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Mantoux test

The Mantoux test, also known as the tuberculin skin test (TST), is a diagnostic tool used to detect latent infection with Mycobacterium tuberculosis. It involves intradermal injection of purified protein derivative (PPD) tuberculin into the forearm, which elicits a delayed-type hypersensitivity reaction measured as induration at the site 48 to 72 hours later.^[1] The test is valuable for screening high-risk populations, including healthcare workers, immigrants from TB-endemic areas, and close contacts of active TB cases.^[2] Developed by French physician Charles Mantoux in 1907 based on Robert Koch's 1890 discovery of tuberculin, the test has become a standard for TB infection detection worldwide.^[2] Although simple and cost-effective, especially in resource-limited settings, it can yield false positives due to prior BCG vaccination or nontuberculous mycobacteria exposure, and false negatives in immunocompromised individuals.^[1] Interferon-gamma release assays (IGRAs) provide alternatives with greater specificity in certain populations, but the Mantoux test remains widely endorsed by the CDC and WHO for TB screening and control.^[1]^[3]

Background and History

Development and Invention

The Mantoux test was invented in 1908 by Charles Mantoux, a French physician, who developed an intradermal injection technique for administering tuberculin to assess tuberculosis exposure. This method built upon Robert Koch's 1890 discovery of tuberculin, a glycerin extract of heat-killed Mycobacterium tuberculosis cultures originally intended as a therapeutic agent but repurposed for diagnostic purposes after its diagnostic potential was recognized.^[4]^[5] Mantoux's innovation involved using a syringe to inject a small amount of tuberculin into the dermis of the forearm, eliciting a delayed-type hypersensitivity reaction in individuals previously sensitized to the pathogen's antigens. Initially employing "old tuberculin"—a crude preparation—the test aimed to detect immune responses indicative of prior infection with M. tuberculosis, rather than confirming active disease. This approach marked a shift from earlier cutaneous scarification methods, offering greater precision and reproducibility in identifying sensitized individuals.^[6]^[7] In the 1910s, early clinical evaluations, including Mantoux's own presentations, demonstrated the test's utility in distinguishing latent tuberculosis infection—where bacteria persist without causing symptoms—from overt illness, laying the groundwork for its use in epidemiological surveys. These trials highlighted the reaction's specificity for prior exposure, though variability in tuberculin potency posed challenges that were later addressed through refinements.^[8] Following World War I, amid heightened tuberculosis prevalence in war-ravaged Europe and the United States due to malnutrition, overcrowding, and population movements, the Mantoux test gained traction for mass screening programs in high-risk communities, such as military recruits and schoolchildren, to identify and isolate potential sources of infection. This period underscored its role in public health efforts to curb TB transmission in endemic areas. The test's evolution into standardized protocols followed in subsequent decades.^[9]^[10]

Standardization and Global Adoption

In the 1930s and 1940s, efforts to standardize the Mantoux test focused on replacing crude old tuberculin with purified protein derivative (PPD), developed by biochemist Florence B. Seibert to ensure greater consistency and reduced variability in test reactions.^[11] A key advancement came in 1941 when Seibert and her colleague Jessie T. Glenn produced a large batch of standardized PPD (designated PPD-S), which became the reference material for tuberculin potency in the United States.^[12] This formulation used a dose of 5 tuberculin units (TU) in 0.1 ml of solution, established as the standard for intradermal injection to elicit reliable delayed-type hypersensitivity responses.^[13] Following World War II, the test saw expanded adoption through public health initiatives, particularly in the United States, where the Public Health Service implemented widespread TB screening programs targeting schools, workplaces, and high-risk populations using the Mantoux method alongside chest radiography.^[14] These efforts contributed to a significant decline in TB incidence during the 1950s, as early detection of latent infections allowed for preventive treatment and isolation of active cases.^[15] Further refinements in the 1950s centered on PPD production, with PPD-S officially adopted as the international standard by the World Health Organization (WHO) in 1952, enabling more uniform manufacturing and calibration across suppliers to minimize batch-to-batch variability.^[16] By the 1970s, WHO guidelines emphasized the Mantoux test's utility in low-resource settings, recommending its integration into national TB control programs for contact tracing and routine screening in endemic areas.^[12] By the 1980s, the Mantoux test had become a cornerstone of global TB surveillance, routinely employed in over 100 countries for detecting latent tuberculosis infection, particularly in high-burden regions of Asia and Africa. This widespread implementation was associated with measurable reductions in TB incidence, as screening and isoniazid preventive therapy for positive reactors interrupted transmission chains and averted progression to active disease.^[17]

Procedure

Administration of the Test

The administration of the Mantoux test begins with patient preparation, which includes assessing for potential contraindications such as a history of severe reaction to the test (e.g., necrosis or ulceration) or recent administration of a live attenuated virus vaccine, in which case testing should be delayed for at least one month to avoid interference with results. The test should not be administered to individuals who have had a documented positive reaction to a previous TST or who have been treated for latent TB infection or TB disease.^[1]^[18] The appropriate dose of purified protein derivative (PPD) tuberculin is 5 tuberculin units (TU) of PPD-S in 0.1 mL (or the equivalent 2 TU of PPD RT23 in 0.1 mL where used), for all individuals regardless of age, using a standardized PPD such as PPD-S or equivalent.^[13]^[19] The test must be performed by a trained healthcare worker following standardized protocols to ensure accuracy.^[20] The preferred injection site is the volar aspect (inner surface) of the forearm, approximately 2-4 inches below the elbow joint, with the arm palm-up; select an area free of hair, scars, sores, or visible veins to minimize discomfort and ensure proper absorption.^[13] Clean the site with an alcohol swab and allow it to dry. Use a single-dose 1 mL tuberculin syringe fitted with a short-bevel 27-gauge needle (1/4 to 1/2 inch long). Draw up exactly 0.1 mL of the PPD solution, ensuring no air bubbles, and inject intradermally at a 5-15° angle with the bevel facing up, advancing the needle just under the skin surface. Administer the solution slowly over 3-5 seconds to form a pale, tense wheal of 6-10 mm in diameter; if the wheal is smaller than 6 mm, repeat the injection at a site at least 2 inches away without re-disinfecting the skin.^[13]^[18]^[19] Following injection, provide post-injection care instructions to the patient, advising them to avoid scratching, rubbing, or applying any substances to the site to prevent irritation or infection.^[13] Schedule the reading appointment for 48-72 hours after administration, as readings outside this window may require rescheduling the test.^[13]

Reading and Measurement

The Mantoux tuberculin skin test reaction is read between 48 and 72 hours after intradermal administration to capture the peak induration response.^[21] Readings performed earlier than 48 hours may underestimate the reaction, while those after 72 hours can yield inaccurate results, often necessitating a repeat test within 7 days.^[22] Only trained health care providers should perform the reading to ensure consistency and reliability.^[1] To assess the reaction, the provider first palpates the injection site on the volar surface of the forearm to identify the indurated area, which presents as a firm, dense, raised swelling distinct from surrounding normal skin texture.^[23] Induration, rather than erythema (redness) or ecchymosis (bruising), is the sole parameter measured, as it specifically indicates the delayed-type hypersensitivity response to tuberculin.^[1] The transverse diameter of the induration is then determined at its widest point, perpendicular to the long axis of the forearm.^[23] A ballpoint pen is used to delineate the edges by gently sliding the pen tip across the skin at a 45- to 90-degree angle until it encounters resistance at the induration border, followed by measurement using a millimeter ruler or flexi-ruler placed directly on the marked area.^[19] The size is recorded precisely in millimeters, even if no induration is palpable (recorded as 0 mm).^[22] Common errors in measurement include assessing erythema or blistering instead of true induration, which can inflate the recorded size and lead to misinterpretation.^[21] Additionally, improper timing outside the 48- to 72-hour window or failure to measure transversely (e.g., along the forearm's length) may compromise accuracy.^[1] To mitigate these, readers should inspect and palpate systematically, avoiding pressure that could alter the site's appearance.^[22] Documentation of the measurement involves recording the induration size in millimeters on standardized health care forms, along with the reading date, time, and provider's initials for traceability.^[22] In educational or quality assurance contexts, photographs of the site may be taken post-measurement to support training, though this is not standard for routine clinical use.^[23]

Interpretation of Results

Classification of Tuberculin Reactions

The Mantoux test elicits a type IV delayed-type hypersensitivity reaction, which is a cell-mediated immune response primarily involving T-lymphocytes sensitized to purified protein derivative (PPD) antigens derived from Mycobacterium tuberculosis.^[22] Upon intradermal injection of PPD, memory T-cells recognize the antigens, leading to the recruitment of macrophages and other inflammatory cells at the site, resulting in localized induration that peaks at 48 to 72 hours.^[1] This reaction indicates prior sensitization to mycobacterial antigens but does not differentiate between latent infection, active disease, or exposure to non-tuberculous mycobacteria.^[22] Tuberculin reactions are broadly classified based on the presence and extent of induration, a palpable, hardened area of skin swelling distinct from surrounding erythema. A negative reaction typically shows no induration or less than 5 mm of induration, reflecting absence of hypersensitivity to PPD.^[1] A positive reaction involves measurable induration of 5 mm or greater, signifying immune sensitization, though the clinical significance depends on contextual factors.^[22] In rare cases of intense hypersensitivity, reactions may progress to vesiculation (blistering) or ulceration, occurring in approximately 1-2% of positive tests and usually resolving without intervention.^[24] Historically, tuberculin reactions were graded on a semi-quantitative scale from 1+ to 4+ to describe increasing severity: 1+ for mild induration (e.g., 5-9 mm), 2+ for moderate induration (e.g., 10-14 mm), 3+ for strong induration (e.g., ≥15 mm), and 4+ for severe responses involving necrosis or tissue breakdown.^[25] However, contemporary practice emphasizes precise measurement of induration diameter in millimeters using a ruler or caliper, as this provides a more objective and standardized assessment over subjective grading.^[22] The strength of the reaction is influenced by the administered dose of PPD, typically standardized at 5 tuberculin units (0.1 mL of solution), which ensures reproducibility but can vary in potency across preparations.^[18] Individual immune status also plays a key role, with robust cell-mediated immunity amplifying the response, while subtle variations in T-cell function can modulate induration size even among sensitized individuals.^[26]

Risk-Based Cutoff Guidelines

The interpretation of the Mantoux tuberculin skin test (TST) relies on risk-based cutoff values for induration diameter, which determine whether a reaction is classified as positive for latent tuberculosis infection (LTBI). According to the Centers for Disease Control and Prevention (CDC) guidelines, a reaction of ≥5 mm is considered positive in high-risk individuals, including those with HIV infection, recent close contacts of persons with infectious tuberculosis (TB), patients with chest radiographs consistent with prior untreated TB, organ transplant recipients, and individuals on immunosuppressive therapy such as corticosteroids (≥15 mg/day of prednisone) or tumor necrosis factor-alpha (TNF-α) antagonists.^[1] A ≥10 mm induration indicates positivity in medium-risk groups, such as persons born in or from high TB-prevalence countries, injection drug users, residents and employees of high-risk congregate settings (e.g., correctional facilities, homeless shelters, nursing homes), mycobacteriology laboratory personnel, children younger than 5 years, and those with medical conditions that increase the risk of progression to TB disease (e.g., diabetes mellitus, chronic renal failure, silicosis, or body weight <90% of ideal).^[1] For low-risk individuals with no known risk factors for TB, a ≥15 mm induration is required for a positive result.^[1] The World Health Organization (WHO) recommends a risk-based approach to TST interpretation and emphasizes interferon-gamma release assays (IGRAs) over TST in settings with high BCG vaccination coverage to improve specificity. In special populations, such as infants and young children, cutoffs are adjusted for age-related immune responses; for example, children under 5 years use the ≥10 mm threshold due to higher progression risk from LTBI to active disease, while newborns may require alternative diagnostics if TST is inconclusive.^[1] Recent converters—individuals with a new positive TST within 2 years—often necessitate two-step testing to distinguish true infection from a boosted response due to prior exposure, with the second test confirming an increase of ≥10 mm over baseline.^[1] These risk-based criteria are derived from epidemiological studies evaluating the TST's diagnostic performance, which demonstrate a sensitivity of 80-90% for detecting active TB but lower rates (60-81%) for LTBI across various induration thresholds, with specificity exceeding 95% in low-prevalence populations without BCG vaccination.^[27] Recommendations include confirmatory IGRA testing in BCG-vaccinated individuals to mitigate false positives from cross-reactivity, particularly in high-risk groups where TST specificity drops to 50-70%.^[1]

Limitations and Sources of Error

Causes of False Positive Results

False-positive results in the Mantoux test, also known as the tuberculin skin test (TST), occur when individuals exhibit a positive reaction without active or latent infection by Mycobacterium tuberculosis. These reactions are primarily due to cross-reactivity with antigens shared between M. tuberculosis and other mycobacteria. Prior vaccination with the bacille Calmette-Guérin (BCG) vaccine, derived from Mycobacterium bovis, introduces such cross-reactive antigens, leading to positive TST responses that can persist for years, particularly if the vaccination occurred in infancy or later.^[1] Similarly, environmental exposure to nontuberculous mycobacteria (NTM), such as Mycobacterium avium complex, can sensitize the immune system to tuberculin purified protein derivative (PPD), causing cross-reactivity and false-positive indurations.^[28] NTM-related false positives can occur but are often less widespread than BCG effects globally; however, they may be more prominent in high NTM prevalence regions like subtropical areas.^[29]^[30] In populations from low-tuberculosis-burden countries where BCG vaccination is routine, false-positive TST rates can be substantial, with positivity rates often exceeding 40% in some BCG-vaccinated groups without TB infection, particularly when using a 10 mm induration cutoff, as the vaccine's influence wanes over time but remains detectable in a substantial minority.^[31] This overestimation of infection prevalence complicates public health screening, prompting higher rates of unnecessary follow-up evaluations. Other contributors to false positives include hypersensitivity reactions to components of the PPD solution, such as preservatives or the tuberculin itself, which may induce localized skin responses mimicking infection-related induration, though these are rare and typically present as atypical or exaggerated reactions.^[18] Recent viral infections, including those from live-virus vaccines like measles or varicella, have been associated with altered immune responses that occasionally boost TST reactivity through non-specific sensitization, though evidence is limited and primarily anecdotal.^[32] To mitigate false positives in ambiguous cases, especially among BCG-vaccinated or NTM-exposed individuals, interferon-gamma release assays (IGRAs) such as QuantiFERON-TB Gold are recommended for confirmatory testing, as they target M. tuberculosis-specific antigens and avoid cross-reactivity with BCG or most NTM.^[33] Guidelines from health authorities emphasize using IGRAs in low-prevalence settings to improve specificity and reduce overtreatment.^[34]

Causes of False Negative Results

False-negative results in the Mantoux test occur when individuals with active or latent tuberculosis (TB) infection do not exhibit the expected delayed-type hypersensitivity reaction to purified protein derivative (PPD). This can lead to missed diagnoses, particularly in high-risk populations, and underscores the test's limitations in sensitivity.^[21] One primary cause is immune suppression, which impairs the T-cell mediated response necessary for a positive reaction, resulting in cutaneous anergy (reduced or absent skin test reactivity). Conditions such as HIV infection significantly increase false-negative rates; for instance, up to 60% of persons with TB and AIDS may show false-negative results due to CD4+ T-cell depletion in untreated or advanced cases (pre-ART era data), though sensitivity improves to ~70% or higher with effective antiretroviral therapy (ART).^[35]^[36] Similarly, immunosuppressive therapies like high-dose corticosteroids (>15 mg prednisone equivalent daily) can suppress delayed hypersensitivity, leading to false negatives in patients with rheumatic diseases or other conditions requiring such treatment.^[37] Malnutrition, particularly protein-calorie deficiency, also contributes by weakening immune function; severe undernutrition in children is associated with reduced TST positivity (e.g., 30% vs. 54% in well-nourished contacts), contributing to false negatives particularly in vulnerable groups, though rates are higher in immunocompromised individuals.^[1]^[38] In HIV patients on effective ART, TST sensitivity improves significantly, reducing false negatives compared to untreated cases.^[39] Another key factor is recent TB infection, during which the immune system has not yet developed sufficient sensitization to PPD. This "window period" typically lasts 2 to 8 weeks after initial exposure, though it can extend to 10 weeks in some cases, delaying detectable reactivity.^[40]^[26] Technical errors in test administration or materials can further contribute to false negatives. Improper intradermal injection, such as subcutaneous placement instead of the required 6-10 mm bleb formation, fails to deliver PPD effectively into the dermis where immune cells reside.^[22] Use of expired or degraded PPD, due to improper storage (e.g., exposure to heat or light), reduces antigen potency and reactivity.^[41] Additionally, incorrect reading—such as measuring induration too early (before 48-72 hours) or misinterpreting the reaction—can erroneously classify a true positive as negative.^[21] In cases of suspected anergy from immune suppression, follow-up with anergy testing using control antigens may be considered to assess overall delayed hypersensitivity, though this is addressed in specialized protocols.^[21]

Influence of BCG Vaccination

The Bacille Calmette-Guérin (BCG) vaccine, derived from an attenuated strain of Mycobacterium bovis, induces cell-mediated hypersensitivity that cross-reacts with the purified protein derivative (PPD) antigens in the Mantoux test, as these antigens are shared with Mycobacterium tuberculosis. This cross-reactivity commonly results in false-positive reactions among vaccinated individuals without active or latent TB infection.^[1]^[42] The duration of BCG-induced TST reactivity typically persists for 5 to 15 years following vaccination, with the effect generally waning over time due to declining immune memory. However, reactivity can last longer than 15 years in some cases, particularly when vaccination occurs after infancy or if repeated TSTs cause a booster phenomenon that amplifies the response.^[43]^[44] Different BCG strains vary in their potential to interfere with TST results, with the Danish and Japanese strains generally eliciting stronger PPD-specific responses and larger indurations compared to the Russian strain. This strain-dependent reactivity tends to diminish progressively with time since vaccination and can be further modulated by booster effects from prior testing.^[45]^[46] World Health Organization guidelines advise cautious interpretation of TST indurations ≥10 mm in individuals with a history of BCG vaccination, recommending interferon-gamma release assays (IGRAs) as the preferred diagnostic tool for detecting latent TB infection in vaccinated adults to minimize false positives.^[47] Historical studies from the 1950s and 1970s, including large-scale trials evaluating BCG efficacy, reported positivity rates of 40-70% on the Mantoux test among vaccinated children confirmed free of TB infection, underscoring the vaccine's substantial impact on test specificity during that era.^[48]

Special Testing Protocols

Anergy Testing

Anergy, or cutaneous anergy, is defined as the absence of a delayed-type hypersensitivity (DTH) response to intradermal antigens due to impaired cell-mediated immunity, often seen in conditions like HIV infection or immunosuppression.^[49] This state can result in false-negative tuberculin skin test (TST) results, masking latent tuberculosis infection (LTBI) despite underlying risk.^[50] The procedure for anergy testing involves administering control antigens, such as candida, mumps, or tetanus toxoid, via the Mantoux method alongside the standard TST.^[49] Each antigen is injected intradermally (0.1 ml) on the forearm, typically at separate sites from the tuberculin injection, and reactions are read 48-72 hours later by measuring induration.^[50] Anergy is indicated if there is no induration (≥5 mm) to at least two of these antigens, suggesting global impairment of DTH and warranting consideration of LTBI treatment in high-risk individuals despite a negative TST.^[49] Historically, anergy testing was recommended as a routine adjunct to TST in the 1990s for populations at high risk of immunosuppression, such as HIV-infected persons or those on corticosteroids, to identify those who might benefit from preventive therapy.^[50] Guidelines from that era, including those from the CDC, advised concurrent testing to avoid over-reliance on isolated negative TST results in such groups.^[49] However, by 2000, the CDC's targeted testing guidelines explicitly discouraged routine anergy testing due to its low specificity, variability in antigen preparations, and poor predictive value for identifying true LTBI or progression to active disease.^[51] Current practices (as of 2025) limit its use, with interferon-gamma release assays (IGRA) preferred in many settings for their higher specificity in immunocompromised patients and lack of need for DTH assessment.^[1] In immunosuppressed individuals, anergy contributes to false-negative TST results by blunting the immune response to tuberculin.^[51]

Two-Step Mantoux Testing

The two-step Mantoux testing protocol is employed to establish an accurate baseline tuberculin skin test (TST) reaction in individuals at risk for serial screening, such as healthcare workers, prison staff, and elderly residents in long-term care facilities. Its main purpose is to identify "boosted" immune responses from remote or subclinical prior exposure to Mycobacterium tuberculosis, which could otherwise be misinterpreted as new infections during subsequent periodic testing. This approach helps prevent unnecessary treatment and overestimation of recent transmission in low-prevalence settings.^[1]^[52] The protocol begins with the administration of the initial Mantoux TST using 5 tuberculin units of purified protein derivative (PPD) injected intradermally into the forearm. The reaction is read 48-72 hours later by measuring the diameter of induration in millimeters. If the first test shows 0-9 mm of induration (considered negative based on standard risk-stratified cutoffs), a second TST is administered 1-3 weeks later in the contralateral arm, with reading performed similarly. An increase of 10 mm or more in induration on the second test signifies a boosted response indicative of past infection rather than recent conversion, while no significant increase confirms the initial negative result as the true baseline.^[1]^[53] The Centers for Disease Control and Prevention (CDC) recommends two-step testing specifically for baseline evaluation in U.S. healthcare personnel and others requiring ongoing surveillance in low-incidence environments, as outlined in their 2017 guidelines co-authored with the American Thoracic Society and Infectious Diseases Society of America. This recommendation stems from evidence in studies from the 1970s and 1980s demonstrating boosting rates of approximately 10-20% among screened populations, such as hospital employees and institutionalized individuals, where repeat testing without the two-step method led to false-positive conversions. For instance, a 1981 study of chronic care hospital employees found an 8.3% booster rate in 1978 testing, highlighting the protocol's role in refining baseline accuracy.^[54] In interpretation, the result of the second TST is designated as the individual's baseline for future comparisons, ensuring that any subsequent increase of 10 mm or more represents a genuine conversion warranting further investigation for active tuberculosis. This method is particularly valuable for occupational health programs, where distinguishing historical from new infections supports targeted interventions without inflating reported incidence.^[1]

Heaf Test

The Heaf test, developed in 1951 by British physician Frederick Heaf as an alternative to the Mantoux test for detecting tuberculosis exposure, employs a multiple-puncture technique using a spring-loaded gun device fitted with a disposable head containing six short needles arranged in a circular pattern.^[55] A drop of purified protein derivative (PPD) tuberculin, typically in a concentrated solution equivalent to about 2 tuberculin units (TU) delivered intradermally across the punctures, is applied to the cleaned skin of the volar surface of the forearm, and the gun is pressed firmly to drive the needles to a depth of approximately 2 mm, creating multiple small punctures through the tuberculin film.^[56]^[57] This method was designed for efficient screening, particularly in settings requiring rapid assessment of large groups, such as schoolchildren or contacts of tuberculosis cases.^[58] The procedure is performed in a single step without the need for precise intradermal injection, and the site is read 48 to 72 hours later, though some protocols extend to 7 days for confirmation.^[56] Induration around the puncture sites forms distinct raised areas or rings, graded on a scale from 0 to 4: grade 0 indicates no induration (negative); grade 1 shows only discrete punctures without palpable induration (negative); grade 2 features 4 to 6 discrete papules forming incomplete rings (equivocal, often positive in unvaccinated individuals); grade 3 shows confluent induration forming a ring greater than 15 mm in diameter (positive); and grade 4 exhibits central blistering or ulceration with surrounding induration (strongly positive).^[59] This grading system relies on visual and palpatory assessment of the reaction's extent, emphasizing the formation of palpable rings rather than linear measurement.^[60] Compared to the Mantoux test, the Heaf method offers advantages in speed and simplicity, requiring less operator training and allowing for quicker administration in mass screening programs, which facilitated its widespread use in the UK from the 1950s through the 1990s for routine tuberculin testing in schools and communities.^[61] However, it is less precise due to variability in needle penetration depth and subjective grading, leading to higher inter-observer variability and a greater likelihood of false-positive results from cross-reactivity with environmental mycobacteria or BCG vaccination.^[56] Diagnostic studies indicate the Heaf test has sensitivity similar to the Mantoux (approximately 70-80% in detecting latent tuberculosis infection), but with reduced specificity, particularly in low-prevalence settings, resulting in more unnecessary follow-ups.^[60]^[62] The Heaf test was phased out in the UK in 2005, primarily due to manufacturing challenges, including the inability to source reliable suppliers for the specialized tuberculin solution and disposable gun heads, compounded by safety concerns over small metal fragments occasionally left in the skin, and the increasing adoption of more specific interferon-gamma release assays (IGRAs) as alternatives.^[61]^[63] Prior to discontinuation, it had been a cornerstone of tuberculosis screening, but the shift to the Mantoux test and IGRAs reflected broader advancements in diagnostic accuracy and reduced reliance on skin tests for mass applications.^[60]

Recent Guidelines and Alternatives

In recent updates from the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) as of 2025, the Mantoux tuberculin skin test (TST) remains emphasized for latent tuberculosis infection (LTBI) screening in resource-limited settings due to its low cost, simplicity, and lack of need for specialized laboratory equipment.^[1] These guidelines recommend integrating a positive Mantoux result with chest X-ray evaluation to exclude active tuberculosis disease before initiating LTBI treatment, particularly in high-burden areas where access to advanced imaging may be combined with clinical assessment for efficiency.^[64] The 2025 WHO consolidated guidelines on TB diagnosis further consolidate recommendations for TB infection testing, underscoring the TST's role in scalable screening strategies for vulnerable populations such as children and HIV-positive individuals in low-resource contexts.^[65] As alternatives to the Mantoux TST, interferon-gamma release assays (IGRAs) such as QuantiFERON-TB Gold and T-SPOT.TB are increasingly preferred, especially for BCG-vaccinated individuals or those at low risk of infection, owing to their higher specificity of 96% or greater in low-prevalence populations and lack of interference from prior BCG vaccination.^[66]^[33] These blood-based tests offer advantages in convenience, as they require only a single visit and provide objective results unaffected by reader variability inherent in skin test interpretation.^[67] Developments in the 2020s include research on digital mobile applications that use image analysis to measure induration size more accurately and objectively, reducing subjectivity in Mantoux reading and potentially minimizing the need for return visits.^[68] Hybrid protocols combining TST and IGRA have also emerged in select guidelines to enhance diagnostic confidence, particularly in intermediate-risk scenarios where one test's limitations may be offset by the other.^[69] Globally, Mantoux TST usage has declined in high-income countries, with a notable shift in the United States where 2023 CDC guidelines for healthcare worker screening moved toward IGRA as the preferred method upon hire, eliminating routine annual TST due to improved specificity and logistical ease.^[70] This trend reflects broader adoption of IGRAs in settings with higher BCG vaccination rates or lower TB prevalence, prioritizing tests less prone to false positives.^[71]

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USPSTF Review: Screening for Latent Tuberculosis Infection in Adults
May 2, 2023 · The pooled sensitivity for TST ranged from 0.60 to 0.81 across induration thresholds for a positive test result (ie, 5 mm, 10 mm, or 15 mm). The ...
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WHO launches update on consolidated guidelines to diagnose TB
Apr 17, 2025 · Updates in the companion Handbook include consolidation of guidance on TB infection, diagnosis and drug resistance testing, considerations for ...
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what is the absolute effect of BCG and non-tuberculous mycobacteria?
BCG received after infancy produces more frequent, more persistent and larger TST reactions. NTM is not a clinically important cause of false-positive TST, ...
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Diagnosing Latent Tuberculosis Infection | Turning Glitter to Gold
In addition, the tuberculin skin test does not reliably separate latent tuberculosis infection from prior immunization with Mycobacterium bovis bacille Calmette ...
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A meta-analysis of the effect of Bacille Calmette Guérin vaccination ...
The effect of BCG vaccination on PPD skin test results was less after 15 years. Positive skin tests with indurations of >15 mm are more likely to be the result ...
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TB Skin Test Interpretation - Medscape Reference
Possible causes of false positive results include: prior BCG vaccine, infection with non-tuberculous mycobacterium, incorrect interpretation of reaction, ...
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Clinical Testing Guidance for Tuberculosis: Interferon Gamma ... - CDC
May 9, 2024 · False-positive results. Errors in running and interpreting the test can decrease the accuracy of TB blood tests and lead to false-positive ...
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Gamma Interferon Release Assays for Detection of Mycobacterium ...
Evidence suggests that both TST and IGRA are acceptable but imperfect tests. They represent indirect markers of Mycobacterium tuberculosis exposure and indicate ...
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Prevention and Control of Tuberculosis in Facilities Providing Long ...
False-negative reactions to the tuberculin test may occur for up to 30% of persons with tuberculosis but without acquired immunodeficiency syndrome (AIDS); ...Missing: immunocompromised | Show results with:immunocompromised<|control11|><|separator|>
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Steroids Decrease Prevalence of Positive Tuberculin Skin Test in ...
North Carolina TB Control Program policy manual states that false negative TST reactions may be caused by high-dose steroids (>15 mg of Prednisone or its ...
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Severe undernutrition in children affects tuberculin skin test ... - NIH
Jul 16, 2021 · Severe undernutrition in children was associated with decreased odds of TST positivity. False-negative TSTs may result from undernutrition; ...
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[PDF] Targeted Testing and the Diagnosis of Latent Tuberculosis Infection ...
In this module, you will learn about targeted testing and the diagnosis of latent tuberculosis infection. (LTBI) and tuberculosis (TB) disease.
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The positive tuberculin test is not synonymous with latent tuberculosis
A possible failure in the PPD cold chain caused by exposure to light or heat, subcutaneous injection, the use of expired PPD, or an incorrect reading (the ...Missing: Mantoux improper
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The Effect of BCG Vaccination on Tuberculin Skin Testing
The findings of Chee and colleagues corroborate prior studies which have shown that BCG vaccination can confound interpretation of TST in 0–80% of individuals, ...Missing: prevalence | Show results with:prevalence
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Jan 31, 2025 · The BCG vaccine may cause a false-positive TB skin test reaction. There is no reliable way to distinguish a positive TB skin test reaction ...
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The Long-term Effect of Bacille Calmette-Guérin Vaccination on ...
This study provides evidence that BCG vaccination after infancy may influence TST results beyond the 10-year period conventionally accepted by the Centers ...
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Early Vaccination With Bacille Calmette-Guérin-Denmark or BCG ...
Both BCG-Denmark and BCG-Japan induced better immune responses (PPD reactivity, BCG reactions) and more lymphadenitis than BCG-Russia. Strengths and ...Missing: variations | Show results with:variations
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Bacillus Calmette-Guérin Skin Reaction Predicts Enhanced ...
Aug 15, 2021 · Different effects of BCG strains—a natural experiment evaluating the impact of the Danish and the Russian BCG strains on morbidity and scar ...
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Latent tuberculosis infection: updated and consolidated guidelines ...
Feb 15, 2018 · These new guidelines supersede previous WHO policy documents on the management of LTBI in people living with HIV, household contacts of people with active TB.
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Protection by BCG Vaccine Against Tuberculosis - Oxford Academic
We searched for studies reporting primary data on BCG vaccination efficacy in preventing tuberculosis disease in human populations of any age, in which BCG ( ...
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Anergy Skin Testing and Preventive Therapy for HIV-Infected Persons
Anergy or DTH tests placed by using the Mantoux method of intradermal injection have conventionally been classified as positive if an induration measuring ...
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Purified Protein Derivative (PPD)-Tuberculin Anergy and HIV Infection
Summary of guidelines for anergy testing. All persons with HIV infection should receive a PPD-tuberculin skin test (5TU, PPD by Mantoux method). Because of ...
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Targeted Tuberculin Testing and Treatment of Latent Tuberculosis ...
Jun 9, 2000 · In the United States and other countries with a low incidence of TB, most new, active cases have occurred among persons who were once infected, ...
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Baseline Tuberculosis Screening and Testing for Health Care ... - CDC
Dec 19, 2023 · Two-step testing is recommended for the initial TB skin test for adults who may be tested periodically, such as health care personnel. This ...
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Tuberculin Skin Test (TST) - MN Dept. of Health
Aug 27, 2024 · Mantoux refers to the technique for administering the test. Tuberculin (also called purified protein derivative or PPD) is the solution used to ...Missing: original | Show results with:original
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The use of repeat skin tests to eliminate the booster phenomenon in ...
The booster rate for 1978 was 8.3%, and elimination of these employees from subsequent annual testing resulted in a decrease in the conversion rate from 8.7% in ...
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Latent Tuberculosis | Encyclopedia MDPI
Nov 2, 2022 · 0.1 ml of tuberculin (100 units/ml), which delivers a dose of 5 units is given by intradermal injection into the surface of the lower forearm ( ...
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Skin Testing for Tuberculosis - Clinical Methods - NCBI Bookshelf
The American Thoracic Society now suggests that a PPD test should be applied via the Mantoux technique using a standard 5 TU dose (Snider et al., 1987). In the ...Missing: Trudeau | Show results with:Trudeau
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Heaf test gun, Oxford, England, 1978
Tuberculin liquid was placed on the skin, left to form a film and then six needles were plunged into the skin to a depth of 2 mm. If a red hard area appeared ...
[57]
The Heaf Multiple Puncture Tuberculin Test - JAMA Network
dipping in 95% alcohol and burning off the alcohol in the flame of an alcohol lamp. This procedure is carried out after each individual test. The tuberculin ...
[58]
[PDF] Comparison of T-cell-based assay with tuberculin skin test for ...
read-out of the automated Heaf test is quantified less precisely than the Mantoux test—ie, grades 0–4 instead of mm of induration, a continuous variable—the ...Missing: procedure | Show results with:procedure
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Improved Diagnostic Evaluation of Suspected Tuberculosis
Mar 4, 2008 · We considered induration of 15 mm or greater on the Mantoux test or grade 3 or 4 on the Heaf test (which is considered equivalent to the 15-mm ...
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Diagnosis of latent tuberculosis infection: The potential role of new ...
Different tests are available e.g. Heaf test, used in the UK, and Mantoux test, used in most other countries. The Heaf test, however, has been recently ...
[61]
Improved Diagnostic Evaluation of Suspected Tuberculosis in ... - NIH
... Heaf test showed a nonsignificant increase in diagnostic sensitivity and a significant decrease in specificity relative to the Mantoux test. Subgroup ...
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https://pmc.ncbi.nlm.nih.gov/articles/PMC2761734/
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Comparing the Diagnostic Performance of QuantiFERON-TB Gold ...
The specificity of both QFT tests among individuals with low risk of LTBI was above 96% [2, 3]. However, the sensitivity of both QFTs is reduced in people with ...
[64]
QuantiFERON-TB Gold+ for the Diagnosis of Mycobacterium ... - AAFP
Feb 1, 2021 · QuantiFERON-TB Gold+ is more specific than tuberculin skin testing in patients with a history of BCG vaccination, and the BCG vaccine does not ...
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[2506.17954] Mobile Image Analysis Application for Mantoux Skin Test
Jun 22, 2025 · This paper presents a newly developed mobile application designed to diagnose Latent Tuberculosis Infection (LTBI) using the Mantoux Skin Test (TST).Missing: digital 2020s research
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Clinical Testing and Diagnosis for Tuberculosis - CDC
Apr 17, 2025 · CDC recommends testing people who are at increased risk for TB infection. People with symptoms of TB disease or positive TB blood test or TB ...Tuberculin Skin Test · TB blood tests · Clinical and Laboratory...<|control11|><|separator|>
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Clinical Testing Guidance for Tuberculosis: Health Care Personnel
CDC recommends all U.S. health care personnel should be screened for TB upon hire. Annual TB testing is not recommended unless there is a known exposure or ...Frequency of Tuberculosis... · Baseline Tuberculosis... · MMWRMissing: Mantoux | Show results with:Mantoux
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Screening for Latent Tuberculosis Infection in Adults: US Preventive ...
May 2, 2023 · Approximately 30% of persons exposed to Mycobacterium tuberculosis will develop LTBI and, if left untreated, approximately 5% to 10% of healthy, ...