the data Swiss authorities found that

In Switzerland, incidence of TB is low (8.5 per 100 000 population). Over the past 10 years, as in most countries of Western Europe, the proportion of indigenous TB cases has continuously decreased while that of foreigners (presently 76%) has increased. In recent years, the overall incidence of tuberculosis in Switzerland has stabilized due to immigration from high prevalence countries

This seems to be the global pattern

In a globalizing world, TB anywhere really is TB everywhere. 

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Getting up

The Get-QFT site has been updated, a total of 129 labs (up by 27 from the last update) are now listed as having agreed to provide QFT testing services to outside physicians and laboratories. Included is the first correctional facility - the Corrections Medical Center in Ohio

Ruled out

The State of Delaware has put a line through the Mantoux tuberculin skin test, it is now the "Tuberculosis Test" which

means a Mantoux skin test, Quantiferon Gold blood test, or other test approved by the Delaware Division of Public Health.

The new regulation has also made changes to those requiring to have a “Tuberculosis Test”:

• New school staff and extended services personnel;
• New school enterers (unless acceptable results of a Tuberculosis Risk Assessment administered in the previous 12 months prior to school entry can be provided).
  

Delaware is now open for business.

Another one bites the dust.

In a letter to the AJRCCM Dr. Eduardo Hernandez-Garduno disputed the claim that QuantiFERON was a better predictor of progression from latent to active TB. Amongst other things he said that

due to its cost and the inconvenience of venipuncture, the use of QFT should be restricted to the BCG vaccinated

TB in kids - France

Doctors from Brabois Hospital, Nancy France compared QFT in tube with other available diagnostics in this contact study

despite its objectivity and its higher specificity (especially in Bacille Calmette-Guérin vaccinated children), the real place of QFT-G IT in TB diagnosis in children remains difficult to define.

To put QFT into context, they did say that

Tuning in to the Doctors Channel

In response to the Reuters Health article "Interferon assays better than skin test for detecting active TB" Doctors Channel has a short but sweet film clip on IGRA with QFT putting in an award winning performance

According to webTraffic Doctors Channel gets 2,479 daily visits.

It's in the bag

The recent communique from Mayo A New Approach for the Diagnosis of Tuberculosis also includes an easy to see guide relating to the high altitude version of QuantiFERON - Mayo even have their own bag for these high flyers;

Figure 1 QTB validated fill range Used with permission Cellestis Inc.

Figure 2 Blood should be frothy and coat the entire inner surface

Figure 3 QTB transport kit

Mayo Clinics are also doing outside work, Minnesota Childrens Hospital and Clinics have adopted both  QFT and the Mayo bag. 

Special kits are required for specimen collection. Please contact the lab for Mayo Supply T628. Following specific collection instructions included with kit.

Mayo were the preferred provider

Updates: 4/27/2009: Moved from Abbott Northwestern Hospital to MML

Toast and marmalade

This popped up in the Google machine this morning;

A method for detecting whether an individual will progress to having active mycobacterial disease comprising determining whether the individual has a T cell response to one or more of the following mycobacterial antigens: CFP-10, Rv1989c, Rv3873, or Rv3878.

Mayo again

Back in 2005 a representative from Mayo said

Quantiferon (or something similar) will be the gold standard and possibly replace the skin test, although it still has a role in the transition.

Seachange for QuantiFERON

It wasnt that long ago that Mayo were "cool" on QFT

Technically difficult assay to perform

Now it is the TST that is copping some heat;

QuantiFERON in the news

This article from Reuters (Interferon Assays Better Than Skin Test for Detecting Active TB) fleshes out the original Diel study;

Only a few published studies examined test specificity. Nonetheless, QuantiFERON-TB Gold was found to have a significantly higher specificity than T-Spot.TB: 99.2% vs. 86.3% (p < 0.0001).

"Considering sensitivity for diagnosing active tuberculosis as a surrogate parameter for latent tuberculosis infection, tuberculin skin test-based two-step screening strategies (tuberculin skin test first, interferon-gamma release assays second) for contact tracing should be critically reconsidered due to the poor tuberculin skin test accuracy among tuberculosis patients," the authors conclude.

Alan Kohler casts the runes for 2010

from the latest ASX newsletter;

The bottom line for 2010: bet on China, not America. That means bet on Australia - it is in the right place at the right time.

TB in India - picking up their act

Any notion of a public health system in India must be tempered by this piece by the Indian Express. The article relates to MDR-TB in the Indian state of Maharashtra, which is regarded as the richest state in India. With a population of 96.8M any problem in Maharashtra is bound to occur on a large scale.

The Maharashtra Public Health Dept doesn't hold back on their TB work

In 1992, the Government of India, together with the World Health Organization (WHO) and Swedish International Development Agency (SIDA), reviewed the national programme and concluded that it suffered from managerial weakness, inadequate funding, over-reliance on x-ray, non-standard treatment regimens, low rates of treatment completion, and lack of systematic information on treatment outcomes. As a result, a Revised National Tuberculosis Control Programme (RNTCP) was designed.

The RNTCP has established a goal of detecting 70% of TB (via sputum microscopy) and curing 85% of those cases. Maharashtra claim to have some success in that area

With around 600,000 tests undertaken annually the task is enormous. What they are finding is that of those tested 55% are smear positive with 59% of those positives being confirmed by sputum culture and of these new cases 5% are MDR-TB - which should be around 9,700 cases per year.

Extending these detection rates over the entire population of 96.8M gives a sense of the scale of the problem. To that end they are to open 2 new MDR-TB labs, one in Pune and the other in Mumbai.

With active and drug resistant TB remaining to be brought under control it is unlikely that latent TB will be a priority. However, India remains a breeding ground for disease and the potential for both TB and MDR-TB to travel to developed countries remains large.

Positivism is a mass delusion

Writing in Forbes Michael Fumento finds that being happy is no laughing matter;

The Negative Side Of Positive Thinking

..and more changes to CDC

From the same newsletter, an indication of both the frustration experienced by the CDC in addressing health issues on a national level and a possible resolution via regulation reform;

We heard an interesting report on health care reform from Mr. Michael Craig and Mr. Donald Shriber of the CDC Washington office. Indicating that some kind of health reform bill is expected to pass this year, they described how CDC might be affected by health reform. It is anticipated that CDC might gain new, higher priority authority to address health issues. Also, public health institutions could be strengthened within and across government, and reforms could give more individuals access to preventive services such as vaccines and screenings.

CDC update..major changes..

From the latest CDC TB Notes;

We received an update from Dr. Dolly Katz on the revised guidelines for preventing TB in foreign-born persons in the United States. Major changes from the previous guidelines include the recommendation to provide latent TB infection (LTBI) testing at least once to every foreign-born person from a high-risk country. The guidelines will also state that interferon gamma release assays (IGRAs) are preferable to tuberculin skin tests in these populations. The document will include specific guidance for follow-up and evaluation of immigrants with class B notifications.

Charles Daley, who is conducting the HCW IGRA trial reported that they have experienced boosting by TST;

Dr. Daley reported that the effect of TST on subsequent IGRAs occurred within 2 weeks, and occurred in persons who initially had a definitive negative IGRA result.

Mental disorders caused by infected DNA

Whilst a link between some infectious diseases (eg herpes, encephalitis and influenza) and mental illnesses such as schizophrenia has been established new research shows that viral mutations can be integrated into the human genome and passed on to succeeding generations.

A recent study on the 8 percent of human DNA that is derived from viruses may show a cause of cell mutation and psychiatric disorders such as schizophrenia and mood disorders,

..Researchers have known since 2001 that 8 percent of human genetic material is derived from retroviruses.

.."These data yield a testable hypothesis for the alleged, but still controversial, causative association of BDV (Bornavirus) infection with schizophrenia and mood disorders,"

Wales watching

According to the press TB services in Wales have been left floundering as demand outstrips NHS supply

In their own words

Lincoln Indicators list Cellestis under Elio D'Amato's ASX Top 10 best stocks to buy for January 2010;

The long and short of it

At about 10.30am December 30 2009 an unusually large transaction was made - 1.33 million Cellestis shares @ $3.15. This transaction was later confirmed by way of ASX announcement as being a sale by 3 of the directors, links here and here.

This transaction generated considerable debate on various forums. Allegations of impropriety and insider trading were made along with estimates of liquidity, or lack thereof with the resultant dire forecasts being predicted.

The fact is that there has been no evidence of a breach or impropriety committed - to the best of everyone's knowledge the transaction complies with all current laws, rules and guidelines.

Perceptions and estimates of liquidity are irrelevant - the fact is that the buyers were able to buy the stock - therefore the stock is liquid.

Poster Alfa nails it in one;

1.3 % of the stock is now in new hands. That is by definition an improvement in liquidity, albeit not a dramatic one.

It signals 2 other things to the market;

1) Shareholding is less concentrated
2) A large investor has confidence in the stock.

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Myths busted

Economist James K. Galbraith looks at the crumbling ruins of the last failed economic experiment and asks  

Who Are These Economists, Anyway?

Back in 2002 Galbraith wrote that

Slowly making haste.

New Jersey is to finally change its law on TB testing; the Department of Health and Senior Services is to allow for IGRA

Amendments at N.J.A.C. 8:42C-3.4(h) that would provide an option for how to test employees and contract personnel for tuberculosis by adding interferon gamma release assay (IGRA) as an acceptable test and to establish the meaning of a positive, negative, or intermediate test result.

Mining the data

Playing around with Google trends can have some surprising results. Firstly, Google define trends as;

a portion of Google web searches to compute how many searches have been done for the terms you enter, relative to the total number of searches done on Google over time.