Editing Mantoux test

{{short description|Immunological method to test for tuberculosis}}
{{Infobox diagnostic
| name            = Mantoux test
| image           = File:Mantoux tuberculin skin test.jpg|thumb|
| alt             =
| caption         = The Mantoux skin test consists of an intradermal injection of one-tenth of a milliliter (ml) of PPD tuberculin. The circular shape is known as a [[wheal response]].
| pronounce       =
| purpose         = screen for tuberculosis
| test of         =
| based on        =
| synonyms        = Mantoux screening test
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The '''Mantoux test''' or '''Mendel–Mantoux test''' (also known as the '''Mantoux screening test''', '''tuberculin sensitivity test''', '''Pirquet test''', or '''PPD test''' for purified protein derivative) is a tool for [[screening (medicine)|screening]] for [[tuberculosis|tuberculosis (TB)]] and for [[tuberculosis diagnosis]]. It is one of the major [[tuberculin]] skin tests used around the world, largely replacing multiple-puncture tests such as the [[tine test]]. The [[Heaf test]], a form of tine test, was used until 2005 in the UK, when it was replaced by the Mantoux test. The Mantoux test is endorsed by the [[American Thoracic Society]] and [[Centers for Disease Control and Prevention]]. It was also used in the [[Soviet Union|USSR]] and is now prevalent in most of the [[post-Soviet states]], although Soviet mantoux produced many false positives due to children's allergic reaction.<ref>{{cite web | url=https://tass.ru/obschestvo/11013165 | title=Эксперт: проба Манту часто дает ложноположительные результаты из-за аллергической реакции - ТАСС }}</ref>

==History==
[[File:Mantoux test.jpg|thumb|The size of [[induration]] is measured 48–72 hours later. Erythema (redness) should not be measured.]]

[[File:Negative Mantoux Test.jpg|thumb|Mantoux test injection site in a subject without chronic conditions or in a high-risk group clinically diagnosed as negative at 50 hours]]

[[Tuberculin]] is a [[glycerol]] extract of the tubercle [[bacillus]].  Purified protein derivative (PPD) tuberculin is a precipitate of species-nonspecific molecules obtained from filtrates of sterilized, concentrated cultures. The tuberculin reaction was first described by [[Robert Koch]] in 1890. The test was first developed and described by the German physician Felix Mendel in 1908.<ref>F. Mendel. Therapeutische Monatshefte, Berlin, 1903, 16: 177. Die von Pirquet'sche Hautreaktion und die intravenöse Tuberkulinbehandlung.Medizinische Klinik, München, 1908, 4: 402-404.</ref> It is named after [[Charles Mantoux]], a French physician who built on the work of Koch and [[Clemens von Pirquet]] to create his test in 1907. However, the test was unreliable due to impurities in tuberculin which tended to cause false results.<ref name=CHF/>

[[Esmond R. Long]] and [[Florence B. Seibert]] identified the active agent in tuberculin as a protein.  Seibert then spent a number of years developing methods for separating and purifying the protein from ''Mycobacterium tuberculosis'', obtaining purified protein derivative (PPD) and enabling the creation of a reliable test for tuberculosis.<ref name="CHF">{{cite web|title=Esmond R. Long and Florence B. Seibert|url=http://www.chemheritage.org/discover/chemistry-in-history/themes/pharmaceuticals/diagnosing-diseases/long-and-seibert.aspx|work=Chemical Heritage Foundation|access-date=April 27, 2011 |url-status=dead |archive-url=https://web.archive.org/web/20120113010259/http://www.chemheritage.org/discover/chemistry-in-history/themes/pharmaceuticals/diagnosing-diseases/long-and-seibert.aspx|archive-date=January 13, 2012}}</ref>  Her first publication on the purification of tuberculin appeared in 1934.<ref name=ChemEx>{{cite web|title=Florence Seibert, American Biochemist, 1897–1991|url=http://www.chemistryexplained.com/Ru-Sp/Seibert-Florence.html|website=Chemistry Explained|access-date=26 October 2015}}</ref> By the 1940s, Seibert's PPD was the international standard for tuberculin tests.<ref name=Dacso>{{cite book|last1=Dacso|first1=C. C.|chapter=Chapter 47: Skin Testing for Tuberculosis |editor-last1= Walker |editor-first1=H. K.|editor-last2= Hall| editor-first2= W. D. | editor-last3=Hurst |editor-first3=J.W.| title=Clinical Methods: The History, Physical, and Laboratory Examinations|date=1990|publisher=Butterworths|location=Boston|edition=3rd|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK369/|access-date=26 October 2015|isbn=9780409900774}}</ref> In 1939, [[Russia]]n M.A. Linnikova created a modified version of PPD. In 1954, the Soviet Union started mass production of PPD-L, named after Linnikova.<ref>{{Cite web|url=http://www.edubilla.com/invention/mantoux-test/|title=Mantoux test, Mantoux test inventors|website=Edubilla.com|language=en|access-date=2019-04-25}}</ref><ref>{{Cite web|url=https://www.scribd.com/document/121892998/Mantoux-test|title=Mantoux test {{!}} Clinical Medicine {{!}} Medical Specialties|website=Scribd|language=en|access-date=2019-04-25}}</ref>

==Procedure==
In the Mantoux test, a standard dose of 5 tuberculin units (TU – 0.1&nbsp;ml), according to the [[Centers for Disease Control and Prevention|CDC]],<ref>{{cite web|title=TB Elimination - Tuberculin Skin Testing|url=https://www.cdc.gov/tb/publications/factsheets/testing/skintesting.pdf|website=CDC.gov|publisher=CDC - National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention - Division of Tuberculosis Elimination|access-date=5 June 2017|date=October 2011}}</ref> or 2 TU of Statens Serum Institute (SSI) tuberculin RT23 in 0.1&nbsp;ml solution, according to the [[National Health Service]],<ref>{{cite web|title=The Mantoux test: Administration, reading and interpretation|url=http://www.immunisation.nhs.uk/files/mantouxtest.pdf|website=NHS.uk|access-date=5 June 2017|archive-url=https://web.archive.org/web/20100215105953/http://www.immunisation.nhs.uk/files/mantouxtest.pdf|archive-date=15 February 2010}}</ref> is injected intradermally (between the layers of dermis) on the flexor surface of the left forearm, mid-way between elbow and wrist. The injection should be made with a tuberculin syringe, with the needle bevel facing upward. When placed correctly, injection should produce a pale wheal of the skin, 6 to 10&nbsp;mm in diameter. The result of the test is read after 48–96 hours, ideally after 72 hours/3rd day. This procedure is termed the 'Mantoux technique'. A person who has been exposed to the bacteria would be expected to mount an immune response in the area of skin containing the bacterial proteins. This response is a classic example of 'delayed-type hypersensitivity reaction' ([[Dth response|DTH]]), a [[Type IV hypersensitivity|type IV]] of [[Hypersensitivity|hypersensitivities]]. [[T cell]]s and myeloid cells are attracted to the site of reaction in 1–3 days and generate local [[inflammation]]. The reaction is read by measuring the diameter of [[induration]] (palpable raised, hardened area) across the forearm (perpendicular to the long axis) in millimeters. If there is no induration, the result should be recorded as "0&nbsp;mm".  [[Erythema]] (redness) should not be measured.<ref>{{Cite web|url=https://www.cdc.gov/tb/publications/factsheets/testing/skintesting.htm|title=Tuberculin Skin Testing Fact Sheet|author=Centers for Disease Control and Prevention|date=16 December 2020 |language=en|access-date=2023-01-20}}</ref> In the Pirquet version of the test  tuberculin is applied to the skin via [[scarification]].<ref>{{Cite web|url=https://www.britannica.com/science/Pirquets-skin-test|title = Pirquet's skin test &#124; medicine}}</ref>

==Classification of tuberculin reaction==
The results of this test must be interpreted carefully.  The person's medical risk factors determine at which increment (5&nbsp;mm, 10&nbsp;mm, or 15&nbsp;mm) of induration the result is considered positive.<ref>From the CDC team of the CDC team at the Saskatchewan Lung Association, [http://www.lung.ca/tb/tbtoday/tbdiagnosis/skin_test.html photos of a PPD bump] {{webarchive|url=https://web.archive.org/web/20070321005807/http://www.lung.ca/tb/tbtoday/tbdiagnosis/skin_test.html |date=2007-03-21 }}.</ref> A positive result indicates TB exposure.
* 5&nbsp;mm or more is positive in
** An HIV-positive person
** Persons with recent contacts with a TB patient
** Persons with nodular or fibrotic changes on chest X-ray consistent with old healed TB
** Patients with organ transplants, and other immunosuppressed patients
* 10&nbsp;mm or more is positive in
** Recent arrivals (less than five years) from [[Tuberculosis#Epidemiology|high-prevalence countries]]
** Injection drug users
** Residents and employees of high-risk congregate settings (e.g., prisons, nursing homes, hospitals, homeless shelters, etc.)
** [[Mycobacteria|Mycobacteriology]] lab personnel
** Persons with clinical conditions that place them at high risk (e.g., [[diabetes]], prolonged [[corticosteroid]] therapy, [[leukemia]], [[renal failure|end-stage renal disease]], chronic [[malabsorption]] syndromes, low body weight, etc.)
** Children less than four years of age, or children and adolescents exposed to adults in high-risk categories
* 15&nbsp;mm or more is positive in
** Persons with no known risk factors for TB<ref>[http://www.eac.int/health/index.php?option=com_content&id=79%3Aclassification-system&Itemid=34 Mantoux Test] {{Webarchive|url=https://web.archive.org/web/20160930155812/http://www.eac.int/health/index.php?option=com_content&id=79%3Aclassification-system&Itemid=34 |date=2016-09-30 }} in eac.int.</ref>

A tuberculin test conversion is defined as an increase of 10&nbsp;mm or more within a two-year period, regardless of age. Alternative criteria include increases of 6, 12, 15 or 18&nbsp;mm.<ref name="pmid9872812">{{cite journal|last=Menzies|first=Dick|title=Interpretation aof Repeated Tuberculin Tests|journal=American Journal of Respiratory and Critical Care Medicine|date=1 January 1999|volume=159|issue=1|pages=15–21|doi=10.1164/ajrccm.159.1.9801120|pmid=9872812}}</ref>

==False positive result==
TST (tuberculin skin test) positive is measured by size of induration. The size of the induration considered to be a positive result depends on risk factors. For example, a low-risk patient must have a larger induration for a positive result than a high-risk patient. High-risk groups include recent contacts, those with HIV, those with chest [[radiograph]] with fibrotic changes, organ transplant recipients, and those with immunosuppression.{{cn|date=May 2024}}

A meta-analysis in 2014 found that the [[BCG vaccine|Bacillus Calmette–Guérin (BCG) vaccine]] reduced infections by 19–27% and reduced progression to active tuberculosis by 71%.<ref name="pmid25097193">{{cite journal | vauthors = Roy A, Eisenhut M, Harris RJ, Rodrigues LC, Sridhar S, Habermann S, Snell L, Mangtani P, Adetifa I, Lalvani A, Abubakar I | title = Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis | journal = BMJ | volume = 349 | pages = g4643 | date = August 2014 | pmid = 25097193 | pmc = 4122754 | doi = 10.1136/bmj.g4643 }}</ref> The Ohio Department of Health states that it give 80% of children protection against [[tuberculous meningitis]] and [[miliary tuberculosis]]. Therefore, a positive TST/PPD in a person who has received BCG vaccine is interpreted as latent TB infection (LTBI).<ref>Information also from ODH lecture at the Ohio State University 5/24/2012.</ref>
Due to the test's low specificity, most positive reactions in low-risk individuals are false positives.<ref name="pmid8668383">{{cite journal | author=Starke JR | title=Tuberculosis Skin Testing: New Schools of Thought|date=Jul 1996 | journal=Pediatrics | volume=98 | issue=1 | pages=123–125 | doi=10.1542/peds.98.1.123| issn=0031-4005 | pmid=8668383 | s2cid=19907614}}</ref> A false positive result may be caused by [[nontuberculous mycobacteria]] or previous administration of BCG vaccine.  Vaccination with BCG may result in a false-positive result for many years after vaccination.<ref>{{cite journal |vauthors=Chaturvedi N, Cockcroft A | title=Tuberculosis screening among health service employees: who needs chest X-rays? | year=1992 | journal=J Soc Occup Med | volume=42 | pages=179–82  | doi = 10.1093/occmed/42.4.179 | pmid=1421331 | issue=4}}</ref>

False positives can also occur when the injected area is touched, causing swelling and itching. If the swelling is less than 5&nbsp;mm, it is possibly due to error by the healthcare personnel causing inflammation to the area.{{cn|date=May 2024}}

Another source of false positive results can be allergic reaction or [[hypersensitivity]]. Although rare (about 0.08 reported reactions per million doses of tuberculin), these reactions can be dangerous and precautions should be taken by having [[epinephrin]] available.<ref>{{cite journal |author1=James E. Froeschle |author2=Frederick L. Ruben |author3=A. Michael Bloh | title=Immediate Hypersensitivity Reactions after Use of Tuberculin Skin Testing| year=2002 | journal=Clinical Infectious Diseases | volume=34 | pages=e12–e13 | doi = 10.1086/324587 |pmid=11731966 | issue=1| doi-access=free }}</ref>

==False negative result==
Reaction to the PPD or tuberculin test is suppressed by the following conditions:
* Recent TB infection (less than 8–10 weeks)
* [[Infectious mononucleosis]]
* Live virus vaccine – The test should not be carried out within 3 weeks of live virus vaccination (e. g. [[MMR vaccine]] or [[Sabin vaccine]]).
* [[Sarcoidosis]]
* [[Hodgkin's disease]]
* [[Corticosteroid]] therapy/[[steroid]] use
* [[Malnutrition]]
* [[Immunodeficiency|Immunological compromise]] – Those on immuno-suppressive treatment or those with [[HIV]] and low CD4 [[T cell]] counts, frequently show negative results from the PPD test.{{Citation needed|date=December 2009}}
This is because the immune system needs to be functional to mount a response to the protein derivative injected under the skin. A false negative result may occur in a person who has been recently infected with TB, but whose immune system hasn't yet reacted to the bacteria.
* [[Common cold|Upper respiratory virus infection]]
In case a second tuberculin test is necessary it should be carried out in the other arm to avoid hypersensitising the skin.

==BCG vaccine and the Mantoux test==
The role of Mantoux testing in people who have been vaccinated is disputed.  The US recommends that tuberculin skin testing is not contraindicated for BCG-vaccinated persons, and prior BCG vaccination should not influence the interpretation of the test.  The UK recommends that [[interferon gamma release assay|interferon-γ]] testing should be used to help interpret positive Mantoux tests of over 5&nbsp;mm,<ref>{{Cite web|url=https://www.nice.org.uk/guidance/ng33/chapter/Recommendations#latent-tb|title = Recommendations &#124; Tuberculosis &#124; Guidance &#124; NICE| date=13 January 2016 }}</ref> and repeated tuberculin skin testing must not be done in people who have had BCG vaccinations. In general, the US recommendation may result in a larger number of people being falsely diagnosed with latent tuberculosis, while the UK approach has an increased chance of missing patients with latent tuberculosis who should be treated.{{Citation needed|date=May 2011}}

According to the US guidelines, [[latent tuberculosis]] infection diagnosis and treatment is considered for any BCG-vaccinated person whose skin test is 10&nbsp;mm or greater, if any of these circumstances are present:{{cn|date=May 2024}}
* Was in contact with another person with infectious TB
* Was born or has lived in a high TB prevalence country
* Is continually exposed to populations where TB prevalence is high

==Anergy testing==
In cases of [[anergy]], a lack of reaction by the body's defence mechanisms when it comes into contact with foreign substances, the tuberculin reaction will occur weakly, thus compromising the value of Mantoux testing. For example, anergy is present in [[AIDS]], a disease which strongly depresses the immune system. Therefore, anergy testing is advised in cases where there is suspicion that anergy is present. However, routine anergy skin testing is not recommended.<ref>{{cite journal|last1=Markowitz|first1=Norman|s2cid=37590470|title=Tuberculin and Anergy Testing in HIV-Seropositive and HIV-Seronegative Persons|journal=Ann Intern Med|date=1993|volume=119|issue=3|pages=185–193|doi=10.7326/0003-4819-119-3-199308010-00002|pmid=8100692}}</ref>

==Two-step testing==
Some people who have been infected with TB may have a negative reaction when tested years after infection, as the immune system response may gradually wane. This initial skin test, though negative, may stimulate (boost) the body's ability to react to tuberculin in future tests. Thus, a positive reaction to a subsequent test may be misinterpreted as a new infection, when in fact it is the result of the boosted reaction to an old infection.<ref>{{Cite web|url=https://www.cdc.gov/tb/publications/factsheets/testing/skintesting.htm|title=Fact Sheets {{!}} Testing & Diagnosis {{!}} Fact Sheet - Tuberculin Skin Testing {{!}} TB {{!}} CDC|date=2018-12-11|website=www.cdc.gov|language=en-us|access-date=2019-05-29}}</ref>

Use of two-step testing is recommended for initial skin testing of adults who will be retested periodically (e.g., health care workers). This ensures any future positive tests can be interpreted as being caused by a new infection, rather than simply a reaction to an old infection.{{cn|date=May 2024}}
* The first test is read 48–72 hours after injection.
** If the first test is positive, consider the person infected.
** If the first test is negative, give a second test one to three weeks after the first injection.
* The second test is read 48–72 hours after injection.
** If the second test is positive, consider the person infected in the distant past.<ref>{{cite web | title=Information on Two-Step TB Skin Test | url=https://www.ccsf.edu/en/student-services/student-health-services/medical-service/tb-testing/_jcr_content/rightlinks/documentlink_0/file.res/Two-Step%20TB%20Skin%20Test.pdf | access-date=2017-03-13 | archive-date=2020-08-03 | archive-url=https://web.archive.org/web/20200803162920/https://www.ccsf.edu/en/student-services/student-health-services/medical-service/tb-testing/_jcr_content/rightlinks/documentlink_0/file.res/Two-Step%20TB%20Skin%20Test.pdf | url-status=dead }}</ref>
** If the second test is negative, consider the person uninfected.<ref>{{cite web | author=Office of Health and Human Services | title=Booster Phenomenon | url=http://www.mass.gov/?pageID=eohhs2terminal&L=7&L0=Home&L1=Provider&L2=Guidelines+and+Resources&L3=Guidelines+for+Clinical+Treatment&L4=Diseases+%26+Conditions&L5=Tuberculosis+Prevention+and+Control&L6=Screening+and+Testing&sid=Eeohhs2&b=terminalcontent&f=dph_cdc_p_tb_testing_booster+&csid=Eeohhs2 | access-date=2008-07-02}}</ref>

A person who is diagnosed as "infected in the distant past" on two-step testing is called a "tuberculin reactor".{{cn|date=May 2024}}

The US recommendation that prior BCG vaccination be ignored results in almost universal false diagnosis of tuberculosis infection in people who have had BCG (mostly foreign nationals).{{cn|date=May 2024}}

==The latest interpretation for Mantoux test results==
According to the guidelines published by Centers for Disease Control and Prevention in 2005, the results are re-categorized into 3 parts based on their previous or baseline outcomes:{{cn|date=May 2024}}
* Baseline test: ≥10&nbsp;mm is positive (either first or second step); 0 to 9&nbsp;mm is negative
* Serial testing without known exposure: Increase of ≥10&nbsp;mm is positive
* Known exposure:
** ≥5&nbsp;mm is positive in patients with baseline of 0&nbsp;mm
** ≥10&nbsp;mm is positive in patients with negative baseline or previous screening result of >0&nbsp;mm

==Recent developments==
In addition to tuberculin skin tests such as (principally) the Mantoux test, [[interferon gamma release assay]]s (IGRAs) have become common in clinical use in the 2010s. In some contexts they are used instead of TSTs, whereas in other contexts TSTs and IGRAs both continue to be useful.<ref name="pmid_26642354">{{Citation |last1=Collins |first1=LF |last2=Geadas |first2=C |last3=Ellner |first3=JJ |s2cid=1059756 |year=2016 |title=Diagnosis of latent tuberculosis infection: too soon to pull the plug on the tuberculin skin test |journal=Ann Intern Med|volume=164 |issue=2 |pages=122–124 |pmid=26642354 |doi=10.7326/M15-1522 |postscript=.}}</ref>

The [[QuantiFERON-TB Gold]] blood test measures the patient's immune reactivity to the TB bacterium, and is useful for initial and serial testing of persons with an increased risk of latent or active tuberculosis infection. Guidelines for its use were released by the CDC in December 2005.<ref>[https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5415a4.htm Guidelines for Using the QuantiFERON-TB Gold Test for Detecting ''Mycobacterium tuberculosis ''Infection, United States<!-- Bot generated title -->]</ref> QuantiFERON-TB Gold is [[Food and Drug Administration|FDA]]-approved in the [[United States]], has [[CE Mark]] approval in [[Europe]] and has been approved by the [[MHLW]] in [[Japan]]. The interferon gamma release assay is the preferred method for patients who have had immunosuppression and are about to start biological therapies.<ref>[http://www.bad.org.uk/shared/get-file.ashx?id=5834&itemtype=document British Association of Dermatologists guidelines for biologic therapy for psoriasis 2017*] {{Webarchive|url=https://web.archive.org/web/20190520060636/http://www.bad.org.uk/shared/get-file.ashx?id=5834&itemtype=document |date=2019-05-20 }} ''www.bad.org.uk'', accessed 11 October 2020</ref>

[[T-SPOT.TB]] is another IGRA; it uses the [[ELISPOT]] method.{{cn|date=May 2024}}

==Heaf test==
{{Main|Heaf test}}

The Heaf tuberculin skin test was used in the United Kingdom, but discontinued in 2005. The equivalent Mantoux test positive levels done with 10 TU (0.1&nbsp;ml at 100&nbsp;TU/ml, 1:1000) are{{citation needed|date=July 2020}}
* &lt;5&nbsp;mm induration (Heaf 0–1)
* 5–15&nbsp;mm induration (Heaf 2)
* &gt;15&nbsp;mm induration (Heaf 3–4)

==See also==
* [[Latent tuberculosis]]
* [[QuantiFERON]]
* [[Geronimo (alpaca)]]
* [[Shambo]]

==References==
{{Reflist}}
{{commons category}}
{{Hypersensitivity and autoimmune diseases}}
{{Tuberculosis}}

[[Category:Immunologic tests]]
[[Category:Tuberculosis]]
[[Category:Dermatologic procedures]]