Tuberculins

(BAN)

💊 Chemical information

Tuberculinas.
ATC — V04CF01.
ATC Vet — QV04CF01.

Pharmacopoeias.

In Eur. and US.

Ph. Eur. 6.2 (Tuberculin for Human Use, Old). It consists of a filtrate, concentrated by heating, containing the soluble products of the culture and lysis of one or more strains of Mycobacterium tuberculosis and/or M. bovis. It contains a suitable preservative that does not give rise to false-positive reactions. In concentrated form, it is a transparent, viscous, yellow or brown liquid. Protect from light.

Ph. Eur. 6.2 (Tuberculin Purified Protein Derivative for Human Use). A preparation obtained by precipitation from the heated products of the culture and lysis of Mycobacterium tuberculosis and/or M. bovis. It contains a suitable preservative that does not give rise to false-positive reactions. It is a colourless or pale yellow liquid; the diluted preparation may be a freeze-dried powder which upon dissolution gives a colourless or pale yellow liquid. Protect from light.

USP 31

(Tuberculin). A sterile solution derived from the concentrated, soluble products of growth of the tubercle bacillus (Mycobacterium tuberculosis or M. bovis) prepared in a special medium. It is provided either as Old Tuberculin, a culture filtrate adjusted to the standard potency by the addition of glycerol and isotonic sodium chloride solution, or as Purified Protein Derivative (PPD), a further purified protein fraction. Store at 2° to 8°.

💊 Adverse Effects

Pain and pruritus may occur at the injection site, occasionally with vesiculation, ulceration, or necrosis in highly sensitive persons. Granuloma has been reported. Nausea, headache, dizziness, malaise, rash, urticaria, oedema, and pyrexia have been reported occasionally; immediate systemic hypersensitivity, including anaphylaxis, has been reported rarely. There have also been rare reports of lymphangitis.

Hypersensitivity.

There are rare reports1-4 of severe anaphylactic or anaphylactoid reactions, occasionally fatal,1 to tuberculin.
1. DiMaio VJM, Froede RC. Allergic reactions to the tine test. JAMA 1975; 233: 769
2. Spiteri MA, et al. Life threatening reaction to tuberculin testing. BMJ 1986; 293: 243–4
3. Wright DN, et al. Systemic and local allergic reactions to the tine test purified protein derivative. JAMA 1989; 262: 2999–3000
4. Sanofi Pasteur, Canada. Risk of serious allergic reactions following TUBERSOL [Tuberculin Purified Protein Derivative (Mantoux)] administration (issued 19th May 2005). Available at: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/ pdf/medeff/tubersol_hpc-cps-eng.pdf (accessed 08/08/08)

Lymphangitis.

Lymphangitis has been reported on 5 occasions after the Mantoux test and on 7 occasions after the Heaf test.1However, it was noted that a tuberculin test may have been inappropriate in some of these patients, particularly older subjects and those with evidence of healed tuberculous lesions.2
1. Morrison JB. Lymphangitis after tuberculin tests. BMJ 1984; 289: 413
2. Festenstein F. Lymphangitis after tuberculin tests. BMJ 1984; 289: 625–6.

💊 Precautions

Tuberculin should be given with caution to patients who have, or are suspected of having, active tuberculosis; although severe local reactions may occur in patients with active tuberculosis, sensitivity may be diminished if it is particularly severe. Sensitivity to tuberculin may also be diminished in the following conditions: viral or severe bacterial infection including HIV infection and infectious mononucleosis; neoplastic disease particularly lymphoma; sarcoidosis; corticosteroid or immunosuppressive therapy; recent use of live virus vaccines; ultraviolet light treatment; chronic renal failure; dehydration; and malnutrition. Tuberculins may be adsorbed onto the surface of syringes and should therefore be given immediately.

💊 Uses and Administration

Tuberculin skin tests are used to detect tuberculoprotein hypersensitivity when BCG vaccination is being considered or as an aid to diagnosis of tuberculosis. A person showing a specific sensitivity to tuberculin is considered to have been infected with the tubercle bacillus, though the infection may be inactive. Tuberculin for sensitivity testing is given by intradermal injection as in the Mantoux test. Multiple-puncture devices such as the Heaf test or tine tests have also been used, although they are no longer available in the UK. In the UK, it is recommended that tuberculin testing should always be performed when BCG vaccination is being considered, and the Mantoux test is recommended. For a routine Mantoux test, a diluted solution of tuberculin purified protein derivative (PPD) is given by intradermal injection and the reaction, which is graded by the degree of induration, read 48 to 72 hours later. A retest with a stronger solution of PPD may be considered if the results of the initial test are unclear. Different commercial preparations vary in labelling format and potency, and doses and interpretation of results cannot therefore be extrapolated from one preparation to another. Individuals with no or minimal reactions who have not previously been given BCG vaccines may be offered BCG vaccination. Patients with a positive reaction are considered to be hypersensitive to tuberculoprotein and should not be vaccinated. Investigation for the presence of active tuberculosis is generally only indicated for patients showing a strongly positive reaction to a tuberculin skin test. However, there are many factors that should be considered when interpreting the results; in addition to those listed under Precautions (see above), there are the effects of previous BCG vaccination, repeated tuberculin testing, and age. In some areas, a positive reaction may be a result of cross-sensitivity of the test to non-tuberculous mycobacteria (see below). For the Heaf test, a solution of PPD is applied to the forearm using a multiple-puncture gun (Heaf gun), and the reaction evaluated about a week later. The term tine test is generally used for disposable multiple-puncture devices coated with dried old tuberculin or PPD. However, some consider tine tests to be unreliable. In some other countries, the population tested, the procedures used, and grading of reactions may differ slightly from that outlined above. Tuberculins have also been used, in conjunction with other antigens, for anergy testing to assess the status of cell-mediated immunity.

Latent tuberculosis.

Full eradication of tuberculosis from developed countries requires identification of latent as well as active cases.1 Tuberculin testing has been in use for over 100 years and, while still considered a useful diagnostic agent for tuberculosis, the problems of false-positive reactions or reduced sensitivity to the test are well recognised.1 Use of the test to identify latent disease has evolved with experience.2 Previous BCG vaccination is one factor that significantly increases the likelihood of a false-positive reaction to tuberculin testing, which makes the diagnosis of latent tuberculosis particularly difficult.3 Interpretation of the skin test should therefore be made by considering the induration size in the context of the individual clinical profile, including other risk factors for infection.2,3 Three different approaches to assess the annual risk of tuberculous infection using tuberculin testing gave different results in a study of schoolchildren who had been given BCG vaccinations early in life.4 This led the authors to conclude that the effect of previous BCG vaccination on tuberculin reactivity may be more complex than assumed, and that the tuberculin test is a poor indicator of latent infection. It has been suggested2 that it is not necessary for lowrisk persons in the general population of the USA to receive routine tuberculin testing for tuberculosis; high-risk groups of adults and children for whom screening might be warranted have been defined, and consensus recommendations made. An opinion has also been ventured5 that tuberculin testing before BCG vaccination is not necessary in children in the UK.
1. Lee E, Holzman RS. Evolution and current use of the tuberculin test. Clin Infect Dis 2002; 34: 365–70
2. American Thoracic Society. Targeted tuberculin testing and treatment of latent tuberculosis infection. 1999. Available at: http://www.thoracic.org/sections/publications/statements/pages/ mtpi/latenttb1-27.html (accessed 14/07/06
3. Wang L, et al. A meta-analysis of the effect of Bacille Calmette Guérin vaccination on tuberculin skin test measurements. Thorax 2002; 57: 804–9. Correction: ibid. 2003; 58: 188
4. Leung CC, et al. Tuberculin response in BCG vaccinated schoolchildren and the estimation of annual risk of infection in Hong Kong. Thorax 2005; 60: 124–9
5. Bothamley GH, et al. Tuberculin testing before BCG vaccination. BMJ 2003; 327: 243–4.

Malignant disease.

Benefit has been reported1 in 2 patients with adult T-cell leukaemia/lymphoma predominantly involving the skin after local treatment with tuberculin purified protein derivative.
1. Kanekura T, et al. Purified protein derivative treatment for skin lesions of adult T-cell leukaemia/lymphoma. Br J Dermatol 1999; 140: 767–8.

Non-tuberculous mycobacterial infection.

The tuberculin skin test is not specific for Mycobacterium tuberculosis, but can also represent a cross-reaction caused by antigens on other nontuberculous mycobacteria. Re-examination1 of results from children with non-tuberculous mycobacterial infection concluded that the avian Mantoux test (avian tuberculin purified protein derivative (PPD) prepared from M. avium) was more sensitive than the human Mantoux test (tuberculin PPD prepared from M. tuberculosis) in the detection of non-tuberculous mycobacteria in regions with a low incidence of tuberculosis, and may be a useful aid to differential diagnosis in areas where tuberculosis is prevalent.
1. Daley AJ, Isaacs D. Differential avian and human tuberculin skin testing in non-tuberculous mycobacterial infection. Arch Dis Child 1999; 80: 377–9.

💊 Preparations

Ph. Eur.: Old Tuberculin for Human Use; Tuberculin Purified Protein Derivative for Human Use; USP 31: Tuberculin.

Proprietary Preparations

Austria: Monotest; Belg.: Monovacc-Test†; Canad.: Tubersol; Fr.: Monotest†; Tubertest; Ger.: Tubergen-Test†; Gr.: Imotest Tuberculin; Ital.: Biocine Test PPD; Monotest†; NZ: Monotest†; Tubersol; S.Afr.: Biocine Test; Japan Freeze-Dried Tuberculin; Monotest†; Spain: Tubersol PPD†; Swed.: Monotest†; USA: Aplisol; Tubersol; Venez.: Imotest Tuberculina†. Multi-ingredient: Austral.: Multitest CMI; Austria: Multitest; Cz.: Imunoskintest†; Ger.: Multitest†; Israel: Multitest CMI; NZ: Multitest CMI†; S.Afr.: Multitest CMI†.
Published May 08, 2019.