IGRA vs. QuantiFERON: Differences in TB Blood Tests

IGRA is the category; QuantiFERON is one product within it. An interferon gamma release assay, or IGRA, is any blood test that detects tuberculosis infection by measuring your immune cells’ response to TB-specific proteins. QuantiFERON (made by Qiagen) is one of two commercially available IGRAs, the other being T-SPOT.TB (made by Oxford Immunotec). The confusion between the two terms is understandable because QuantiFERON dominates the market in many countries and is often used as a shorthand for IGRA testing in general, much the way people say “Band-Aid” when they mean adhesive bandage. But the distinction matters when you are trying to understand your test results or compare studies, because the two IGRA products use different laboratory methods and occasionally give different answers.

Two IGRAs, Two Methods

Both QuantiFERON and T-SPOT.TB work on the same basic principle: they expose a blood sample to proteins found in the tuberculosis bacterium and then measure whether the immune system responds. If you have been infected with TB at some point, your T cells “remember” those proteins and release a signaling molecule called interferon-gamma when they encounter them again. The tests pick up that release. Where the two products diverge is in how they detect it.

QuantiFERON uses an approach called ELISA. Your blood is drawn into specialized tubes that already contain TB antigens. The tubes are incubated overnight, and the total amount of interferon-gamma released into the surrounding fluid is measured. The result comes back as a number in international units per milliliter, and a cutoff determines whether it is positive, negative, or indeterminate.

T-SPOT.TB uses a technique called ELISPOT. Instead of measuring the total interferon-gamma in solution, the lab separates out the mononuclear cells from your blood and places them into wells coated with TB antigens. Each individual cell that responds to the antigens leaves a visible “spot” on the well. The lab counts those spots, so the result reflects the number of responding T cells rather than the total amount of signaling molecule produced.¹ This cell-counting approach has been described as one of the most sensitive ways to measure antigen-specific immune responses in the lab.²

In practical terms, the biggest difference for you as a patient is the blood draw. QuantiFERON requires blood to go directly into the manufacturer’s proprietary tubes, which must be incubated promptly. T-SPOT.TB uses a standard blood draw tube, but the lab must process the sample to isolate the immune cells before running the assay. Both tests require a single blood draw and no return visit, which is a significant advantage over the tuberculin skin test.

The QuantiFERON Upgrade: From Gold In-Tube to Gold Plus

If you have had a QuantiFERON test in the last few years, you likely received the newest version: QuantiFERON-TB Gold Plus (QFT-Plus), which received FDA clearance in 2017 and replaced the older QuantiFERON-TB Gold In-Tube (QFT-GIT).³ The key change is an extra antigen tube. The older version stimulated mainly one branch of the immune response (CD4 T cells). The newer version adds a second tube containing shorter peptide fragments designed to also activate CD8 T cells, which play a role in fighting intracellular infections like TB.⁴

The idea behind this upgrade was to improve detection in three groups where the older test sometimes fell short: people recently exposed to TB, people with weakened immune systems, and young children.⁵ Whether that theoretical advantage translates to meaningfully better real-world performance is still being studied, and the evidence so far is mixed. A systematic review and meta-analysis comparing QFT-Plus with both QFT-GIT and T-SPOT.TB found no statistically significant differences in sensitivity or specificity.⁶ One head-to-head study in elderly patients with active pulmonary TB did find a more striking result: QFT-Plus had a sensitivity of about 94%, compared with about 91% for QFT-GIT and only about 68% for T-SPOT.TB in that specific population, with all three tests showing perfect specificity in low-risk healthy controls.⁷ That is only one study and should not be taken as the final word, but it illustrates that performance can shift depending on the population tested.

How IGRAs Compare to the Tuberculin Skin Test

Before IGRAs existed, the only way to screen for TB infection was the tuberculin skin test (TST), where a small amount of purified protein is injected under the skin of your forearm and a healthcare worker reads the resulting swelling two to three days later. The TST is cheap, requires no laboratory equipment, and has been used for over a century. But it has a well-known weakness: it cross-reacts with the BCG vaccine that most countries outside the United States give to children at birth. If you were vaccinated with BCG, you can test positive on a TST even if you have never been infected with TB.

IGRAs use antigens that are more specific to Mycobacterium tuberculosis and are not shared by the BCG vaccine strain. This makes a big difference in populations where BCG vaccination is common. One study of BCG-vaccinated healthy individuals found that the TST had much higher cross-reactivity, while the IGRA was more suitable for rapid screening in that population.⁸ A study of healthcare workers in Egypt illustrated this gap vividly: about 35% of participants tested positive by TST, but only about 9% were confirmed positive by QuantiFERON, suggesting the skin test was picking up a large number of BCG-related false positives.⁹ In patients with lupus, BCG vaccination was also identified as a factor driving discordance between TST and QuantiFERON results.¹⁰

That said, the TST still has a place. It costs a fraction of what an IGRA costs, needs no lab, and performs reasonably well in unvaccinated populations. In countries with very high TB burden and limited laboratory infrastructure, mass screening with IGRAs is not always practical.

The Problem with Borderline and Indeterminate Results

One frustration clinicians and patients share is the ambiguity that comes with results near the cutoff. The QuantiFERON test uses a threshold of 0.35 IU/mL to distinguish positive from negative. But immune responses are not binary, and values hovering near that line are surprisingly unstable. A study tracking repeat tests in people whose initial QuantiFERON value fell between 0.35 and 0.99 IU/mL found that about 55% reverted to negative on follow-up. Among those just below the cutoff (0.2 to 0.34 IU/mL), about 20% flipped to positive on retest.¹¹ This means a weak positive or a near-miss negative should be interpreted with caution, particularly if there is no clear history of TB exposure. Some clinicians now treat low-positive results as a “borderline” zone rather than a definitive answer.

Then there are indeterminate results, where the test fails to produce a usable answer at all. This usually happens when the positive control tube (the “mitogen” tube, which checks whether your immune cells can respond to anything) does not produce a strong enough signal, or occasionally when the negative control tube (the “nil” tube) runs unusually high. In a large study, about 4% of QuantiFERON tests came back indeterminate, with high nil concentrations accounting for a small fraction of those.¹² Severe illness is one of the strongest drivers: severe COVID-19, pharmacological immunosuppression, severe lymphopenia, anemia, and hospitalization for non-COVID reasons all significantly increased the odds of an indeterminate result in a large analysis.¹³ T-SPOT.TB is sometimes cited as having a lower indeterminate rate in immunocompromised patients because the cell-isolation step can partially normalize the number of immune cells going into the assay, but both products can fail in severely ill people.

Performance in People with Weakened Immune Systems

TB testing matters most in the populations where it performs worst. People on immunosuppressive drugs, organ transplant recipients, those living with HIV, and patients on cancer chemotherapy all face higher risk of TB reactivation and are the very people most likely to get an unreliable IGRA result. A large prospective study found that QuantiFERON-TB Gold Plus had a sensitivity of about 70% in immunocompromised individuals, compared with about 81% in immunocompetent individuals. Specificity also dropped, from about 96% in the immunocompetent group to about 91% in the immunocompromised group.¹⁴

A sensitivity of 70% means roughly three in ten immunocompromised people with TB will get a falsely negative result. That is a real clinical problem. For this reason, guidelines in many countries recommend using clinical judgment alongside IGRA results in immunocompromised patients rather than relying on the test alone. Some clinicians order both an IGRA and a TST in these populations, reasoning that if either one flags the infection, the patient gets treated.

Children Present a Different Challenge

Young children, especially those under five, are another group where IGRA performance drops. A meta-analysis of the older QuantiFERON-TB Gold In-Tube in children under five found a pooled sensitivity of only about 45%, even though specificity remained high at about 96%.¹⁵ One study broke this down by age further and found that sensitivity was as low as 40% in infants, rising to about 77% in one- to four-year-olds and about 82% in older children.¹⁶ The newer QFT-Plus may perform somewhat better: a prospective study in children aged 0 to 17 found that among those diagnosed with active TB, about 83% had a positive QFT-Plus, and the indeterminate rate in LTBI screening was low.¹⁷ Still, the younger the child, the less reliable any IGRA becomes, and most pediatric TB guidelines recommend combining test results with clinical assessment rather than using either test as a standalone decision tool.

Why Sample Handling Can Make or Break Your Result

An underappreciated source of false results with QuantiFERON is what happens between the blood draw and the lab. The tubes need to be incubated at body temperature within a limited window. When researchers deliberately delayed incubation by six hours, about 19% of previously positive samples flipped to negative. At a twelve-hour delay, the reversion rate was about 22%.¹⁸ A separate study found that immediate incubation eliminated indeterminate results entirely in a sample of healthy volunteers, whereas a twelve-hour delay produced indeterminate results in about 17% of samples.¹⁹

This means the circumstances of your blood draw matter. A sample drawn at a remote clinic, transported by courier, and received at the lab six or eight hours later may give a different result than the same blood incubated immediately. If you get an unexpected negative or indeterminate result and there is any question about transport time, it is reasonable to ask about retesting with prompt incubation. T-SPOT.TB has its own handling sensitivities, particularly the need to process the sample within a set window to isolate viable cells, but the specific tube-incubation timing issue is more acute with QuantiFERON.

Can IGRAs Predict Who Will Actually Get Sick?

Most people with latent TB infection never develop active disease. One of the hardest questions in TB medicine is figuring out which ones will. Both IGRAs and the TST have been studied as prognostic tools, and the evidence gives IGRAs a modest edge. In a cohort of close contacts of TB patients followed for four years, the positive predictive value for developing active TB was about 4% for QuantiFERON versus 2% for the TST, and untreated contacts with a positive QuantiFERON had a positive predictive value of 17%.²⁰

Another study from a setting with high recent exposure found that all six contacts who progressed to active TB within two years had been QuantiFERON-positive and had declined preventive treatment, translating to a progression rate of about 15% among untreated QFT-positive contacts. The progression rate among TST-positive contacts who went untreated was far lower, around 2%.²¹ A longer follow-up in a larger cohort confirmed the pattern: all 19 contacts who developed active TB had been QFT-positive, with a progression rate of about 13% among the untreated QFT-positive group, and the gap was even more pronounced in children.²²

These numbers are still not high enough to justify treating every positive result aggressively in all settings, but they suggest that a positive IGRA, particularly a strongly positive one in a recently exposed person, identifies a higher-risk group than a positive TST does.

Nontuberculous Mycobacteria and Cross-Reactivity

One reason IGRAs were developed was to avoid the cross-reactivity problems of the TST, which reacts not only to BCG but also to many nontuberculous mycobacteria (NTM). IGRAs use antigens (ESAT-6 and CFP-10) that are present in Mycobacterium tuberculosis but absent from most NTM species. In practice, this mostly works. An older study found that among patients with pulmonary Mycobacterium avium complex disease, 60% tested positive on TST but only 7% were positive on QuantiFERON.²³ A more recent evaluation in Northern California confirmed very high specificity in NTM patients, with the few false positives largely explained by patients who also had risk factors for latent TB.²⁴

There are a handful of NTM species that do carry ESAT-6 or CFP-10 genes and can therefore cause a true cross-reaction. The most commonly cited ones include M. kansasii, M. szulgai, and M. marinum. If you have a known NTM infection with one of these species, a positive QuantiFERON result is harder to interpret, and your clinician may need additional information to sort out whether TB is also present.

Cost and Access Considerations

IGRAs cost more per test than a TST, and the economics vary dramatically by country. A cost-effectiveness analysis in Colombia found that QuantiFERON-TB Gold Plus was cost-effective relative to TST for diagnosing latent TB in immunocompetent subjects, though the result was sensitive to local TB prevalence and test sensitivity assumptions; QuantiFERON came out cost-effective in roughly 55% of simulated scenarios.²⁵ A study in Brazilian healthcare workers reached the opposite conclusion, finding TST at a 10 mm cutoff to be the most cost-effective strategy and QuantiFERON to add substantial cost without proportional gains.²⁶ In a U.S. model focused on healthcare workers, IGRAs were actually both more effective and less costly than the TST, particularly in BCG-vaccinated workers where the skin test generates a flood of false positives leading to unnecessary chest X-rays and treatment.²⁷

The takeaway is that the economic case for IGRAs depends heavily on context. In a wealthy country with a BCG-vaccinated immigrant workforce and low TB prevalence, the IGRA usually saves money overall by avoiding false-positive cascades. In a resource-limited, high-burden setting where labs are scarce and TB prevalence is high, the TST’s low unit cost and simplicity can win out. Neither strategy is universally superior.

Emerging Biomarkers and Where Testing Is Headed

Both QuantiFERON and T-SPOT.TB measure a single output: interferon-gamma. Researchers have been exploring whether measuring additional biomarkers alongside or instead of interferon-gamma could improve accuracy, particularly in the groups where current tests struggle. One candidate is IP-10 (also called CXCL10), a protein produced in much higher concentrations than interferon-gamma during a TB immune response. A study in children found that combining the standard QuantiFERON assay with an IP-10 measurement pushed the rate of positive results from about 38% with QuantiFERON alone to about 41%, modestly reducing the number of missed infections.²⁸ In bovine TB research, CXCL10 and IL-22 have shown promise as supplementary biomarkers that flag animals missed by both the skin test and the interferon-gamma assay.²⁹ These are still research tools, not yet part of routine clinical testing, but they hint at a future where TB blood tests go beyond a single cytokine measurement. For now, QuantiFERON and T-SPOT.TB remain the only commercially available IGRAs, and the practical choice between them usually comes down to local lab availability, sample-handling logistics, and the patient population being tested.