Tuberculin PPD 1 (Mantoux)--Tubersol® for intracutaneous
(Mantoux) tuberculin testing is available in stabilized solutions
bio-equivalent to 5 U.S. units (TU) PPD-S per test dose (0.1 ml) and stabilized
solutions diluted to a calculated bio-equivalance of 1 Tu and 250 TU strengths
per test dose (0.1 ml).
Tubersol® is prepared by the Connaught Laboratories
Limited from a large Master Batch, Connaught Tuberculin (CT68), which has been
obtained from a human strain of Mycobacterium tuberculosis grown on a
protein-free synthetic medium. The use of a standard preparation derived from a
single batch (CT68) has been recommended 2 in order to eliminate batch to batch
variation by the same manufacturer.
Tubersol® is a sterile isotonic solution of Tuberculin in
phosphate buffered saline containing Tween 80 (0.0005%) as a stabilizer. Phenol
0.28% is added as a preservative. 3,4,5
Independent studies conducted by the U.S. Public Health Service in
humans have determined the amount of CT68 in stabilized solution necessary to
produce bio-equivalency with Tuberculin PPD-S (in phosphate buffer without
Tween 80) using 5 U.S. units (TU) Tuberculin PPD-S as the standard.
Prior to release, each successive lot is tested for potency
in sensitized guinea pigs in comparison with the U.S. Standard Tuberculin PPD-S
distributed by the Office of Biologics, Food and Drug Administration, Bethesda,
Maryland, U.S.A. 6
Intracutaneous tuberculin testing is an accepted aid in the
diagnosis of tuberculosis infection.
The reaction to intracutaneously injected tuberculin is a
delayed (cellular) hypersensitivity reaction. The reaction which
characteristically shows a delayed course, reaching its peak more than 24 hours
after administration, consists of induration due to cell infiltration and
occasionally vesiculation and necrosis. Clinically, a delayed hypersensitivity
reaction to tuberculin is a manifestation of previous infection with M.
tuberculosis or a variety of non-tuberculosis bacteria. In most cases sensitization is induced by a
natural mycobacterial infection or by vaccination with BCG Vaccine.
The sensitization following infection with mycobacteria
occurs primarily in the regional lymph nodes. Small lymphocytes (T lymphocytes)
proliferate in response to the antigenic stimulus to give rise to specifically
sensitized lymphocytes. After several weeks, these lymphocytes enter the blood
stream and circulate for long periods of time. Subsequent restimulation of
these sensitized lymphocytes with the same or a similar antigen, such as the
intradermal injection of tuberculin, evokes a local reaction mediated by these
The tuberculin reaction is characterized by the early
predominance of mononuclear cells (small and medium sized lymphocytes and
monocytes). Only a small proportion of these cells appear to be lymphocytes
sensitized to tuberculin. Most cells are brought into the reaction through the
release of biologically active substances by sensitized lymphocytes. An increase
in vascular permeability leading to erythema and edema also occurs in
Characteristically, delayed hypersensitivity reactions to
tuberculin begin at 5 to 6 hours, are maximal at 48 to 72 hours and subside
over a period of days. In those who are elderly or those who are being tested
for the first time reactions may develop slowly and may not peak until after 72
hours. Immediate hypersensitivity
reactions to tuberculin or to constituents of the diluent can also occur.
Not all infected persons will have a delayed
hypersensitivity reaction to a tuberculin test. A large number of factors has
been reported to cause a decreased ability to respond to the tuberculin test in
the presence of tuberculous infection including viral infections (measles,
mumps, chickenpox), live virus vaccinations (measles, mumps, polio),
overwhelming tuberculosis, other bacterial infections, drugs (corticosteroids
other immunosuppressive agents), and malignancy. 7
INDICATIONS AND USAGE
Tubersol® is indicated as an aid in the detection of
infection with Mycobacterium tuberculosis.
For the initial intracutaneous (Mantoux) tuberculin test
it is customary to use 5 U.S. units (TU) per test dose of 0.1 ml. The 1 TU per
test dose (0.1 ml) preparation is used for individuals suspected of being
highly sensitized since larger initial doses may result in severe skin
reactions. The preparation containing
250 TU per test dose (0.1 ml), should be used exclusively for the testing of
individuals who fail to react to a previous injection of 5 TU and under no
circumstances is it to be used for the initial injection.
Tubersol® should not be administered to known tuberculin
positive reactors because of the severity of reactions (eg. vesiculation,
ulceration or necrosis) that may occur at the test site in highly sensitive
Tubersol® 250 TU per test dose (0.1 ml) is not, under any
circumstances, to be used for the initial injection.
Avoid injecting Tubersol® subcutaneously. If this occurs,
no local reaction will develop, but a general febrile reaction and/or acute
inflammation around old tuberculosis lesions may occur in highly sensitive
A separate sterile syringe and needle must be used for
each individual injection to prevent the possibility of transmission of viral
hepatitis or other infectious agents from one person to another.
The possibility of allergic reactions in individuals
sensitive to the components of the product should be borne in mind. Epinephrine
Hydrochloride Solution (1:1000) should be readily available for use in case an
anaphylactic or acute hypersensitivity reaction occurs. Failure to store and handle Tubersol® as
recommended will result in a loss of potency and inaccurate test results.
b) Information for
Reactivity to the test may be depressed or suppressed
for as long as 5 to 6 weeks in individuals who have received concurrent or
recent immunization with certain virus vaccines (measles, influenza), who have
had viral infections (rubeola, influenza, mumps and probably others) or who are
receiving corticosteroids or immunosuppressive agents. In those who are elderly or being tested for
the first time reactions may develop slowly and may not peak until after 72
Vesiculation, ulceration or necrosis may appear at the
test site in highly sensitive persons. Pain, pruritis and discomfort at the
site may also occur.
Since a positive tuberculin reaction (10 mm or more)
does not necessarily indicate the presence of active tuberculous disease,
individuals showing such positive tuberculin reactions should be subjected to
other diagnostic procedures, such as X-ray examination of the chest and
microbiological examination of the sputum.
In the case of the doubtful tuberculin reactions (5 to
9 mm) to 5 TU, the possibility should not be excluded that the skin sensitivity
is due to previous contact with atypical mycobacteria or previous BCG vaccination.
In the absence of signs of tuberculous disease, differential diagnosis by means
of intracutaneous skin tests with PPDs derived from atypical mycobacteria may
d) Drug Interactions
Reactivity to the test may be depressed or suppressed
in individuals who are receiving corticosteroids or immunosuppressive
agents. Reactivity to PPD may be
temporarily depressed by certain live virus vaccines (measles, mumps, rubella).
Therefore, if a tuberculin test is to be performed, it should be administered
either before or simultaneously with the injection of measles, mumps and
rubella vaccines in combined form or as separate antigens.
Mutagenesis, Impairment of Fertility The product is not used for extended
treatment over a long period of time.
f) Pregnancy Category
Animal reproduction studies have not been conducted
with Tubersol®. It is also not known whether Tubersol® can cause fetal harm
when administered to a pregnant woman or can affect reproduction capacity.
Tubersol® should be given to a pregnant woman only if clearly needed.
However, the risk of unrecognized tuberculosis and the
close post partum contact between a mother with active disease and an infant
leaves the infant in grave danger of tuberculosis and complications such as
tuberculous meningitis. Therefore, the prescribing physician will want to
consider if the potential benefits outweigh the possible risks for performing
the tuberculin test on a pregnant woman or a woman of childbearing age, particularly
in certain high risk populations.
In highly sensitized individuals, strongly positive
reactions including vesiculation, ulceration or necrosis may occur at the test
site. Cold packs or topical steroid preparations may be employed for
symptomatic relief of the associated pain, pruritus and discomfort.
Strongly positive reactions may result in scarring at the
Immediate erythematous or other reactions may occur at the
The reason(s) for these infrequent occurrences are
DOSAGE AND ADMINISTRATION
The Test: The
Mantoux test is performed by intracutaneously injecting, with a syringe and
needle, 0.1 ml of Tubersol®. It is customary to use 5 TU per test dose. The 1
TU per test dose preparation is used for individuals suspected of being highly
sensitized since larger initial doses may result in severe skin reactions. The
preparation containing 250 TU per test dose should be used exclusively for the
testing of individuals who fail to react to a previous injection of 5 TU and
under no circumstances is it to be used for the initial injection.
The result is read 48 to 72 hours after administration and
induration only is considered in interpreting the test.
Method of Administration: The following procedure is recommended for performing the
The site of the test is the flexor surface of the
forearm about 4 inches below the bend of the elbow.
The skin of the forearm is first cleansed with alcohol
and allowed to dry.
The test dose (0.1 ml) of Tuberculin PPD is
administered with a 1 ml syringe calibrated in tenths and fitted with a short,
one-half inch, 26 or 27 gauge needle.
Disposable sterile syringes and needles may be used.
Glass syringes and needles should be sterilized by autoclaving (121°C for 30
minutes), by boiling or by the use of dry heat. Do not sterilize by means of
The rubber cap of the vial should be wiped with sterile
piece of cotton moistened with alcohol and allowed to dry. The needle is then
inserted gently through the cap and the required amount of Tuberculin PPD is
drawn into the syringe.
The point of the needle is inserted into the most
superficial layers of the skin with the needle bevel pointing upward. If the intracutaneous
injection is performed properly, a definite white bleb will rise at the needle
point, about 10 mm ( 3 / 8 ) in diameter. This will disappear within minutes.
No dressing is required.
In the event of a subcutaneous injection (i.e. no bleb formed),
the test should be repeated immediately at another site.
Tubersol® is a stabilized solution of Tuberculin PPD. Data
indicates that Tubersol® will remain stable for at least four weeks when
prefilled into syringes and stored between 2° and 8°C. 4 However, in order to
avoid possible contamination of the product this practice is not recommended.
Parenteral drug products should be inspected visually for
particulate matter and discoloration prior to administration, whenever
solutions and container permit.
Interpretation of the Test: The test should be read 48 to 72 hours after administration of
Tubersol®. Sensitivity is indicated by induration, usually accompanied by
erythema. The widest diameter of distinctly palpable induration should be
recorded in millimeters (mm). Presence of edema and necrosis should also be
A positive reaction indicates a sensitivity to tuberculin,
which may be the result of a previous infection with mycobacteria. This
infection, likely due to Mycobacterium tuberculosis, may have occurred years
ago or may be of recent origin.
Reactions should be interpreted as follows:
Positive ReactionAny palpable induration measuring 10 mm
or more is considered a positive reaction. In the case of tuberculosis suspects
or close contacts of individuals with tuberculosis an induration of 5 mm or
even smaller should be interpreted as a positive reaction and appropriate
additional follow-up measures indicated.
Doubtful ReactionInduration measuring 5 to 9 mm indicates
a doubtful reaction. Retesting is indicated using a different site and 5 TU per
The possibility should not be excluded that the skin
sensitivity is due to previous contact with atypical mycobacteria or previous
Negative ReactionInduration of less than 5 mm is
considered negative. An individual who does not show a positive reaction to
either 1 TU or 5 TU on the first test may be retested with 5 TU and if still
found negative further testing with 0.1 ml containing 250 TU of Tuberculin PPD
(Mantoux) is suggested. If the latter test is employed, it may be given in the
An individual who does not show a positive reaction to an
initial injection of either 1 TU and 5 TU, or 5 TU alone, and to a subsequent
injection of 250 TU of Tuberculin PPD may be considered as tuberculin negative.
Booster EffectInfection of an individual with tubercle
bacilli or other mycobacteria results in a delayed hypersensitivity response to
tuberculin which is demonstrated by the skin test. The delayed hypersensitivity
response may gradually wane over a period of years. If a person receives a tuberculin
test at this time (after several years) the response may be a reaction that is
not significant. The stimulus of the test may boost or increase the size of the
reaction to a second test, sometimes causing an apparent conversion or
development of sensitivity. The booster effect can be seen on a second test
done as soon as a week after the initial stimulating test and can persist for a
year, and perhaps longer.
When routine periodic tuberculin testing of adults is done,
two stage testing should be used to minimize the likelihood of interpreting a
boosted reaction as a conversion, 7,8
Since a positive tuberculin reaction does not necessarily
indicate the presence of active tuberculosis disease, individuals showing a
positive tuberculin reaction should be subjected to other diagnostic
Those individuals giving a positive tuberculin reaction
may or may not show evidence of tuberculosis disease. Chest X-ray examination
and microbiological examination of the sputum in these cases are recommended as
a means of determining the presence or absence of pulmonary tuberculosis.
Tubersol® bioequivalent to 5 U.S. units (TU) PPD-S per test
dose (0.1 ml) is available in 1 ml and 5 ml vials. Tubersol® 1 TU and 250 TU
per test dose (0.1 ml) are available in 1 ml vials. Tubersol® solutions are
ready for immediate use without any further dilution.
Tubersol® should be stored between 2° and 8°C (35° and
46°F). 5,9 Tuberculin solutions can be
adversely affected by exposure to light. The product should be stored in the
dark except when doses are actually being withdrawn from the vial. 10 A vial of Tuberculin PPD which has been
opened and in use for one month should be discarded because oxidation and
degradation may have reduced the potency. 11
NOTE: These photos can be used only for identification by
shape, color, and imprint. They do not depict actual or relative size.
The product samples shown here have been supplied by the
manufacturer and reproduced in full color by PDR as a quick-reference
identification aid. While every effort
has been made to assure accurate reproduction, please remember that any visual
identification should be considered preliminary. In cases of poisoning or suspected overdosage, the drugs
identity should be verified by chemical analysis.
Landi, S.: Preparation, purification, and stability of
Microbiol. 11 : 408-412, 1963.
Canadian Tuberculosis and Respiratory Disease
Association: Classification and reporting of tuberculosis in Canada. Ottawa,
the Association, 1972 p. 42.
Landi, S., Held, H.R., Hauschild, A. H. W., Hilsheimer,
R.: Adsorption of tuberculin PPD to glass and plastic surfaces. Bull. WHO 35 :
Landi, S., Held, H.R., Tseng, M. D.: Disparity of
potency between stabilized and nonstabilized dilute tuberculin solutions. Am.
Rev. Respir. Dis. 104 : 385-393, 1971.
Landi, S., Held, H.R.: Stability of dilute solutions of
tuberculin purified protein derivative. Tubercle 59 : 121-133, 1978.
U.S. Code of Federal Regulations, Title 21, Part 650,
Subpart Btuberculin, 144-146, April 1, 1981.
The Tuberculin Skin Test. Am. Rev. Respir. Dis. 124 :
American Thoracic Society: Diagnostic Standards and
Classification of Tuberculosis and Other Mycobacterial Diseases (14th
ed.), 1980. Am. Rev. Respir. Dis. 123 :
Landi, S., Held, H.R.: Stability of dilute solution of
tuberculin purified protein derivative at extreme temperatures. J. Biol. Stand.
9 : 195-199, 1981.
Landi, S., Held, H.R.: Effect of light on tuberculin
purified protein derivative solutions. Am. Rev. Respir. Dis. 111 : 52-61, 1975.
Landi, S., Held, H.R.: Effect of oxidation on the
stability of tuberculin purified protein derivative (PPD) In: International
Symposium on Tuberculins and BCG Vaccine. Basel: International Association of
Biological Standardization, 1983. (Developments in Biological Standardization)
CONNAUGHT LABORATORIES LIMITED
TORONTO, ONTARIO, CANADA
Connaught Laboratories, Inc.
Swiftwater, Pennsylvania 18370, USA
PASTEUR MÉRIEUX CONNAUGHT
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