PICO SEARCH ASSIGNMENT WORKSHEET              

Brief description of patient problem/setting (summarize the case very briefly):

Patient is a 33 y/o male with no significant past medical history who presented for a job physical in the outpatient family-medicine setting. He recently emigrated from Nigeria and was asymptomatic at the time of evaluation. He denies cough, fever, night sweats, weight loss, hemoptysis, or known recent sick contacts. Routine screening for tuberculosis was performed as mandated in order for him to be cleared to begin working. At his follow-up visit it was revealed that he had a positive result on the interferon gamma assay and was advised to get a chest x-ray to help distinguish whether he had active or latent tuberculosis.

Search Question: Clearly state the question (including outcomes or criteria to be tracked) 

In adults undergoing screening for tuberculosis infection, does the interferon-gamma release assay have better predictive ability than the tuberculin skin test for identifying latent TB infection at risk for progression to active TB?

Question Type: What kind of question is this? (boxes now checkable in Word) 

☐Prevalence      X Screening                X Diagnosis

☐Prognosis                             ☐Treatment                ☐Harms 

Assuming that the highest level of evidence to answer your question will be meta-analysis or systematic review, what other types of study might you include if these are not available (or if there is a much more current study of another type)?  

Please explain your choices.  

If both meta-analyses & systematic reviews were not available to answer my question I would consider prospective cohort studies as my next option. The value in these studies lies in their ability to follow asymptomatic patients who are undergoing TB screening and compare how effective both methods of testing are in identifying patients who ultimately end up with active tuberculosis. These studies also provide the opportunity for researchers to assess the frequency at which each test leads to further workup such as chest x-rays and also identify trends. For example, they could potentially determine if one test is more reliable in certain populations that are high-risk such as recent immigrants from highly endemic regions.

In the event that prospective cohort studies are not available I could then potentially turn to retrospective cohort studies. For this PICO question, retrospective cohorts can be useful because they allow investigators to review existing records from employee health screenings, primary care clinics, or public health programs and provide a direct comparison between both methods of testing. Furthermore, these studies can be very useful in migrant population because they often undergo routine screening following their arrival.

PICO search terms:

P	I	C	O
Adults undergoing TB screening	Interferon-gamma release assay	Tuberculin skin test	Predictive value for progression to active TB
Adults with possible tuberculosis infection	IGRA	PPD	Risk of progression to active TB
Recent immigrants from TB-prevalent countries	QuantiFERON-TB Gold	Mantoux test	Detection of tuberculosis
Adults screened for tuberculosis infection	TB blood test	Purified protein derivative	Positive predictive value
Recent immigrants from TB endemic countries	T-cell based TB assay	Skin test for tuberculosis	Active tuberculosis
Tuberculosis screening		TST	Tuberculosis result

Search tools and strategy used:

I used 3 different databases to search for evidence relevant to my PICO question including CINAHL, MEDLINE, and Pubmed. I strategically developed my search terms around my PICO question and made sure they included the main elements of my question. For the population I tried to keep it focused and I noticed that I got the best search results when I ensured that the population included the word “screening”. It was also important to include “screening” since my patient was also being screened since he was asymptomatic. For the intervention & comparison there wasn’t much to contemplate in that regard as my question was centered around the two TB testing methods of IGRA & TST. Finally for the outcome I used a series of terms ranging from “positive predictive value” to “active tuberculosis”. Additionally, during the process of my research, I utilized filters and limiters such as systematic review and last 10 years, generally this was enough to get refined results. From there I looked at each abstract keenly and I tried to prioritize head to head studies. Overall, I was satisfied with my results and confident that I had enough to establish a clinical bottom line.

Database	Search Terms Used	Number of Results	Filters/Limiters Applied
CINAHL	Adults undergoing TB screening AND Interferon-gamma release assay OR Tuberculin skin test AND Detection of tuberculosis	25	Within last 10 years
MEDLINE	Adults screened for tuberculosis AND tuberculin skin test OR interferon-gamma release assay AND tuberculosis result	9	In the last 10 years, Systematic review
Pubmed	Tuberculosis screening AND IGRA OR TST AND active tuberculosis	29	Last 10 years, free full text, systematic review

Results found: 

1. Zhou, Guozhong, et al. “Interferon-γ Release Assays or Tuberculin Skin Test for Detection and Management of Latent Tuberculosis Infection: A Systematic Review and Meta-Analysis.” The Lancet Infectious Diseases, vol. 20, no. 12, July 2020, https://doi.org/10.1016/s1473-3099(20)30276-0.

1. Study Type: Systematic Review & Meta-analysis
2. Abstract:

1. Background: Use of an interferon-γ (IFN-γ) release assay or tuberculin skin test for detection and management of latent tuberculosis infection is controversial. For both types of tests, we assessed their predictive value for the progression of latent infection to active tuberculosis disease, the targeting value of preventive treatment, and the necessity of dual testing.
2. Methods: In this systematic review and meta-analysis, we searched PubMed, Embase, Web of Science, and the Cochrane Library, with no start date or language restrictions, on Oct 18, 2019, using the keywords (“latent tuberculosis” OR “latent tuberculosis infection” OR “LTBI”) AND (“interferon gamma release assays” OR “Interferon-gamma Release Test” OR “IGRA” OR “QuantiFERON®-TB in tube” OR “QFT” OR “T-SPOT.TB”) AND (“tuberculin skin test” OR “tuberculin test” OR “Mantoux test” OR “TST”). We included articles that used a cohort study design; included information that individuals with latent tuberculosis infection detected by IFN-γ release assay, tuberculin skin test, or both, progressed to active tuberculosis; reported information about treatment; and were limited to high-risk populations. We excluded studies that included patients with active or suspected tuberculosis at baseline, evaluated a non-commercial IFN-γ release assay, and had follow-up of less than 1 year. We extracted study details (study design, population investigated, tests used, follow-up period) and the number of individuals observed at baseline, who progressed to active tuberculosis, and who were treated. We then calculated the pooled risk ratio (RR) for disease progression, positive predictive value (PPV), and negative predictive value (NPV) of IFN-γ release assay versus tuberculin skin test.
3. Results: We identified 1823 potentially eligible studies after exclusion of duplicates, of which 256 were eligible for full-text screening. From this screening, 40 studies (50 592 individuals in 41 cohorts) were identified as eligible and included in our meta-analysis. Pooled RR for the rate of disease progression in untreated individuals who were positive by IFN-γ release assay versus those were negative was 9·35 (95% CI 6·48–13·49) compared with 4·24 (3·30–5·46) for tuberculin skin test. Pooled PPV for IFN-γ release assay was 4·5% (95% CI 3·3–5·8) compared with 2·3% (1·5–3·1) for tuberculin skin test. Pooled NPV for IFN-γ release assay was 99·7% (99·5–99·8) compared with 99·3% (99·0–99·5) for tuberculin skin test. Pooled RR for rates of disease progression in individuals positive by IFN-γ release assay who were untreated versus those who were treated was 3·09 (95% CI 2·08–4·60) compared with 1·11 (0·69–1·79) for the same populations who were positive by tuberculin skin test. Pooled proportion of disease progression for individuals who were positive by IFN-γ release assay and tuberculin skin test was 6·1 (95% CI 2·3–11·5). Pooled RR for rates of disease progression in individuals who were positive by IFN-γ release assay and tuberculin skin test who were untreated versus those who were treated was 7·84 (95% CI 4·44–13·83).
4. Conclusions: IFN-γ release assays have a better predictive ability than tuberculin skin tests. Individuals who are positive by IFN-γ release assay might benefit from preventive treatment, but those who are positive by tuberculin skin test probably will not. Dual testing might improve detection, but further confirmation is needed.
5. Key Points:

1. This is a systematic review and meta-analysis comparing interferon gamma release assays (IGRA’s) with the tuberculin skin test (TST) in both the detection and management of latent TB. The researchers analyzed and compiled information from across 40 studies consisting of 50,592 individuals amongst 41 cohorts. Many of the studies were prospective and retrospective cohort studies in high-risk populations.
2. Considering that there is currently no absolute gold standard test for latent tuberculosis infection the authors did not make an effort to assess the performance of the tests in terms of their sensitivity and specificity. The focus of the authors was to determine which test was better at identifying patients who were more likely to progress into active tuberculosis.
3. They found that IGRA in particular had a better predictive ability than TST. In untreated patients, a positive IGRA was more strongly linked to later progression to active TB as opposed to a positive TST. This suggests that IGRA may better identify clinically meaningful latent TB. The pooled risk ratio for IGRA was 9.35 and 4.24 for TST.
4. Similar findings were seen in terms of the pooled predictive values, for IGRA it was 4.5% and for TST it was 2.3%. In terms of negative predictive values, it was 99.7% for IGRA and 99.3% for TST.
5. The researchers did mention some limitations such as the fact that all the included studies were cohort studies, the fact that confounding could not be fully adjusted for and that some outcomes showed heterogeneity.

Why I chose this study:

• I chose this study because it was great match for my PICO question and it is high level evidence being a systematic review and meta-analysis. This study is also very helpful because it provides clinically meaningful data on which method is better for identifying latent TB with the potential for progression considering the lack of true gold standard test. The results also clearly showed that IGRA is a stronger method and thus supports its use as a potent screening test in asymptomatic adults undergoing TB screening. Another useful aspect of this study was that it examined high-risk populations such as other immigrants from countries with a high tuberculosis burden such as South Africa & China. This ultimately mirrored the presentation of my patient who was also an immigrant from an endemic country.

4. Link to study: 

https://www-sciencedirect-com.york.ezproxy.cuny.edu/science/article/pii/S1473309920302760?via%3Dihub

2. Campbell, Jonathon R, et al. “Absolute Risk of Tuberculosis among Untreated Populations with a Positive Tuberculin Skin Test or Interferon-Gamma Release Assay Result: Systematic Review and Meta-Analysis.” BMJ, 10 Mar. 2020, p. m549, https://doi.org/10.1136/bmj.m549. Accessed 12 Apr. 2020. 

1. Study type: Systematic Review & Meta-analysis
2. Abstract: 
3. Background: Only a few people with a positive test result for latent tuberculosis infection will progress to active disease.7 The risk for progression is affected by time since infection and integrity of the individual’s immune system, which might be compromised as a result of drugs, habits (intravenous drug use, smoking, and alcohol use), or underlying conditions such as HIV infection.2 Although populations with any of these characteristics (at risk populations) are generally prioritized for tuberculosis testing and treatment,2891011 the exact risks for progression are not well established.12 With changing global tuberculosis epidemiology, including the introduction of effective treatment for HIV, better living conditions, and longer life expectancies for immunocompromised people, updated quantification of these risks in the modern era are urgently needed.

Previous summary estimates of tuberculosis incidence in at risk populations have been benchmarked against the general population but have not compared populations on the basis of diagnostic test results for latent tuberculosis infection. The estimates are thus a composite risk of the probability that someone has or will acquire latent tuberculosis infection and the probability someone will progress to active disease.29 This conflates two different phenomena, which are influenced by different factors: risk of latent tuberculosis infection is determined by local epidemiology, transmission dynamics, and patient history,1314 whereas the risk of progression is determined by time since infection and immunocompetency.2 To help inform decision making by providers and patients,15 we conducted a systematic review and meta-analysis to determine the absolute risk of development of active tuberculosis among different populations of untreated people with a positive TST or IGRA result, or both.

2. Objective: To determine the annual rate of tuberculosis development after a positive tuberculin skin test (TST) or interferon-gamma release assay result (IGRA), or both, among untreated populations with characteristics believed to increase the risk of tuberculosis (at risk populations).
3. Methods: In this meta-analysis we followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) and meta-analyses of observational studies in epidemiology (MOOSE) guidelines.
4. Results:

122 of 5166 identified studies were included. In three general population studies, the incidence of tuberculosis among 33 811 participants with a TST induration of ≥10 mm was 0.3 (95% confidence interval 0.1 to 1.1) per 1000 person years. Among 116 197 positive test results for latent tuberculosis infection in 19 different at-risk populations, incidence rates were consistently higher than those in the general population. Among all types of tuberculosis contacts, the incidence of tuberculosis was 17.0 (95% confidence interval 12.9 to 22.4) per 1000 person years for participants with a positive IGRA result and 8.4 (5.6 to 12.6) per 1000 person years for participants with a positive TST result of ≥5 mm. Among people living with HIV, the incidence of tuberculosis was 16.9 (10.5 to 27.3) for participants with a positive IGRA result and 27.1 (15.0 to 49.0) for participants with a positive TST result of ≥5 mm. Rates were also high for immigrants, people with silicosis or requiring dialysis, transplant recipients, and prisoners. Incidence rate ratios among test positive versus test negative participants were significantly greater than 1.0 in almost all risk groups, for all tests.

5. Conclusion: The incidence of tuberculosis is substantial in numerous at-risk populations after a positive TST or IGRA result. The information from this review should help inform clinical decisions to test and treat for latent tuberculosis infection.
6. Key points: 

1. This study is a systematic review & meta-analysis that examined the absolute risk of developing active tuberculosis amongst individuals with a positive TST or IGRA result. 122 studies were included in this study, and it evaluated individuals across a broad range of at-risk populations.
2. As expected, the study found that having a positive TST or IGRA result was associated with substantially higher rates of future active TB compared to the general population or those who tested negative.
3. In tuberculosis contacts they found that the incidence of TB was about 17.0 per 1000 person-years after a positive IGRA result. Individuals that had a TST ≥5 mm had an incidence rate 8.4 per 1000 person-years. This essentially again suggests that IGRA positive individuals have a higher risk of progression to active disease.
4. When they examined immigrant or refugee populations it was found that both tests identified increased future risk of active TB. The difference lies in the fact that the incidence was 10.7 per 1000 person-years after a positive IGRA and 9.5 per 1000 person-years after a positive TST ≥5 mm.
5. The highest rates of progression to active disease after a positive test result was identified in TB contacts, people living with HIV, recent migrants, those on dialysis, those with silicosis, and prisoners.
6. Why I chose this study: 

• I chose this study not only for its relevancy to my question and high level of evidence, but also because many other sources just focus on whether or not the result is positive. This study provides important clinical context in the fact that it helps to clarify how much absolute risk of active TB there is following a positive TB test result. Essentially this helps to gain a better understanding of the actual magnitude of risk after a positive test result which is a lot more clinically applicable. The previous study that I selected also addressed my PICO question as I said but it was more focused on which test performed better than the other. Furthermore, like the last study this one includes key high-risk populations relevant to my patient such as recent immigrants and 

refugees.

5. Link to study: 

https://www.bmj.com/content/368/bmj.m549.long

3. Gao, Qing-Hua, et al. “Predictive Value of Interferon-Gamma Release Assays and Tuberculin Skin Test for Latent Tuberculosis Infection: A Systematic Review and Meta-Analysis of Head-To-Head Comparative Tests.” Journal of Microbiology, Immunology and Infection, 14 Nov. 2025, www.sciencedirect.com/science/article/pii/S1684118225001963?via%3Dihub, https://doi.org/10.1016/j.jmii.2025.11.003.

1. Study Type: Systematic review & Meta-analysis
2. Abstract:

1. Background: This study aimed to evaluate the ability of tuberculin skin test (TST) and interferon-gamma release assay (IGRA) to predict progression of latent tuberculosis (LTBI) to active tuberculosis.
2. Methods: We searched PubMed, Embase, Web of Science, and the Cochrane Library for cohort studies published until October 6, 2024, that used both IGRA and TST to detect LTBI and reported data on active TB development. We assessed the predictive value of IGRA and TST for disease progression by calculating the risk ratio (RR), which compares the progression rates between positive and negative individuals for each test.
3. Results: Out of 2650 potentially eligible studies, 260 were reviewed in full text, and 44 studies with 25637 individuals were included. The pooled RR for disease progression was higher with IGRA than with TST (5.38 [95 % CI: 3.44–8.40] vs. 3.03 [95 % CI: 1.20–4.10]), although this difference did not reach statistical significance (p = 0.0713). PPV with IGRA vs TST: 2.50 % [95 % CI: 1.20 %–4.10 %] vs 1.30 % [95 % CI: 0.60 %–2.40 %] (p = 0.4852). NPV with IGRA vs TST: 99.70 % [95 % CI: 99.40 %–99.90 %] vs 99.60 % [95 % CI: 99.30 %–99.90 %] (p = 0.9630). Furthermore, the PPV of IGRA was similar to the progression rate of IGRA+/TST+ (2.00 % [95 % CI: 0.05 %–4.40 %] vs. 2.50 % [95 % CI: 0.40 %–6.10 %]). Finally, while IGRA identified fewer positive individuals (23.90 % [95 % CI: 18.50 %–29.80 %] vs. 52.20 % [95 % CI: 34.30 %–69.80 %]), the number of positive individuals progressing was similar (265 vs. 268), with similar results also observed in the untreated population.
4. Conclusions & Relevance: IGRA appears to have superior predictive value for TB progression compared to TST. Additionally, incorporating TST alongside IGRA does not seem to significantly enhance predictive accuracy. IGRA effectively reduces the number of individuals requiring treatment while seemingly not missing those at risk of progression.
5. Keywords: Latent tuberculosis infection, Interferon-gamma release assay, Tuberculin skin test, Head-to-head comparison
6. Key Points:

1. This study like the others examined whether IGRA’s or TST’s better predict progression from latent tuberculosis infection to active tuberculosis. It was comprised of 44 studies with 25,637 individuals who underwent IGRA and TST testing.
2. The overserved positive predictive value for IGRA was higher than for TST (2.50% vs. 1.30%). Interestingly, the negative predictive value was quite similar between the two tests (99.7% vs. 99.6%). This basically suggests that IGRA has greater potential for its use in identifying higher-risk patients, but they don’t differ as much in ruling out progression.
3. Interestingly, IGRA actually identified less people as positive compared to TST. However, the data shows that the number of individuals that later went on to progress to active TB was nearly the same. For IGRA 265 progressed to active TB and for TST 268 progressed to active TB.
4. Based on their findings they also concluded that dual testing doesn’t add much value as compared to solely testing with IGRA. Overall, it was also found that the difference between IGRA and TST in pooled risk ratio did not reach statistical significance suggesting some caution should be applied when interpreting the results.
5. Why I chose this study:

• I found this study because it brought some new perspectives to the discussion, it essentially found that IGRA is more specific and more targeted compared to TST. This is based on the fact that IGRA identified far fewer people as positive while still producing similar numbers in terms of which individual went on to develop active TB. As a result, less individuals are unnecessarily labeled as having latent TB but still ensuring those truly at risk are identified. I also appreciated the mention of the cost-effectiveness as it relates to IGRA’s ability to provider higher specificity and positive predictive value compared to TST. This is especially important for most newly emigrating individuals. The work from these researchers also identified that dual testing doesn’t improve predictive ability which further supports the use of a single method with IGRA seemingly being the best choice available.

5. Link to study: https://pubmed.ncbi.nlm.nih.gov/41266157/

What is the clinical “bottom line” derived from these articles in answer to your question? 

Based on the overall findings from these articles, IGRA is backed by evidence as the more clinically useful test when compared to TST. This clinical benefit is most pronounced when assessing the likelihood of latent tuberculosis progressing to active tuberculosis. The 2020 study conducted by Zhou et al. concluded that IGRA (9.35) had a substantially higher pooled risk ratio for progression to active TB when compared to TST (4.24). Furthermore, they concluded that a positive IGRA result seemed to do a better job of identifying the people who benefit the most from treatment for latent TB. They found that in the IGRA-positive group those who were untreated had about 3 times the risk of progressing to active TB whereas TST positive only had about 1.1 times the risk. Essentially what this all tells us is that IGRA seems to be superior at identifying patients with clinically meaningful latent TB. The second study by Campbell et al. further proves IGRA’s superiority by showing the absolute risk after identifying a positive result in these high-risk populations. Those that had TB contact and a positive IGRA were found to have higher progression rates with at 17.0 vs. 8.4 per 1000 person-years which was seen in TST positive individuals. Individuals who were recent immigrants weren’t found to have as big of a difference in progression rates however but overall, the evidence again demonstrates IGRA’s superiority. Finally, the study by Gao et al. added an important consideration in the fact that while IGRA does identify less people as positive compared to TST, it still identifies an equal amount of people who progress to active TB as TST (265 vs 268). Considering all of these findings the clinical bottom line is that IGRA is preferable to TST when the priority is predicting progression from latent to active TB. As a result, its use is associated with more efficient and targeted preventive treatment. TST still does have a role to play in scenarios such as when cost or access limits the use of IGRA but overall, it is less precise in its detection and surveillance.