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Anticipating TB Skin Test Antigen Shortage, CDC Proposes Switch to IGRA Lab Tests

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NEW YORK – At a time when clinicians are already increasingly switching to interferon-gamma release-based assays (IGRAs) for tuberculosis testing, the US Centers for Disease Control and Prevention recently warned of an anticipated shortage of a key antibody for tuberculin skin tests (TSTs) conducted in clinics.

Because of the expected shortage, one IGRA assay provider, Oxford Immunotec Global, anticipates a bump in revenues, and the other, Qiagen, has proactively boosted test kit production according its customer Laboratory Corporation of America.

The CDC recently announced an anticipated three- to 10-month nationwide shortage of Aplisol, one of two purified-protein derivative tuberculin antigens approved by the US Food and Drug Administration for use in TST-based tuberculosis diagnoses. The CDC said that Aplisol's manufacturer, Par Pharmaceuticals, notified it of an anticipated interruption of the supply of Aplisol 5 mL beginning in June followed by an interruption of the supply of Aplisol 1 mL in November, or before then if antigen demand increases. An interruption in supply of 50 multidose vials of Aplisol 5 mL and 10 multidose vials of Aplisol 1 mL is anticipated.

As a remedy, the CDC has recommended that clinicians prioritize allocation of TSTs — and possibly defer TST testing for some patients — in consultation with state and local public health authorities.

Further, it recommended substituting use of IGRA blood tests for TSTs, or substituting Tubersol for Aplisol during skin testing. Tubersol, produced by Sanofi-Pasteur, is the second FDA-approved purified-protein derivative tuberculin antigen.

Clinicians can use the antigen-based TSTs or IGRA blood tests for detecting Mycobacterium tuberculosis, the bacterium that causes tuberculosis in humans. Most TB cases in the US are diagnosed through a combination of methods, including results from one of these tests.

Oxford Immunotec, Qiagen, and their laboratory customers stand to benefit if clinicians decide to switch from skin testing. Oxford Immunotec, based in Oxford, UK, produces the T-Spot.TB test, which has been approved for sale in more than 50 countries. The test is based on the principle that the T cells of an infected patient respond to specific antigens and secrete interferon-gamma.

In April, Hilden, Germany-based Qiagen announced that its QuantiFeron-TB test for detection of tuberculosis infections had surpassed 60 million administered tests. The firm's QuantiFeron-TB Gold Plus test, marketed in more than 75 countries, combines a flexible blood collection workflow with CD4/CD8 T-cell technology.

Whether the current shortage of antigens will drive an increase in IGRA testing is unclear.

Donnica Smalls, a spokesperson for the CDC, noted that substituting IGRA blood tests for TB skin tests is only one of the three approaches the CDC is recommending to prevent a decrease in tuberculosis testing capacity.

"Despite the availability of IGRAs, many public health clinics and community partners still use TSTs for screening," Julie Higashi, president of the National Tuberculosis Controllers Association (NTCA), said in an interview. "Although we are early in the shortage, the impact is likely to affect populations having limited access to care and who need to be tested for access to services like shelter and treatment for substance use and mental health," she said.

By Oxford Immunotec's estimates about 75 percent of all TB testing still relies on skin tests.

Elitza Theel, a consultant in the division of clinical microbiology at Mayo Clinic Laboratories, said in an interview that some clinicians may opt to increase purchases of Tubersol, the alternative to Aplisol, because it is easy to implement the type of test they have already been using.

In spite of that convenience, some clinicians may convert entirely to IGRA testing partly because the approach enables clinicians to give patients results from a single visit, Theel said. A patient taking a skin test has to return to the clinic about 48 hours after receiving an intradermal injection.

Mayo Clinic Laboratories, which uses Qiagen's QuantiFeron product for testing, is already seeing clinicians select IGRAs over skin tests, reflected by increases in IGRA test volumes of between 10 and 15 percent in recent years, Theel said.

LabCorp spokesperson Monique Smalls told 360Dx that the Burlington, North Carolina-based company and Qiagen, its IGRA test supplier, "are prepared for potential increases in demand as a result of the CDC's recommendation to substitute IGRA blood tests for TSTs." She said that Qiagen has "proactively boosted test kit production" to prepare "for a potential uptick in volume."

Hema Kapoor, medical director of infectious diseases and immunology at Quest Diagnostics, said in an interview that while the response to the current announcement will depend on how clinicians react to it, over the years she has seen continuing growth for IGRA testing, supported by guidelines that have recommended blood-based TB testing over skin testing for certain populations.

A 2016 guideline from the American Thoracic Society, Infectious Diseases Society of America, and the CDC recommended performing an IGRA test rather than a tuberculin skin test in people five years or older who meet certain criteria. The guideline, recommended IGRA testing for people who are likely to be infected with M. tuberculosis; have a low or intermediate risk of disease progression; either have a history of BCG vaccination or are unlikely to return to have their TSTs read; or for whom testing for latent tuberculosis infection is warranted. However, the guideline stated that a TST is an acceptable alternative, "especially in situations where an IGRA is not available, too costly, or too burdensome."

"For more than 12 years that Quest has been offering the IGRA test, we have seen … a lot of healthcare settings and providers switch over from TST to IGRA," Kapoor said, adding that there are a few reasons clinicians are switching to IGRA tests, including better accuracy, the ability to provide screening in a single visit, and lack of cross-reactivity with the Bacillus Calmette–Guérin vaccine for tuberculosis, which has proven to be a problem with skin tests.

Quest said it provides TB testing services based on Qiagen and Oxford Immunotec's IGRA blood tests.

It's not the first time there has been a shortage of purified-protein derivative tuberculin antigens. In April 2013, Sanofi Pasteur announced that there would be a nationwide shortage of Tubersol until at least the end of May of that year. At the same time, JHP Pharmaceuticals notified the FDA that its product was available in restricted quantity.

On its website, Vasserve, a Sanofi Pasteur company, said that Tubersol is "currently on ordering restriction."

Neither Par Pharmaceuticals, based in Woodcliff Lake, New Jersey, nor Sanofi-Pasteur, based in Lyon, responded to e-mails requesting comments for this article. Qiagen also did not respond to e-mails requesting comments.

Oxford Immunotec said the CDC announcement is further evidence of the need for clinicians to shift to IGRA testing.

"When we previously saw a shortage of Tubersol, we experienced a modest bump in test volumes," Jonathan Friend, vice president of US commercial operations for Oxford Immunotec, said in an interview. "A lot of the customers that switched because of supply chain issues at the time continued to order T-spot testing after the supply issues were resolved," he said.

Since 2014, the firm has seen "significant growth" in volume and revenues for its T-Spot product, Friend said, adding, "With the recent acquisition by Quest of our US service laboratory, T-spot is also more readily available."

He noted that with skin tests still retaining about a 75 percent share of the TB testing market, there is plenty of additional room for revenue and volume growth for the IGRA testing companies.

"We are confident that as skin testing becomes less of an option because of supply chain and other issues, more people will opt for blood tests," Friend said.

Nonetheless, the firm's CFO Matthew McLaughlin said that in considering the potential uptick in test volumes based on the current announcement, the firm will "wait and see what happens over the next couple of months and quarters."

Mayo Clinic Hospital, in its inpatient and outpatient services, had previously conducted skin testing and sometimes also ordered IGRA tests from its laboratories, but because of an earlier CDC announcement that updated recommendations for tuberculosis screening, testing, and treatment of US healthcare personnel, "it will now stop doing annual skin testing and convert to IGRA for all baseline testing," Theel said.

That has implications for the hospital's laboratories, and especially its preanalytical processing of samples, which includes whole-blood incubation, centrifugation, and volume checking. The switch to IGRA testing requires increases in lab space and the number of people conducting tests, and requires installing additional incubators, Theel said.