INT J TUBERC LUNG DIS 2(10):857–860
© 1998 IUATLD
SHORT COMMUNICATION
Tuberculin PPD RT23: has it lost some of its potency?
S. J. Kim, Y. P. Hong, G. H. Bai, E. K. Lee, W. J. Lew
Korean Institute of Tuberculosis, Korean National Tuberculosis Association, Seoul, Korea
SUMMARY
PPD RT23 is a tuberculin that is used worldwide. Korea
has been using 1TU RT23 for its nationwide tuberculosis prevalence surveys at five-yearly intervals since 1965,
and found a drop in its potency after the 1975 survey.
This finding draws attention to the interpretation of
tuberculin survey data observed with RT23 at different
time periods.
K E Y W O RD S : tuberculin RT23; potency
TUBERCULIN SKIN TESTING is the only tool for
diagnosing tuberculosis (TB) infection, although its
sensitivity and specificity are not faultless.1–4 The
prevalence or incidence of tuberculosis infection, which
is an important epidemiological parameter, can be
measured only by tuberculin testing. However, the
potency of the tuberculin must be stable; if it is not, it
would be difficult to compare the data observed at
different time frames.
Because the various preparations of tuberculin varied in potency, it was necessary to produce a large single batch of tuberculin to make the standardization of
every new batch of tuberculin unnecessary, and to
improve the comparability of data on tuberculin testing in different areas and at different periods.3 This
led the Statens Serum Institute, in Copenhagen, Denmark, to produce a special batch of tuberculin, PPD
RT23, by agreement with UNICEF and the World
Health Organization (WHO) in 1958.2–4
Korea has used this tuberculin not only for its
nationwide TB prevalence surveys, conducted since
1965 at five-yearly intervals,5 but also to evaluate its
BCG vaccination programme. The findings from the
surveys cast doubts on the potency of 1TU of PPD
RT23, the dosage used in the last seven surveys.5 This
paper aims to present these findings in order to create
discussion as to the potency of PPD RT23, as 2TU of
RT23 is recommended as a standard dose by both the
WHO and the IUATLD.
1995 surveys.5 The data necessary for discussion
within the scope of this paper were analyzed.
Tuberculin PPD RT23 (1TU) was purchased
directly or through UNICEF from Statens Serum
Institute, Copenhagen, for all except the most recent
survey (1995). For the 1995 survey, tuberculin was
diluted at the Korean National Institute of Health with
a concentrated tuberculin provided by Statens Serum
Institut, using a procedure described by Magnusson.6
Tuberculin skin testing was performed by nurses
trained by international experts. Tuberculin was injected intradermally in the volar skin of the left forearm, and the reaction (induration) sizes were measured transversely.
MATERIALS AND METHODS
The Korean nationwide surveys5 have been carried
out with sample populations selected by the multistage stratified sampling method since 1965, at fiveyearly intervals. Tuberculin testing was done for all
age groups in 1965, 1970, 1975 and 1990, and for
those under 30 years of age in the 1980, 1985 and
RESULTS AND DISCUSSION
The prevalence of tuberculosis infection in children
aged 5–9 years was 33.7% in the 1965 survey,5
26.1% in 1970, 15.9% in 1975, 12.6% in 1980,
8.9% in 1985, 8.1% in 1990, and 3.4% in 1995,
when the cut-off point was arbitrarily taken at 10 mm
induration. The average annual risks of infection,
based on the prevalences of TB infection in the years
of the surveys, were respectively 5.3%, 3.9%, 2.3%,
1.8%, 1.2%, 1.1% and 0.5%. Reductions in the
prevalence of infection correlated fairly well with a
decreasing prevalence of smear-positive cases, i.e.,
640 per 100 000 population in 1965, 575 in 1970,
480 in 1975, 309 in 1980, 239 in 1985, 143 in 1990,
and 93 in 1995.5
As seen in Figure 1, the bimodal distributions of
the tuberculin reactions are distinct except in the last
two surveys. The mode of reactors was found at 18–
19 mm in the 1965, 1970 and 1975 surveys, while it
shifted to the left in the following survey years, to 14–
15 mm in 1980, 16–17 mm in 1985, and 14–15 mm
in 1990. It was not clear in the 1995 survey. The anti-
Correspondence to: Dr S J Kim, Director, Korean National Tuberculosis Association, 14 Woomyundong, Sochogu, Seoul
137-140, Korea.
858
The International Journal of Tuberculosis and Lung Disease
Figure 1 Tuberculin skin reactions of 5–9-year old children without BCG scar in the 7 nationwide tuberculosis prevalence surveys,
1965 to 1995.
mode was distinct in the 1965 to 1975 surveys, thus it
was easy to distinguish positive reactors from negative reactors by the arbitrarily chosen cut-off point of
10 mm. It is not clear, however, that the 10 mm cutoff point could be reasonable or acceptable for measuring positive reactors in the following survey years.
The shift in mode was also observed in Vietnam
between the 1961–1962 survey and the 1986–1989
survey, when non-BCG-vaccinated children approximately 7.5 years of age were tested with 1TU of
tuberculin PPD RT23.7
It is not clearly understood what factors led to this
shift in mode. It is assumed that the mode might have
shifted from right to left due to 1) the reduced risk of
reinfection, which, in turn, might result in a decrease
in larger reactions; 2) the appearance of non-specific
reactions induced by mycobacteria other than Mycobacterium tuberculosis (MOTT), as a result of reduced
risk of TB infection; 3) the effects of expanding BCG
vaccination coverage; 4) a change in the potency of
tuberculin PPD RT23 (1 TU); 5) the technical variations in tuberculin testing, especially in reading tuberculin reactions; or 6) some other reason.
The reduced risk of reinfection seems to be irrelevant because the prevalence of TB infection decreased
continuously from 1965 to 1975 with no shift in the
mode. Heterologous tuberculin reactions in MOTTsensitized individuals should be smaller than the
homologous reaction, so the mode would shift left.
However, this would occur gradually, and the shift in
mode in our surveys was quite abrupt after 1975.
Thus the MOTT hypothesis seems improbable.
BCG vaccination coverage revealed by scar observation increased gradually from 28.1% in the 1965
survey to 54.4% in 1970, 72.7% in 1975, 74.2% in
1980, 75.7% in 1985, 77.9% in 1990, and 84.1% in
1990. However, the effect of increased BCG vaccination coverage on the shift in the mode is also uncertain. Technical variations also seem unrelated to a
mode shift, as all health workers who participated in
tuberculin skin testing were trained in standardized
techniques by international experts.
So how can it be explained? It is axiomatic that the
mode should not shift if the potency of the tuberculin
remains unchanged. We therefore compared the tuberculin reaction patterns of bacteriologically proven TB
patients screened in the 1975 and 1990 surveys. As
seen in Figure 2, the reaction patterns show a distinct,
unimodal distribution. The patients screened in the
1975 survey showed a distinct mode at 18–19 mm,
with a mean induration size of 18.4 mm, while those
found in the 1990 survey showed a mode at 14–15
mm, with a mean induration of 15.1 mm. The difference was statistically significant (P 0.01), and was
not influenced by age and sex distribution because no
significant difference in reaction pattern was observed between the different age and sex groups. Thus
it seems clear that the shift in mode after the 1975
Short Communication
Figure 2
859
Tuberculin skin reactivity of the patients with pulmonary tuberculosis found in 1975 and 1990 surveys.
survey resulted from a change in the potency of tuberculin PPD RT23 1 TU.
The findings in 159 Cambodian smear-positive TB
patients tested with RT23 1 TU were even worse,
showing an induration size of 11.2 ± 3.3 mm, and a
mode appearing at 10–11 mm.8
Possible factors leading to a loss in the potency of
tuberculin RT23 1 TU could conceivably be dilution
error and/or denaturation of certain antigenic components by oxidation on long-term storage.9,10 Although the manufacturers have used strict production
controls, it is not clear what factors may have caused
the loss of potency in the tuberculin.
CONCLUSION
Tuberculin PPD RT23, which was adopted as a standard tuberculin by the WHO and the IUATLD, has
been found unstable in its potency, which is reflected
in the observed shift in mode in the distribution of
tuberculin reaction sizes in healthy infected children
and in TB patients. We need to understand the cause
of such an unprecedented and disturbing finding, by
calling for more studies and asking other TB workers
who have ideas or better yet, data, to join in the
discussion.
References
1 Rieder H L. Methodological issues in the estimation of the
tuberculosis problem from tuberculin surveys. Tubercle Lung
Dis 1995; 76: 114–121.
2 Arnadottir T, Rieder H L, Trébucq A, Waaler H T. Guidelines
for conducting tuberculin skin test surveys in high prevalence
countries. Tubercle Lung Dis 1996; 77 (Suppl): 1–20.
3 World Health Organization. The WHO standard tuberculin
test. WHO/TB/Technical Guide/3; Geneva; WHO 1963.
4 Edwards P Q, Edwards L B. Story of the tuberculin test. Am
Rev Respir Dis 1960; 81 (No 1, Part 2).
5 The Ministry of Health and Welfare, Korean National Tuberculosis Association. Reports on the tuberculosis prevalence
surveys in Korea (in Korean). Seoul, 1965, 1970, 1975, 1980,
1985, 1990, 1995.
6 Magnusson M, Bentzon M W. Preparation of purified tuberculin RT23. Bull World Health Organ 1958; 19: 829–843.
7 Broekmans J. The tuberculosis problem in Vietnam and its
trend. Preliminary results of the WHO resurvey. Tuberculosis
Surveillance Research Unit of the IUATLD, Progress report
1989. Volume 2.
8 The Office of the WHO Representative to Cambodia. Tuberculin reaction of smear positive tuberculosis patients, Phnom
Penh in 1995. WPR-Memorandum dated 19 September 1997.
(unpublished data)
9 Landi S. Production and standardization of tuberculin. In: Kubica G P, Wayne L G, ed. The mycobacteria, a source book.
New York and Basel; Marcel Dekker, 1984: pp 505–535.
10 Volkin D B, Klibanov A M. Minimizing protein inactivation.
In: Creighton T E, ed. Protein function, a practical approach.
New York; IRL Press 1989: p 6.
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The International Journal of Tuberculosis and Lung Disease
RÉSUMÉ
La PPD RT23 est une tuberculine d’usage mondial. La
Corée a utilisé 1 UI de RT23 pour les enquêtes nationales de prévalence de l’infection tuberculeuse, à un
intervalle de 5 ans depuis 1965, et a mis en évidence une
certaine perte d’efficacité après l’enquête de 1975. Cette
observation attire l’attention sur les conséquences
qu’elle peut avoir sur l’interprétation des données
d’enquêtes tuberculiniques réalisées avec la RT23 à des
périodes différentes.
El PPD RT23 es la tuberculina usada en todo el mundo.
Corea ha usado 1 UT de RT23 para las encuestas
nacionales de prevalencia de la tuberculosis cada 5 años
desde 1965 y ha encontrado cierta disminución en su
potencia después de 1975. Estos hechos llaman la atención sobre la interpretación de los datos de las encuestas
efectuadas con RT23 en diferentes períodos.
RESUMEN