INVITED ARTICLE CLINICAL PRACTICE

Ellie J. C. Goldstein, Section Editor

Evolution and Current Use of the Tuberculin Test

Elsie Lee and Robert S. Holzman
Department of Medicine, New York University School of Medicine, New York

Since it was first introduced in the late 1800s, the tuberculin test has undergone continual refinement in its formulation,
standardization, and dosage, as well as its interpretation and indications for use. New guidelines have replaced universal
screening with targeted testing and rigid definitions of positivity with individualized criteria formulated from a Bayesian
approach. This review summarizes the evolution of the test and provides information to help gauge its predictive value.

In 1890, Robert Koch reported to the Tenth International Con-
gress of Medicine in Berlin that Mycobacterium tuberculo-
sis–infected guinea pigs evinced a destructive inflammatory re-
action at the site of injection of heat-killed tubercle bacilli and
extracts prepared from them [1]. Although not the cure he
prematurely announced [2], the description of the Koch phe-
nomenon and tuberculin hypersensitivity led ultimately to the
practical tuberculosis screening tests (TSTs), first introduced
by von Pirquet in 1909 [3] and now in common use today [4].
EVOLUTION OF TUBERCULOPROTEINS
Koch’s “old tuberculin” (OT) was prepared by dissolving, in a
glycerin-containing solvent, the residue from cultures of M.
tuberculosis heated for several hours at 100C and concentrated
10-fold by evaporation. Because of its impurity, toxicity, non-
specificity, and inadequate standardization, Koch’s OT and sev-
eral similar products are not used in TSTs in the United States.
OT was quickly adopted as a screening test for active tuber-
culosis and subsequently for the screening of apparently healthy
people for “inactive” or latent infection. A total of 4 or 5
sequential injections of graded strengths were used until 1932,
when D’Arcy Hart [5] demonstrated that a 1:10 dilution of
OT was the highest concentration needed and that some re-
actions to higher doses were probably not due to M. tuberculosis.
Fenger et al. [6] found that 92% of tubercular patients re-
Received 5 July 2001; revised 25 September 2001; electronically published 13 December
2001.
Reprints or correspondence: Dr. Robert S. Holzman, Dept. of Medicine, New York University
School of Medicine, 550 First Ave., New York, NY 10016 (robert.holzman@med.nyu.edu).
Clinical Infectious Diseases 2002; 34:365–70
 2002 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2002/3403-0011$03.00
acted to 0.01 mg of OT, an amount equivalent to 0.0005 mg
of a more purified material, MA-100. MA-100 preparations
from bovine, avian, and botanical mycobacteria elicited reac-
tions from uninfected persons, again suggesting that reactions
to large doses of OT resulted from sensitization to nontuber-
culous mycobacteria. There was a clear need for a purer tu-
berculin with less propensity to cross-react.
Florence B. Seibert at the Henry Phipps Institute in Phila-
delphia established that OT preparations contained varying
amounts of proteins and polysaccharides and that the proteins
were the relevant TST antigens. She produced purified protein
derivative (PPD), a more consistent and standardizable material
than OT, by steaming cultures of M. tuberculosis in an Arnold
sterilizer and purifying the proteins by repeated precipitation
with neutral ammonium sulfate [7].
In 1939, Seibert [8] prepared a large lot (PPD lot 49608)
that became the reference standard for the US Public Health
Service’s Bureau of Biologics Standards. In 1944 this lot was
renamed PPD-S (“S” meaning “standard”), and in 1952 PPD-
S was adopted as an international standard by the World Health
Organization. By convention, 5 test units (TU) is the bioas-
sayable skin test activity contained in 0.0001 mg of PPD-S [8].
By 1940, standard TSTs used 2 sequential injections: 1 TU
(“first-strength”) and 250 TU (“second-strength”). In 1942,
Furcolow et al. [9] recommended substitution of a single 5 TU
(“intermediate-strength”) injection, on the basis of the fact that
5 TU caused reactions in 99.6% of patients with active tuber-
culosis. They noted that even infants !6 months of age, and
therefore unlikely to be infected, would react if sufficiently high
doses were given. Goddard et al. [10] contemporaneously noted
that intermediate-strength PPD was highly efficient for iden-
tifying persons with tuberculous pulmonary infiltrates or
calcifications.

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 In 1969, Grzybowski et al. [11], and in 1971, Holden et al.
[12] reported inconsistencies when marketed TSTs were com-
pared with PPD-S. Holden et al. [12] found the cause to be
alterations in the delivered dose of PPD due to varying degrees
of adsorption by surfaces of syringes and containers. In 1972,
the Division of Biologics Standards mandated that stabilized
liquid formulations replace tableted PPD formulations (which
lost more activity as the time between adding of diluent and
use increased). In addition, all commercially produced, stabi-
lized, PPDs were required to be bioassayed and shown equi-
potent to 5 TU of PPD-S before marketing. Since then, master
lots of PPD products marketed in the United States have been
standardized by bioassay in both tuberculin-sensitized guinea
pigs and skin test–positive humans.
Nontuberculous mycobacteria contain proteins analogous to
those of M. tuberculosis, and considerable cross-reactivity exists.
PPD-B (from Mycobacterium intracellulare), PPD-G (Myco-
bacterium scrofulaceum), and PPD-Y (Mycobacterium kansasii)
have been helpful in epidemiological studies and in clarifying
the interpretation of modest degrees of reactivity to the PPD
of M. tuberculosis. Their clinical role is limited [13], because
no standard comparable to PPD-S exists and they are not com-
mercially available.
Two commercial TSTs are marketed in the United States:
Aplisol (Parkdale Pharmaceuticals) and Tubersol (Connaught).
Although each is tested for bioequivalence to PPD-S, numerous
reports state that Aplisol elicits more or larger reactions [14].
Other reports document equivalence [15], although this has
been challenged [16]. It is best to use one of these products
consistently and not shift from one to the other.
Outside of the United States, another purified protein de-
rivative, RT-23, is used. Introduced in 1958 by the World Health
Organization, the master batch was prepared at the Statens
Serum Institute and standardized by bioassay [17]. The stan-
dard skin test dose for RT-23 is 2 TU, and human testing
indicated that reactions in sensitive persons, tested simulta-
neously, averaged 16.8 mm for 2 TU of RT-23 and 18.7 mm
for 5 TU of Tubersol [18]. Field studies have questioned
whether preparations of RT-23 have lost potency over time [19,
20] and, in response, Statens Serum Institute has published its
quality control data and information suggesting that reported
declines in RT-23 potency result from dilution and handling
at local sites and not from a change in the product as manu-
factured [18]. Additional studies suggest comparable results
with the two preparations [21, 22].
It has been 160 years since Seibert produced PPD-S. To
anticipate the eventual depletion of this primary standard, Vil-
larino et al. [23] have developed a new batch of PPD, PPD-
S2, and compared the old and new standards in a randomized,
double-blinded clinical trial to establish relative potency.
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TESTING TECHNIQUES
Several techniques have been used for tuberculin skin testing.
Multiple puncture tests, such as the Heaf test, tine test, and
MONO-VACC test, used concentrated tuberculin, but the var-
ying dose of PPD or OT contained on each tine results in
inadequate sensitivity and specificity. Intracutaneous injections
may be given by the jet injector or by the Mantoux test, but
only the Mantoux test is recommended for clinical assessment
or screening. It is more sensitive and specific than the other
methods [24]. In the Mantoux test, 0.1 mL of PPD solution is
injected intracutaneously with a #27 steel (or #26 platinum)
needle attached to a 1.0-mL syringe. Creation of a visible wheal
is crucial; subcutaneous administration will result in a false-
negative test. After 48 h, the diameter of induration transverse
to the long axis of the forearm is measured. A number of
specialized rulers and other aids to assessment of reaction size
have been advocated, such as drawing a ballpoint pen across
the skin to mark the border, but accurate measurement requires
experience.
The tuberculin reaction, which is read after 48 h, is a delayed-
type hypersensitivity reaction. Sensitivity develops 2–12 weeks
after infection with M. tuberculosis [25]. Macroscopically, red-
ness and induration at the site peaks at 48–72 h and slowly
wanes over several days. Intense reactivity may be associated
with fever, more general swelling of the limb, regional lym-
phadenopathy, or rarely lymphangitis (H. S. Lawrence, personal
communication) [26]. Microscopically the test site shows
edema and a dense infiltration of the dermis by mononuclear
cells, especially around small blood vessels.
Immediate or accelerated reactions to TSTs occur occasion-
ally. Urticarial reactions may occur within 20 min of admin-
istration, possibly because of reactivity with polysaccharides in
the test material. Accelerated reactions may represent Arthus
reactivity, generally peaking within the first 24 h and blending
with an evolving delayed-type reaction. Immediate and hyper-
sensitivity reactions to constituents of the diluent can also oc-
cur. These reactions occur within 24 h and should not be con-
fused with delayed-type hypersensitivity [27]. Repeated
tuberculin skin testing will not cause a truly tuberculin-negative
person, who has never been infected with M. tuberculosis or
sensitized to other mycobacteria, to become TST-positive [28].
In some M. tuberculosis–infected persons, the ability to react
to TST diminishes over time. Administration of a TST to them
can restore reactivity, boosting the response to future TSTs [29].
Believed to result from recall of waned, cell-mediated immunity,
boosting is common in persons 155 years of age and in those
born outside the United States who have been vaccinated with
BCG. Two-step tests are used to avoid interpreting the boost
as a new infection. If the reaction to the first TST is negative,
a TST is repeated in 1–3 weeks. The second test is interpreted
as measuring the degree of reactivity. Two-step testing is es-
 pecially important when initially testing persons who have not
had a test in the prior 12 months and will be subject to regular
testing in the future, such as health care workers and employees
and residents of congregate settings. In a study of 1478 hospital
employees retested within a 7-day period, the mean difference
in reaction size between the first and the second TST was 0.54
mm (P ! .001). Fifty-four (3.7%) had a ⭓6-mm increase in
induration, with a diameter of 110 mm on the second test.
The average increase was 13 mm [30].
EVOLUTION OF CURRENT PRACTICES
AND GUIDELINES
During much of the past 50 years, TSTs were used for universal
screening of the general population and periodic screening of
high-risk populations [27, 31]. Current guidelines suggest that
low-risk persons in the US general population need not receive
routine screening [32]. The anticipated yield is low, and there
is an increasing risk of false-positive results due to the low
prevalence of latent tuberculous infection but high prevalence
of sensitization to nontuberculous mycobacteria. Groups of
high-risk adults and children in whom screening is likely to be
productive have been defined, and consensus recommendations
of the American Thoracic Society (ATS) [32] and Centers for
Disease Control and Prevention (CDC) [33] can be viewed on
the Internet at http://www.thoracic.org/statements/. They have
been endorsed by the Infectious Diseases Society of America
and the American Academy of Pediatrics.
ATS/CDC guidelines emphasize that administering a TST
implies a commitment to administer therapy if latent infection
is diagnosed. Over the last half of the 20th century, there has
also been an evolution in the definition of what degree of
reactivity is accepted as diagnostic of latent infection. In 1952,
Palmer and Bates [34] established that among hospitalized pa-
tients with (predominantly pulmonary) tuberculosis, reactions
averaged a mean (SD) of 18.3  5.3 mm. Evidence that sim-
ilar reactivity occurred in those with active and latent tuber-
culosis was obtained in a 1962 study of Alaskan Inuit, among
whom tuberculosis was prevalent but exposure to nontuber-
culous mycobacteria was absent [35]. The data showed a bi-
modal distribution of reactions with peaks at 0 and 18 mm
and few reactions between 2 and 5 mm. Because cross-reactivity
was not an issue, the authors concluded that Inuit with 15 mm
of induration should be considered to be infected with M.
tuberculosis.
Between 1958 and 1964, a total of 643,694 male navy recruits
were enrolled in a large study conducted by the US Public
Health Service [36]. This included persons sensitized to non-
tuberculous mycobacteria, M. tuberculosis, or both. In contrast
to the sharply separated bimodal distribution seen in the Inuit,
there was much greater overlap. By subtracting the imputed
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distribution of the M. tuberculosis–infected, it was possible to
infer the shape of the distribution of those reactions due to
nontuberculous mycobacteria. At ⭐5 mm, virtually all reactiv-
ity could be so ascribed (“negative”). Above 10 mm, almost all
reactivity could be ascribed to M. tuberculosis (“positive”). Be-
tween 6 mm and 10 mm, however, reactivity might well be due
to either (“indeterminate”). Figure 1, redrawn from [37], con-
trasts the distributions of PPD reactions seen among the recruits
with that seen among the Inuit.
Over the last 2 decades, a Bayesian approach to the inter-
pretation of TSTs has replaced rigid criteria for positive, neg-
ative, and indeterminate tests. Under ATS/CDC guidelines, the
criterion for a positive test (i.e., a test indicative of tuberculous
infection) is determined by assigning the testee to 1 of 3 pretest
risk levels, on the basis of both the prevalence of infection in
similar testees and an assessment of risk of the progression of
latent to active infection. Reactions of ⭓5 mm of induration
are considered positive for those at highest risk, ⭓10 mm for
those at intermediate risk, and ⭓15 mm for those at low risk
and who would not be otherwise targeted for a TST (table 1).
Rose et al. [38] calculated the sensitivity and specificity of
the Mantoux test from the data provided by the navy recruits.
Sensitivity was 1.00 at a 2-mm cutoff, falling to 0.59 at a 16-
mm cutoff. Specificity was 1.0 at a 14-mm cutoff, falling to
0.95 at a 2-mm cutoff. The area under the receiver operating
characteristic curves was 0.994–0.998, indicating that the test
discriminated well between M. tuberculosis–infected and –un-
infected persons. Results of a second analysis of a different test
population showed similar results and demonstrated that sen-
sitivity and specificity did not depend on the prevalence of
tuberculosis.
We used data from Rose et al. [38] to calculate, for each of
Figure 1. Frequency distribution of tuberculin purified protein deriv-
ative reactions observed in 643,694 navy recruits and 865 Inuit (redrawn
from [37]).
CLINICAL PRACTICE • CID 2002:34 (1 February) • 367
 Table 1. American Thoracic Society and Centers for Disease Control and Prevention criteria for tuberculin positivity, by risk
group.

Reaction ⭓5 mm of induration Reaction ⭓10 mm of induration Reaction ⭓15 mm of induration

HIV-positive persons
Recent contacts of TB case patients
Fibrotic changes on chest radiograph
consistent with prior TB
Patients with organ transplants and
other immunosuppressed patients
(receiving equivalent of ⭓15 mg of
b
prednisone/day for ⭓1 month)
Recent immigrants (within last 5 years) from high-prevalence Persons with no risk factors for TB
countries
Injection drug users
a
Residents and employees of following high-risk congregate set-
tings: prisons and jails, nursing homes and other long-term facili-
ties for the elderly, hospitals and other health care facilities, resi-
dential facilities for patients with AIDS, and homeless shelters
Mycobacteriology laboratory personnel
Persons with following clinical conditions that place them at high
risk: silicosis, diabetes mellitus, chronic renal failure, some hema-
tologic disorders (e.g., leukemias and lymphomas), other specific
malignancies (e.g., carcinoma of head or neck and lung), weight
loss of ⭓10% of ideal body weight, gastrectomy, and jejunoileal
bypass
Children !4 years of age or infants, children, and adolescents ex-
posed to adults at high risk

NOTE. Criteria are from [32, 33].

a
For persons otherwise at low risk and tested at start of employment, reaction of ⭓15 mm of induration is considered positive.
b
Risk of TB in patients treated with corticosteroids increases with higher dose and longer duration.

the currently recommended cutoffs, the predictive value (or
posttest probability) of a positive and a negative TST result as
a function of the prevalence of tuberculous infection (or pretest
probability). Figure 2 should be helpful in approximating the
reduction in uncertainty afforded by a positive or negative test.
To provide perspective, some relevant approximate estimates
of prevalence include ∼1% in US children entering school,
∼5%–10% in the total US population, and ∼25% among con-
tacts of a new case of tuberculosis [23].
ANERGY TESTING
such as thrombolysis, immediate-type allergy testing, or desen-
sitization therapy, and modified by the user for Mantoux test-
ing. Skin reactions could be produced in most persons by suit-
ably increasing the doses of the antigens, and there was no
standardization as to what degree of reactivity to the anergy
panel would predict tuberculin reactions of any given size. De-
spite this, anergy testing became popular in the last quarter of
the 20th century and it was only in 1997 that CDC guidelines
recommended that an anergy panel should not be done in
conjunction with a TST to assess an HIV-infected person’s risk
for tuberculous infection [40].

Many studies attest that some with tuberculosis will not react
or have only small reactions, especially those with disseminated
or advanced tuberculosis, severe malnutrition, and immune
deficiency due to HIV or immunosuppressive chemotherapy.
To assess whether someone with suspected tuberculosis but a
negative TST result was capable of mounting a cellular immune
reaction, it became popular to test with a battery of ubiquitous
antigens, such as streptokinase, Candida extract, Trichophyton
extract, and mumps antigen. In addition, a multiple-puncture
antigen test was developed by Merieux Diagnostics. The com-
bination of a positive anergy panel result and a negative TST
result for a patient with pulmonary disease consistent with
tuberculosis was to be taken as evidence against the diagnosis
[39]. Anergy testing was also advocated to assess the degree of
immune suppression of persons with HIV infection.
Several problems attended the interpretation of anergy tests.
Most of the antigens were actually marketed for other purposes,
SPECIAL POPULATIONS
Recipients of BCG. BCG vaccine has never been recom-
mended for routine use in the United States. Aside from efficacy
issues, the major argument against its use has been the desir-
ability of preserving the utility of the TST by keeping the prev-
alence of positive tuberculin tests low.
Postvaccination BCG-induced tuberculin reactivity ranges
from no induration to induration of 15 mm at the skin test
site [41]. Twelve weeks after vaccination, 190% of BCG vac-
cinees will have developed tuberculin reactions of ⭓10 mm.
This reaction wanes over the subsequent decade [42, 43] but
may be maintained by boosting from repetitive TSTs or if con-
comitant infection with M. tuberculosis occurs [44].
Current ATS/CDC recommendations are that BCG vaccinees
receive a TST when warranted by increased risk for recent
infection or medical condition. Under the guidelines, the cri-

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 Figure 2. Predictive value (posttest probability of presence or absence of tuberculous infection) of tuberculin skin test (TST) as function of population
prevalence of tuberculous (TB) infection. Data were calculated from [38] by use of standard formulas.
teria for test positivity are similar to those for unvaccinated
persons. Because the prevalence of boosting is higher among
BCG recipients than among unvaccinated persons, we believe
that it is prudent to use a 2-step test to evaluate those vaccinated
15 years before the TST.
Infants and children. As in adults, a Mantoux test with
5 TU of PPD is used for tuberculin skin tests in infants and
children. Universal testing of children, including screening in
school-based programs, has a low yield of positive results and
a large proportion of false-positive results [45, 46], resulting
in the inefficient use of health care resources. ATS/CDC guide-
lines advocate the replacement of universal screening with tar-
geted skin testing of selected groups at increased risk. A child
can receive a TST simultaneously with immunizations, includ-
ing live virus vaccines. Prior BCG vaccination is not a contra-
indication to an indicated TST.
The interpretation of TST results in children is based on a
Bayesian approach analogous to that in adults. ATS/CDC guide-
lines should be consulted for specific criteria.
HIV-infected persons. A TST reaction of ⭓5 mm in per-
sons who are infected with HIV is considered “positive” (table
1), but if the HIV-positive person is known to have been ex-
posed to a case and there is any palpable reaction whatsoever,
the possibility that the reaction represents tuberculous infection
should be considered. With the success of effective antiretroviral
therapy, repeat TSTs may be indicated for HIV-infected persons
who were TST-negative on initial evaluation and whose general
health has been restored.
Recent immigrants from high-prevalence countries. In
1986, there were 4925 cases among foreign-born persons in the
United States (22% of total) and in 1997 there were 7702 (39%
of total). ATS/CDC guidelines are that those who immigrated
to the US from high prevalence countries within the 5 years
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before assessment be considered TST-positive if the reaction is
⭓10 mm.
CONCLUSION
Over the last century, the decline in tuberculosis and the ev-
olution of tuberculin testing have resulted in the creation of a
very useful test for latent M. tuberculosis infection. Eradication
of tuberculosis from the United States will require identification
of such cases and the administration of effective therapy to
prevent reactivation.
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