Chapter 4: Diagnosis of tuberculosis infection

Figures & data

Table 1. Interpretation of TST results and cutoff thresholds in various populations. ⁷

TST Result	Situation in which reaction is considered positive
<5 mm	In general, this is considered negative
≥5 mm	People living with HIV
	Known recent (<2 years) contact with a patient with infectious TB disease
	Fibronodular disease on chest x-ray (evidence of healed, untreated TB)
	Prior to organ transplantation and receipt of immunosuppressive therapy
	Prior to receipt of biologic drugs, such as tumor necrosis factor alpha inhibitors, or disease-modifying antirheumatic drugs
	Prior to receipt of other immunosuppressive drugs, such as corticosteroids (equivalent of ≥15 mg per day of prednisone for at least one month)
	Stage 4 or 5 chronic kidney disease (with or without dialysis)
≥10 mm	Recent (<2 years) conversion of TST from negative to positive
	Diabetes (controlled or uncontrolled)
	Malnutrition (<90% of ideal body weight)
	Current tobacco smoker (any amount)
	Daily consumption of >3 alcoholic drinks
	Silicosis
	Hematologic malignancies (lymphomas and leukemia) and certain carcinomas (such as cancers of head, neck, lung and/or gastrointestinal tract)
	Any population considered at low risk of disease.

Abbreviations: TST, tuberculin skin test; HIV, human immunodeficiency virus; TB, tuberculosis.

Figure 1. BCG World Atlas.

Table 2. Risk of TB disease and the incidence rate ratio of TB disease among different populations stratified by risk.

Risk factor	Annual risk of TB disease for the first 2-3 years after testing positive (%) ^a	Reference
VERY HIGH RISK
People living with HIV	1.7 to 2.7	^2 ^, ^56
Child or adolescent (<18 y) tuberculosis contact	2.9 to 14.6	^56 ^, ^57
Adult (≥18 y) tuberculosis contact	0.8 to 3.7	^2 ^, ^56
Silicosis	3.7	^2
HIGH RISK
Stage 4 or 5 chronic kidney disease with or without dialysis	0.3 to 1.2	^2
Transplant recipients (solid organ or hematopoietic)	0.1 to 0.7	^2
Fibronodular disease	0.2 to 0.6	Extrapolated from: ^75–77
Receiving immunosuppressing drugs (eg, tumor necrosis factor α inhibitors or steroids)^b	0.5	^2
Cancer (lung, sarcoma, leukemia, lymphoma or gastrointestinal)	0.1 to 0.4	Extrapolated from: ^70
MODERATE RISK
Granuloma on chest x-ray	0.1	Extrapolated from: ^77 ^, ^78
Diabetes	0.1 to 0.2	Extrapolated from: ^83
Heavy alcohol use (at least 3 drinks/day)	0.1 to 0.2	Extrapolated from: ^79
Heavy tobacco cigarette smoker (at least 1 pack/day)	0.1	Extrapolated from: ^80–82
LOW RISK
General (adult) population with no known risk factor	0.03	^2
Persons with a positive two-step TST booster and no known risk factor	0.02	Extrapolated from: ^84 ^, ^85

Abbreviations: TB, tuberculosis; HIV, human immunodeficiency virus; TST, tuberculin skin test.

^aRisks are expected to halve after this period and continue to decrease subsequently.

^bRisk does not appear significantly elevated with low-dose steroids (i.e., prednisone), but elevated with moderate or high dose (low dose, ≤9 mg/day; medium dose, 10–19 mg/day; and high dose, ≥20 mg/day). ⁸⁶

Figure 2. Online tools that can support decision-making with respect to TST and IGRA interpretation and offering of TPT: The Online TST/IGRA Interpreter, Version 3.0 (A) and PERISKOPE TB (B). Abbreviations: TST, tuberculin skin test; IGRA, interferon-gamma release assay; TPT, tuberculosis preventive treatment.

Figure A1. Technique of TST administration.

Figure A2. Ballpoint pen method for measuring the transverse diameter of the TST induration.

Table A1. Causes of variation with TST or IGRA. ^{88–90 , 92 , 115}

Common Causes of Variation	Causes of IGRA Variation	Causes of TST Variation
Pre-analytical errors. For the TST, this includes possible issues with the PPD solution and administration (e.g., volume injected), while for IGRA these may include improper shaking of the tube after collection, delays in transport and/or incubation of samples, or errors in the actual time the sample is incubated. Within-person variations over time. For the TST, responses may vary by up 5 mm in reaction size between tests. For the IGRA, a previous systematic review suggested there was a mean difference in two consecutive samples of 0.2 IU/mL between two QFT tests; similar data for T-SPOT.TB was not reported. Analytical errors. For the TST, a mis-recording of TST measurements may lead to an incorrect conclusion of a change in induration on a second test. For the IGRA, if not recorded automatically, data-entry errors on quantitative values and interpretation may occur.	Test-retest variation. While agreement is generally quite good when the same sample is tested in the same lab twice, there may be variation in the spots counted or IU/ml measured from the same sample. Inter-laboratory variation. There may be different measurements when the same sample is tested in different labs. TST-induced variation. A previous TST may “boost” a subsequent IGRA result. Conversions in a systematic review were uncommon but did occur with both T-SPOT.TB and QFT. Whether the risk of disease among persons with a boosted response is different than risk among those without a boosted response is unclear.	Variability associated with the reader (eg, two different readers may measure the same induration differently).

Reichman LB. Hershfield ES. Reichman and Hershfield’s Tuberculosis: A Comprehensive, International Approach. 1400. New York: Informa Healthcare USA; 2006.

 Google Scholar

Campbell JR, Winters N, Menzies D. 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. 2020;368:m549. doi:10.1136/bmj.m549.

 PubMedGoogle Scholar

Gupta RK, Calderwood CJ, Yavlinsky A, et al. Discovery and validation of a personalized risk predictor for incident tuberculosis in low transmission settings. Nat Med. 2020;26(12):1941–1949. doi:10.1038/s41591-020-1076-0.

 PubMed Web of Science ®Google Scholar

Martinez L, Cords O, Horsburgh CR, et al. The Risk of Tuberculosis in Children After Close Exposure: An Individual-Participant Meta-analysis Including 137,647 Children from 46 Cohort Studies. Lancet (London, England). 2020;395(10228):973–984. doi:10.1016/S0140-6736(20)30166-5.

 PubMed Web of Science ®Google Scholar

Kumar DS, Ronald LA, Romanowski K, et al. Risk of active tuberculosis in migrants diagnosed with cancer: a retrospective cohort study in British Columbia, Canada. BMJ Open. 2021;11(3):e037827 doi:10.1136/bmjopen-2020-037827.

 PubMed Web of Science ®Google Scholar

Grzybowski S, Fishaut H, Rowe J, Brown A. Tuberculosis among patients with various radiologic abnormalities, followed by the chest clinic service. Am Rev Respir Dis. 1971;104(4):605–608. doi:10.1164/arrd.1971.104.4.605.

 PubMedGoogle Scholar

Horwitz O, Wilbek E, Erickson PA. Epidemiological basis of tuberculosis eradication. 10. Longitudinal studies on the risk of tuberculosis in the general population of a low-prevalence area. Bull World Health Organ. 1969;41(1):95–113.

 PubMed Web of Science ®Google Scholar

Jeon CY, Murray MB. Diabetes Mellitus Increases the Risk of Active Tuberculosis: A Systematic Review of 13 Observational Studies. PLoS Med. 2008;5(7):e152. doi:10.1371/journal.pmed.0050152.

 PubMed Web of Science ®Google Scholar

Lönnroth K, Williams BG, Stadlin S, Jaramillo E, Dye C. Alcohol use as a risk factor for tuberculosis - a systematic review. BMC Public Health. 2008;8(1):289 doi:10.1186/1471-2458-8-289.

 PubMedGoogle Scholar

Comstock GW, Edwards LB, Livesay VT. Tuberculosis morbidity in the U.S. Navy: its distribution and decline. Am Rev Respir Dis. 1974;110(5):572–580. doi:10.1164/arrd.1974.110.5.572.

 Google Scholar

Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis. A general review. Bibl Tuberc. 1970;26:28–106.

 PubMedGoogle Scholar

Brode SK, Jamieson FB, Ng R, et al. Increased risk of mycobacterial infections associated with anti-rheumatic medications. Thorax. 2015;70(7):677–682. doi:10.1136/thoraxjnl-2014-206470.

 PubMed Web of Science ®Google Scholar

Metcalfe JZ, Cattamanchi A, McCulloch CE, Lew JD, Ha NP, Graviss EA. Test variability of the QuantiFERON-TB gold in-tube assay in clinical practice. Am J Respir Crit Care Med. 2013;187(2):206–211. doi:10.1164/rccm.201203-0430OC.

 PubMed Web of Science ®Google Scholar

Rose W, Kitai I, Kakkar F, Read SE, Behr MA, Bitnun A. Quantiferon Gold-in-tube assay for TB screening in HIV infected children: influence of quantitative values. BMC Infect Dis. 2014;14:516. doi:10.1186/1471-2334-14-516.

 PubMed Web of Science ®Google Scholar