Blood Test for Tuberculosis Shows Strengths and Gaps in Chinese Children

Tuberculosis remains one of the most stubborn infectious threats to children worldwide, and diagnosing it in the youngest patients has long frustrated clinicians. A new retrospective study from China, published in BMC Pediatrics, offers one of the most detailed pictures yet of how a widely used commercial blood test performs in children and young adults carrying Mycobacterium tuberculosis. The test, QuantiFERON-TB Gold Plus, is a second-generation interferon gamma release assay, or IGRA, designed to detect the immune fingerprint of tuberculosis infection without relying on the skin reactions that can be difficult to interpret in children who have received the BCG vaccine. The findings confirm that the assay is a genuinely useful diagnostic aid, but they also expose clear blind spots, particularly in infants under one year of age and in children burdened by other illnesses.

The research team, led by investigators at Beijing Children’s Hospital, Capital Medical University, together with colleagues at Shenyang Chest Hospital and other Chinese institutions, enrolled 448 patients aged under 22 years who had confirmed Mycobacterium tuberculosis infection, a QuantiFERON-TB Gold Plus result, and complete clinical records. Recruitment took place between August 2022 and March 2024 at the two hospitals. Of the total cohort, 138 patients, or 30.8 percent, had active tuberculosis disease, while 310, or 69.2 percent, were diagnosed with latent tuberculosis infection, a state in which the bacteria persist in the body without causing symptoms but can reactivate into full disease later in life. This split between disease states allowed the researchers to ask a question that matters enormously in pediatric practice: does the immune signal measured by the test differ depending on whether the infection is latent or actively causing illness?

The technical logic of the assay is worth unpacking, because the study’s most interesting findings hinge on it. QuantiFERON-TB Gold Plus works by mixing a small blood sample with synthetic peptides that mimic two proteins, ESAT-6 and CFP-10, which are produced by Mycobacterium tuberculosis but absent from most environmental mycobacteria and from the BCG vaccine strain. Sensitized T cells in the blood respond by releasing interferon gamma, a signaling molecule of the immune system, and the amount released is quantified by enzyme immunoassay. The Plus version of the test splits the antigen stimulation into two tubes, TB1 and TB2. TB1 contains peptides that preferentially stimulate CD4 T cells, the classic helper cells of adaptive immunity, while TB2 adds longer peptides intended to additionally engage CD8 T cells, which are thought to play a role in controlling active tuberculosis. Comparing the responses in these two tubes therefore offers a window into different arms of the anti-tuberculosis immune response.

The headline result was a sensitivity of 82.8 percent for active tuberculosis across the whole cohort. In other words, roughly five out of six children with confirmed active disease produced a positive result. That figure places the assay in familiar territory for IGRAs in pediatric populations, where sensitivity has consistently lagged behind the near-perfect specificity these tests achieve in low-burden settings. Specificity is rarely the problem, because the tuberculosis-specific antigens virtually eliminate false positives caused by BCG vaccination or nontuberculous mycobacteria. The problem is the false negative: a child with active tuberculosis who tests negative may have treatment delayed, and in pediatric tuberculosis, where disease can progress rapidly from a small lung focus to disseminated infection, delay carries real consequences. The authors are explicit that the test should not be used as a rule-out tool, particularly in the most vulnerable patients.

Agreement between the two antigen tubes emerged as another notable finding. The percent agreement between TB1 and TB2 responses was 91.8 percent, indicating that in the vast majority of infected children the CD4-focused and CD8-inclusive stimulation tubes returned concordant results. This high concordance suggests that, in this population, adding the TB2 tube does not dramatically change who is classified as infected, although it may still contribute quantitative information about the breadth of the immune response. Notably, the researchers found no significant difference in the response to the QFT-Plus TB antigens between patients with active tuberculosis and those with latent infection. The magnitude of interferon gamma release to the antigen tubes was similar in both disease states, reinforcing the established understanding that IGRAs are tests of infection rather than tests of disease activity. A positive result tells a clinician that the immune system has encountered tuberculosis; it cannot by itself distinguish a sleeping infection from an active one.

Perhaps the most biologically revealing part of the study concerns age. The researchers measured interferon gamma production in response to both the mitogen and the tuberculosis antigens and found that children younger than one year produced lower responses to both the mitogen and the TB-specific antigens than children in other age groups. The mitogen tube, which contains a potent nonspecific stimulant of T cells, serves as a positive control: it verifies that the patient’s blood cells are capable of mounting an interferon gamma response at all. A low mitogen response in infants points to genuine immunological immaturity rather than a technical failure. This observation aligns with a well-established body of immunology showing that the neonatal and infant immune system is skewed toward tolerogenic responses, with T cells that are less effector-like and interferon gamma signaling pathways that are not yet fully developed.

The correlation analysis added further nuance. The team found a significant positive correlation between age and interferon gamma responses to the mitogen, meaning that the nonspecific immune capacity measured in the tube grows steadily as children get older. In contrast, there was a significant negative correlation between age and interferon gamma responses to the TB1 and TB2 antigen tubes. This inverse pattern is intriguing: as children age, their general T-cell responsiveness increases while their antigen-specific response to tuberculosis peptides, at least as measured in this assay, tends to decline. One plausible interpretation is that recent infection in younger children drives stronger antigen-specific responses, whereas older children and young adults in the cohort may have had more remote or more contained infections with waning antigen-specific reactivity. Whatever the mechanism, the practical implication is that a single quantitative cutoff applied across a pediatric age range from infancy to young adulthood may not capture the biology of every patient equally well.

The study also flagged comorbidities as a source of diagnostic difficulty. Children with underlying conditions showed a higher rate of indeterminate results, meaning tests that could not be interpreted because the mitogen control failed or the background interferon gamma was elevated. Indeterminate results are a well-recognized limitation of all IGRAs in immunocompromised patients, including those with malnutrition, HIV infection, malignancy, or immunosuppressive therapy, all of which can blunt T-cell function. Combined with the suboptimal sensitivity observed in infants, the authors conclude that the assay’s performance is weakest precisely in the children who are at highest risk of severe tuberculosis, including those under one year old and those with comorbidities. In these groups, clinicians must treat a negative QuantiFERON-TB Gold Plus result with skepticism and rely on a broader diagnostic toolkit, including the tuberculin skin test, microbiological culture, molecular tests such as nucleic acid amplification, radiological imaging, and careful clinical judgment.

Context matters for interpreting why this Chinese cohort is important. China carries one of the world’s largest tuberculosis burdens, and BCG vaccination at birth is universal there, which complicates the traditional tuberculin skin test because vaccine-induced immune memory can produce false-positive skin reactions. IGRAs sidestep that problem, which is a major reason they have been adopted for contact investigation and latent infection screening. At the same time, pediatric tuberculosis in high-burden settings is notoriously paucibacillary, meaning that children harbor few bacteria, making microbiological confirmation difficult and forcing clinicians to lean heavily on immunological tests. Studies like this one, grounded in a large, well-characterized cohort of confirmed infections, provide the evidence base that national guidelines need when deciding how to position IGRAs relative to skin testing and other tools.

The study, conducted under the Declaration of Helsinki with ethics approval from Beijing Children’s Hospital and informed consent from participants or their guardians, was supported by the National Natural Science Foundation of China, the Beijing Natural Science Foundation, and other national and municipal funders. Its practical message is balanced rather than dramatic. QuantiFERON-TB Gold Plus earns its place as a useful diagnostic aid for both active tuberculosis and latent infection in children and young adults, with high tube-to-tube agreement and disease-state-independent antigen responses. But the numbers also counsel humility: with sensitivity below 85 percent overall, weaker performance in infancy, and elevated indeterminate rates in children with comorbidities, the assay functions best as one instrument in a diagnostic ensemble rather than a standalone verdict. For the youngest and sickest patients, a negative result must never close the door on a tuberculosis diagnosis that clinical suspicion has opened.

Subject of Research: Diagnostic performance of the QuantiFERON-TB Gold Plus interferon gamma release assay in children and young adults with tuberculosis infection

Article Title: Analysis of QuantiFERON-TB gold plus assay in children and young adults with Mycobacterium tuberculosis infection in China

Article References: Zheng, H., Yu, Y., Wang, Y., Guo, Y., Wang, Y., Li, F., Xiao, J., Qi, H., Jiao, W., Wang, X., Chen, Y., & Sun, L. (2026). Analysis of QuantiFERON-TB gold plus assay in children and young adults with Mycobacterium tuberculosis infection in China. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07717-2

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07717-2

Keywords: tuberculosis, QuantiFERON-TB Gold Plus, interferon gamma release assay, children, latent tuberculosis infection, active tuberculosis, Mycobacterium tuberculosis, pediatrics, diagnostics, China, IFN-gamma, TB1 and TB2 antigens