319
CONTRIBUTORS’
SECTION
PUBLIC
HEALTH,
NURSING,
MEDICAL
SOCIAL
WORK
Myron E. Wegman, M.D., Contributing Editor
As a pediatric problem, tuberculosis has undergone striking chamige in the past decades, vet
few diseases have the complicated interrelationship of personal and community significance that
is peculiar to tuberculosis. Management of the tuberculous patient has become largely a matter for hospital and specialized outpatient services, and the individual practitioner has been chiefly
concerned with case finding in his own practice. Since the tuberculin test is such an important tool in this respect, the editors thought such a review as presented by Dr. Feldmamin of particular importance.
A fluml)er of controversial poimits are touched on. In any public health procedure a routine
screemiing test has value in relation to the proportion of positives likely to result. A test which
results in more than 50% positive is not very helpful. On the other hand, a test with one positive in 1 ,000 is probably too expelisive. Dr. Feldmann points out the cogent reasons for routine tuberculin testing and the pediatrician will need to consider these reasons in the light of the conditiomis in his community and the relevant local and state health program.
Some miav be disturbed by the criticism made of the patch test, yet it is important to recognize
its limitations. Failure of the patch test to detect all positives has been well known amid most
pediatricians have thought it useful chiefly as a preliminary test to find the more sensitive reac-tors. Advantages such as simplicity, reads’ availability for individual use, lack of need for needles
or sterile technique have been great inducements. If, however, one wishes to be able to say with
confidence to a paremit that his child is not infected with tuberculosis, only a Mantoux test will
do. Fumrthermore, evidence that an appreciable number of positives to the patch test may be erroneous leads to the conclusion that in its present form the patch test is of limited usefulness.
Dr. Feldmamin is Medical Director and Director of Medical Research of the National
Tuber-culosis Association, a position to which he came from a distinguished career in epidemiology and
general public health, followed by specialization in the field of tuberculosis. The tuberculin test has been omie of his chief interests and he has written extensively on the subject. Physicians mas’
obtain additional material on tuberculosis through their local Tuberculosis Association or through the National Tuberculosis Association at 1790 Broadway, New York 19, N.Y.
MEW.
THE
PRACTICAL
VALUE
OF
THE
TUBERCULIN
TEST
By Floyd M. Feldmann, M.D.
Medical Director, National Tuberculosis Association
T
lIE TUBERCULIN ‘I’EST has long l)een ac- s’here, have Providied nitich ValtIal)leSI)e-cel)tedi as a simple aiid highly specific cific information. There is still niuch to be test for tile presence of tuberculous infec- learned.
tion, but its possibilities and also its
limita-tions tend to be overlooked. The large-scale SIGNIFICANCE OF DOSE OF
studies done in recent years by the Tuber- TUBERCULIN
cumlosis Research Office of the World Health For one thing, there is a tendlencv to
Organization in connection Witil world- think of tile tuberculin reaction as an “all
wide BCG vaccination programs,1 and oh- or none” phenomenon, although every
pe-servations made by the U.S. Public Health diatrician knows from his experience that
Service amid! others in the U.S.A. and! else- there is a Widie range of tuberctmlin
sensi-ADDRESS: (F.M.F.) 1790 Broadway, New York 19, New York.
tivity in any group tested. It has been
cus-tomary to call a tuberculin test positive or negative on the basis of size of reaction. If a Mantoux test is done, the indurations
larger than 5 or 6 mm in diameter are
ar-bitrarily called positive, but there are many
smaller than this which represent some
de-gree of sensitivity. Are these people with
jtist a little sensitivity infected with tuber-cle bacilli? Undoubtedly some are but there is now good evidence that many of these
reactions represent a cross sensitization with some other antigen.13 The percentages
of reactors to small doses of tuberculin
have a high correlation geographically with
tuberculosis case rates and death rates, but
the percentages of children who react only
to high doses show no such relationship.
Certain areas of the world, such as India
and the southern part of the United States,
exhibit a high prevalence of this slight
tuberculin sensitivity among children.2’
Studies now in progress may reveal the
nature of the antigen or antigens able to
produce some tuberculin sensitivity. These findings give additional emphasis
to earlier work which had revealed the
im-portance of evaluating reactions to different
doses in order to take full advantage of the
specificity of tuberculin. In 1941 Furcolow
and his associates4 studied the results of 12 different graduated dosages of Purified
Pro-tein Derivative (PPD) in groups of patients
and in others. In tuberculosis patients
ex-tremely small doses produced no reactors
but with a gradual stepping up of the PPD
strength an increasing percentage was
posi-tive until the dose of 0.0001 mg was
reached. At this point practically all
per-sons with tuberculosis had a reaction of 5
mm or more. If the dose was further
in-creased, reactions were obtained in large
numbers of children who were probably
not infected. The rate of reactions was as
high as 90% in children 6 months to 3 years of age with doses of 1.0 mg. This with other
studies indicates that a standard dose of
0.0001 mg of PPD is satisfactory for most
purposes.
The size of the tuberculin reaction may
also be of some diagnostic and prognostic
significance. Recent preliminary studies
(unpublished) at the Phipps Institute in
Philadelphia indicate that the size of the
tuberculin reaction is correlated with the
probability of active tuberculous disease;
the bigger the reaction, the more likely it is that active disease is present.
These many observations point tip the
in-creasing usefulness of the tuberculin test to
the pediatrician. The interpretations of
various degrees of tuberculin sensitivity
may be summarized as follows:
If a child has no reaction to 0.0001 mg
of PPD there is very little possibility that
he has tuberculosis. One must bear in mind
that it takes a little time, approximately 2
months, for sensitivity to develop after
in-fection. Retesting may be in order if there
is some doubt about the diagnosis or if
there is a history of recent exposure to a
patient with active tuberculosis. Periodic testing, at least annually, would establish
the approximate time that a tuberculous
infection was acquired.
A low degree of sensitivity with
indura-tion less than 5 mm in diameter could be
the result of some other infection, or an
insignificant tuberculous infection. The
chance of active disease being present is
extremely small.
In this connection a word should be said
about the immunologic significance of low
degrees of tuberculin sensitivity. The
Brit-ish Medical Research Council in its study
of BCG and Vole bacillus vaccines5 also
followed up a group of children who had
been tuberculin positive only to a large
dose (100 TU). In a period of 23 years the
annual rate for the development of tubercu-losis cases was only 0.74/1,000 for this
group of slight sensitivity, whereas it was
1.75/1,000 for those who originally had
strong reactions, that is, who reacted to 3
TU. It seems clear that those with a low
degree of sensitivity possessed some
im-munity. The exact significance of this is
un-known, but this result emphasizes the
im-portance of using measured doses in
in-PUBLIC HEALTH terpretation to be given to different degrees
of tuberculin sensitivity.
With increasing size of reaction over 5
mm, the chances increase that active
tuber-culosis is present, or will develop in the
future. Each child should have a thorough
examination to confirm or exclude the
presence of an active lesion somewhere in
his body.
Most of such children will not have
ac-tive lesions but will have an increased risk
between the ages of 15 and 30 years, so
long-term follow-ups and periodic
exami-nations are important.
EFFECT OF BCG ON TUBERCULIN TEST
If a child has a positive test when first
seen by the pediatrician, it will be
impor-tant to know whether BCG has been given
or not. If it has, the test loses much of its significance. The reaction may be a result
of the BCG inoculation or a result of
in-fection with virulent tubercle bacilli. Al-though some physicians feel that strong
actions represent a virulent infection
su-perimposed on a BCG infection, others are
not so sure there is any real difference
which can be depended upon clinically.
In any case, a positive test should lead to a
search for tubercle bacilli if there is any
reason to suspect a virulent infection. Some children do acquire serious tuberculous dis-ease in spite of a BCG vaccination.
CHEMOPROPHYLAXIS IN TUBERCULIN-POSITIVE CHILDREN
Debre6 has recently reported that among
1,062 infected but untreated children
be-tween July 1948 and July 1955, pleuritis
occurred in 44, mihiary tuberculosis in 1,
meningitis in 3, and progressive pulmonary
tuberculosis in 13. During the same period
there was only 1 case of progressive
pul-monary tuberculosis among 600 children
treated with antimicrobial drugs. In a
progress report from the U.S. Public Health
Service7 on a study of isoniazid prophylaxis
in primary tuberculosis, it is stated that
among 1,356 children taking placebos, 26
developed serious extrapulmonary
compli-cations, but this occurred in only 5 of 1,394 children taking isoniazid.
Perhaps these studies will provide more
precise indications for chemoprophylaxis. So far, however, opinion is divided and the
physician will have to use his own
judg-ment based on such considerations as
re-cency of infection, age of the child, size of
tile tuberculin reaction, presence of lesions
roentgenographically, presence of
predis-posing conditions such as diabetes, and
probability of further exposure to infection
from others. One can say that these
in-vestigations have confirmed the
considera-ble risk of future disease in tuberculin
re-actors.
TUBERCULIN TESTING IN COMMUNITY CASE-FINDING
Tuberculin testing in private practice will pay an extra dividend in community
tu-berculosis control by providing leads to
active cases which might escape detection otllerwise. If the test is positive in a young
child, the infection must be recent and the
source of infection is likely to be an active case among close associates. In older
chil-dren the source of infection may be more
remote unless the time of development of
infection can be determined from previous
negative tests. The size of the reaction is
important here too. Not only are those with
larger reactions much more likely to have
active tuberculosis, but higher rates of
tuberculosis are found among their
con-tacts. In one study,8 almost 30 times as much
tuberculosis was found among the contacts
of children whose reactions to 0.0001 mg
PPD measured 25 mm or more in diameter
as among those whose induration measured
5 to 9 mm in diameter.
The physician can be of great assistance
to public health authorities by insisting
that all associates of tuberculin reactors re-ceive adequate examinations.
A logical extension of such case finding
in private practice is the use of the
tuber-culin test in school children. Few cases of
children, but the contacts of reactors are likely to yield a significant number.
In one city8 29 new cases of active
tuber-culosis were found on examination of 1,777
household contacts of tuberculin positive
school children. This is a rate of 1.6% In
addition to these cases previously unknown,
this survey also turned up 52 other eases
previously diagnosed. Such results depend
on an efficient follow-up program to insure
examinations of as many contacts as
possi-ble but the tuberculin test used as an
mi-tial screen narrows the search.
The costs of finding cases by this method
have not been accurately determined. The
initial cost of testing is low but the follow-up
of reactors is an individual procedure
in-volving considerable public health nursing
time and examination expense. In general,
the few studies of costs reported have
com-pared favorably with costs of finding eases by roentgenograms of adults in the general
population. The decrease in tuberculosis prevalence coupled with the current efforts
to reduce all forms of radiation exposure as
much as possible will undoubtedly lead to
further trial of the tuberculin test as a
pre-liminary procedure.
TUBERCULIN TESTING AS AN INDEX TO
TUBERCULOSIS PREVALENCE
Aside from its value in case finding, the
tuberculin test is a useful tool in evaluating
the incidence of tuberculosis in a
eom-munity and the success attained in control-ling it. It is a relatively simple and!
inex-pensive procedure for determining infection
rates in groups of children and adults. If
these groups are retested! at intervals,
trends in the rates of new infections can be
detected. The testing of children in schools,
young adults in colleges, aIXI adults in
in-dustrial and institutional situations, has been
common in the United States. There have
also been attempts made to test the entire
1)oPulation of some communities.’”’ ‘
Al-though the tests reported do not represent a true statistical sampling of the popula-tion, useful estimates of rates of infection
have been obtained and it is quite clear
that the rates have dropped markedly in
the last few years in the United States. In
many areas the rate of new infections is
probably as low as 1 per 1,000 persons per
year.3
Witil the passage of time, the need for more accurate measurement of the degree
of tuberculin sensitivity is becoming
ap-parent. If smaller degrees mean nonspecific or insignificant tuberculous infections with
some immunity, and higher degrees mean
specific infection plus increased probabili-ties of active disease in the patient and his contacts, it is important to ilave more than a simple positive or negative reading.
METHODS OF TUBERCULIN TESTING
The only quantitative procedure now
available is the Mantoux or intradermal
test. This is done with a tuberculin syringe,
which should not be used for any other
purpose, a short sharp hypodermic needle
of 25 or 26 gauge, and a dilution of PPD
made up so 0.1 ml will contain 0.0001 mg.
With the needle bevel up, the injection of
exactly 0.1 ml is made as superficially as
possible into tiie outer layers of the skin. A pale elevation (6 to 10 mm iii (liameter) dimpled! by the hair follicles shotmld resumlt.
The reading is made 48 to 72 hours later. The diameter of the inciuiration is measured
in millimeters with a ruler as accurately as
1)OSSible and recordied. Any dliscoloration
is disregard!ed and the extent of the
indiura-tion dietermined by running the fingers
lightly over the skin.
Old Tuberculin (OT) cami be used in
1)laee of PPD amid! it is usually less expen-sive. However, it is a mixture of substances
and! varies greatly in potency. if OT can be
Obtaine(! which tpprximnttd’s the
interna-tional stand!ard!, the recommended! (lose
(5 TU) would i)e 0.1 ml of a 1:2,000
dliltm-tion (.05 mg). Both PPD and OT are
semisi-tive to light amid! heat and should i)e kept in tile refrigerator.
The 1ateh test has i)eeii U5Cd! extensively
because of its convenience and the fact that
mb nee(ile is necessary. Hovever, it does
recommendedi. In 1945, the New York State
Health Department ran several series of
concurrent patch and intracutaneous tests
using 0.0001 mg PPD as the intracutaneous
dlose.’ In a vocational institution, 31 of
reactors to PPD failed to react to the patch,
although only one had a “false positive”
patch test. In one tuberculosis hospital, 11%
of the reactors to a smaller dose of PPD
(
0.00002 mg) failed to react to the patchand in another tuberculosis hospital these
“false negatives” amounted to 18%.
In a similar study reported in the June
1957 issue of Di$eases of the Chest, 196
had reactions to the intracutaneous test,
but 113 of these failed to demonstrate
re-actions to the patch. There were 3 “false
positives.” Ten per cent of the patches came
off prematurely.
Others have experienced large errors in
patch testing on the “false positive” side.
One such report appeared recentlyhi and
tile author has had several similar personal
communications. In one instance only 58
of 156 supposedly positive patch tests could be confirmed as positive by an intracutane-otis 0.0001 mg PPD test.’5
In a recently pumblished book on Diseases of
the Chest
by
Hinshaw and Garland,1 the following appears on page 525:“Pediatri-cians sometimes employ the ‘patch test’ for
determination of tuberculin sensitivity, a
method which is distrusted if not actively
condemned by some internists wilo
special-ize ill pulmonary diseases. The value of any test is related to its reliability and many
studies indicate that patch tests are
seri-ously deficient, yielding tip to 15% falsely
negative tests and nearly as many falsely
I)Ositive tests. Many pediatricians-still a minority, perllal)s-believe tilat tile physical
and emotional trauma of a needle prick is
justified when so much is at stake and have returned to the intracutaneous tuberculin
test. Incidentally, the emotional trauma is
reduced and the quiet atmosphere of the
office preserved if tile test is applied where the cilildi cannot observe tile performance;
the intraseapular region, for example.”
Many attempts have been made to
im-prove patch test results but the dose of
tuberculin cannot be controlled. This would
be expected because of the many factors
which affect absorption of tuberculin
through the skin.
TUBERCULIN TESTING SCHEDULE
A practical age schedule for tuberculin
testing must always be a compromise. One
would like to know exactly when a child
receives a tuberculous infection but the
frequent testing which would be necessary
is out of the question. No standards have
been agreed upon universally but it seems
to be common practice to test at least once
each year as long as there is no reaction,
substituting annual roentgenographic
ex-amination if the test becomes positive. The
pediatrician may well ask if children with
significant tuberculous infections are found
often enough to justify the time spent in
doing routine tests. It is true that tuberculin reactor rates have been falling steadily and
in the United States have reached low
levels in many places. However, even
find-ing an occasional new infection silould be
worth the little effort it takes in view of
the risk to that child of serious complica-lions in the future and the increasing effec-tiveness of therapy.
If school children are being tested, the
grades tested will depend somewhat on the
number of new infections expected per
year. In a low rate area it may be sufficient to test beginning students in kindergarten or the first grade, children about to leave
elementary school, and the last year in
high school. In a high rate area it may be
worth while to test all grades every year.
To be worth doing, such group tuberculin
testing programs must be carefully planned
so the essential follow-up of contacts will
not be neglected and so a critical
evalua-tion can be made at the end. This
evalua-tion is important in planning for
subse-quent years.
One must keep in mind the fact that
tuberculin testing of children cannot take
the place of the established public health
and treatment of infectious patients, super-vision and periodic examination of inactive cases, examination of contacts of active
cases, roentgenographi’c screening of high
rate groups, and programs to improve
gen-eral public health are basic to any
organ-ized attack on the disease. However,
rou-tine tuberculin testing by all physicians
coupled with well planned group testing
of school children and others in a
commu-nity can provide additional specific
infor-mation useful for a more direct attack on
the disease with the effective therapeutic tools at hand today.
REFERENCES
1. Edwards, L. B., Palmer, C. E., and
Mag-nus, K. : BCC vaccination studies by the
WHO Tuberculosis Research Office,
Copenhagen. Monograph Series, World
Health Organization, No. 12, 1953. 2. Palmer, C. E. : Ceographic variations in
sensitivity to tuberculin.
J.
Indian M. A., 21:509, 1952.3. Palmer, C. E., Krohn, E. F., Manos, N. E., and Edwards, L. B. : Tuberculin sensi-tivity of young adults in the United States. Pub. Health Rep., 71:633, 1956.
4. Furcolow, M. L., Hewell, B., Nelson,
W. E., and Palmer, C. E. : Quantitative
studies of the tuberculin reaction. I. Titration of tuberculin sensitivity and its relation to tuberculous infection. Pub.
Health Rep., 56: 1082, 1941.
5. Tuberculosis Vaccines Clinical Trials
Com-mittee, Medical Research Council:
B.C.G. and vole bacillus vaccines in the
prevention of tuberculosis in adoles-cents. Brit. M.
J.,
1:413, 1956.6. Debr#{233},R. : Systemic treatment of primary
tuberculosis. New England
J.
Med., 255:794, 1956.7. Mount, F. : Prophylactic effects of isoni-azid on primary tuberculosis in children: a preliminary report-A U.S. Public Health Service Cooperative Clinical
In-vestigation. Am. Rev. Tuberc., 76:942,
1957.
8. Wood, L. E., Furcolow, M. L., and Willis, M.
J.
: An evaluation of tuberculosis case finding by tuberculin testing among Young school children. Paper presented at meeting, American Trudeau Society, May 7, 1957.9. Myers,
J.
A., Boynton, R. E., Kernan, P., Cowan, D., and Jablon, S. : Sensitivity to tuberculin among students at the Uni-versitv of Minnesota. Am. Rev. Tuberc.,75:442, 1957.
10. Ireland, H. D. : Tuberculin reactors in the general population. Dis. Chest, 25:221, 1954.
11. Jordan, K. B., and Jordan, L. S.: Couiity wide tuberculin testing. Dis. Chest, 26: 528, 1954.
12. Plunkett, R. E. : The diagnostic accuracy of the patch tuberculin test. Staff Bulletin,
New York State Department of Health,
26:3, 1945.
13. Waegele, V. C., Rothrock, W.
J.,
and Van Scoyoc, R. : Simultaneous Mantoux and Vohlmer patch tests in 855 school chil-dren. Dis. Chest, 31:634, 1957.14. Israel, H. L. : Treatment of tuberculin
re-actors with no clinical evidence of dis-ease (Queries and Minor Notes). J.A.M.A., 164:715, 1957.
15. Stocklen,
J.
B.: Personal communication.16. Hinshaw, H. C., and Carland, L. H.:
Diseases of the Chest. Philadelphia,
