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Journal of Experimental Medicine

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A C U T A N E O U S R E A C T I O N IN S Y P H I L I S . *BY H I D E Y O N O G U C H I , M.D.

(From the Laboratories of the Rockefeller Institute for Medical Research,
Neov York.)
PLATES

50-52.

Active or passive immunity, the state of allergy, and numerouso t h e r phenomena, which have been so commonly observed andprofitably studied in certain infectious diseases since the successful
pure cultivation of their respective causative agents, are rather
imperfectly understood in syphilis. Soon after obtaining pure cultures of Treponema pallidum, I commenced to study these questions
experimentally. While the results of my experiments on the effects
of repeated injections o f living and killed pallida on experimental
syphilis in animals will be presented later, I wish to make a briefreport here on one of the phases of study that seems to me to beof interest not only to those who are engaged in experimental work
but also to clinicians at large; namely, on a cutaneous reaction inexperimental and human syphilis, to the possible existence of which
my attention was directed by Professor Welch.
Stimulated by von Pirquet's discovery of a specific cutaneous
reaction for tuberculosis, several investigators (Meirowsky, WolffEisner, Tedeschi, Nobl, Ciuffo, Nicolas, Favre and Gauthier,
Neisser and Bruck, and Jadassohn) attempted to obtain a specificreaction for syphilis by applying extracts of syphilitic tissues, prepared from syphilitic fetal liver or chancre, to the skin of syphilitic
patients. Their results were, on the whole and in spite of someencouraging effects, contradictory. Neisser and Bruck, however,found that a reaction similar to that produced with syphilitic extract
can be obtained also with a concentrated extract of normal liver.
This peculiarity of the skin of syphilitics is ascribed by Neisser
to what he calls the state of "Umstimmung" in the later stages of*Received for publication, October 2, 1911.
557

558

A Cutaneous Reaction in Syphilis.

syphilis. Neisser, nevertheless, expresses the hope that the reaction may possibly be improved by employing an extract of the pallidum free from tissue constituents. This had not been accomplished before. Pure cultures of Treponema pallidum obviously
offer many advantages, since in them we possess not only pallida
of different ages, but also their metabolism products, which doubtless are important factors in establishing an allergic state in syphilitic subjects.
THE

PREPARATION

OF C U L T U R E S

FOR T H E

CUTANEOUS

REACTION.

T w o strains of the pallidum were used for the present seriesof experiments. Pure cultures were allowed to grow for periodsof six, twelve, twenty-four, and fifty days at 37 ° C. under anaerobic
conditions. One was cultivated in ascitic fluid containing a piece ofsterile placenta, and the other in ascitic fluid agar also containing
placenta. The lower portion of each solid culture in which a dense
growth had occurred was cut out and the tissue removed. The
agar columns which contained innumerable spirochaetae were thencarefully ground in a sterile mortar. The resulting thick paste was
gradually diluted by adding, little by little, the fluid culture which
also contained an enormous mass of the pure organisms. The dilution was continued until the emulsion became perfectly liquid. The
preparation was next heated to 60 ° C. for sixty minutes in a waterbath, and then 0. 5 per cent. carbolic acid was added. When examined under the dark-field microscope, 4 ° to Ioo dead pallida per
field could be seen. Cultures made from this suspension remained
sterile, and with them no infection could be produced in the testiclesof rabbits. The suspension was kept in a refrigerator when not inuse. I propose to speak of this preparation under the name of luetin.
In order to ascertain whether the reaction produced with this suspension might not be due to the introduction of the carbolized
culture mediuin alone, it was necessary to prepare a similar emulsion
with uninoculated media to be used for control purposes.
METHOD OF APPLICATION.
For rabbits, the hair on the lower side of the back is shaved off
and one or two injections of the luetin and one injection of theHideyo Noguchi.

559

control suspension are made in different spots. The injections are
made intradermically with a very fine needle, the amount injected
being in each case 0.05 of a cubic centimeter. For human subjects,
the skin of the upper arm was selected as the site for the intradermic
injection of the luetin and the control suspension. In the earlier experiments, different spots on the same upper arm were used for
both, but later, one arm was used for luetin and the other for thecontrol. The amount injected in each instance was 0.05 of a cubic
centimeter, and the skin was always sterilized 'with alcoholic sublimate solution before the injection.
THE

C U T A N E O U S R E A C T I O N I N RABBITS.

Before the skin test was applied to human subjects, several seriesof experiments were performed on rabbits. The tests may be
divided into five groups according to the treatment previous to the
cutaneous tests. The first group comprised four rabbits which
received within five months twelve intravenous injections of emulsions prepared from syphilitic orchitis or rabbits rich in pallida,the last injection being given two months before the date of application of the skin reaction. Ten different strains of pallidum wererepresented in this series. The second group was composed offour rabbits which had been injected with similar emulsions, thedifference being that the pallidum had been killed by heating theemulsions to 60 ° C. for thirty minutes before injection. The thirdgroup included twelve rabbits which were showing, four to six
weeks after inoculation, syphilitic orchitis experimentally producedwith several different pallidum strains. The fourth group consistedof four rabbits in which experimental syphilitic orchitis had been
cured about four months previously by the intravenous administration of salvarsan. The fifth group consisted of eight normal male
rabbits. The intradermic injections of the luetin and control emulsions were made on the same day to all the rabbits.
RESULTS OF THE

TESTS.

In the control group, a very slight erythematous condition appeared at the injection sites twenty-four hours after inoculation,
which disappeared within forty-eight hours, the skin resuming its

560

A Cutaneous Reaction in Syphilis.

normal appearance. The first and second groups of treated rabbits
gave different reactions. The sites of injection of the control
emulsion became normal within forty-eight hours, while the sites
of injection of the luetin became distinctly red and indurated after
forty-eight hours. The point of redness gradually spread and became raised to the size of a pea. This condition persisted for fourto six days, when the reaction commenced to recede. The redness
and induration disappeared in most animals within ten days. In
one instance, a round sterile pustule developed on the fifth day on
the site of each of the two inoculations of the luetin (figure I).
These pustules resembled variolous pustules in general appearance
and healed with crust formation. The third group gave only slight
reactions, which possibly were somewhat greater than in the control
rabbits. But, as a whole, they were not, except in a few instances,distinct enough to be considered positive. The fourth group behaved like the control. No constitutional effects were observed
even among the animals with positive cutaneous reactions.
THE

CUTANEOUS REACTION IN

1VIAN.

Through the courtesy and collaboration of Dr. Martin Cohen(Harlem Hospital, Randall's Island Asylum, New York Ophthalmic
and Aural Institute), Dr. Henderson (State Hospital, Ward's
Island, New York), Dr. Lapowski (Good Samaritan Dispensary),Dr. McDonald (King's County Hospital), Dr. Orleman-Robinson(North-Western Clinic, New York Polyclinic), Dr. Pollitzer (German Hospital), Dr. Rosanoff (King's Park State Hospital), Dr.
Satenstein (City Hospital, Blackwell's Island, New York), Dr.
Schmitter (Captain United States Army, at Fort Slocum), Dr.
Schradieck (King's County Hospital), Dr. Charles Schwartz (California), Dr. Smith (Long Island State Hospital), Dr. Strong(Manhattan Eye, Ear, and Throat Hospital), Dr. Swinburn (Good
Samaritan Dispensary), Dr. Windfield (King's County Hospital),Dr. Wiseman (King's Park State Hospital), and the Hospital of
the Rockefeller Institute for Medical Research, I was enabled toapply the skin reaction to a number of human cases.
The total number of cases studied was 400; of these 177 wereof syphilitic nature, 77 of parasyphilitic nature, while 146 represented various controls.

Hideyo Noguchi.

561

The emulsions were always injected intradermically, that is, inthe skin as superficially as possible. When the injection is successfully carried out, the epidermic layer is raised up sharply from thecuffs, the pale swelling thus produced going down in from ten to
fifteen minutes.
D E S C R I P T I O N OF T H E R E A C T I O N S .

Normal or Negative Reactions.--After applying the emulsions,both luetin and control, to about fifty normal individuals, I wasable to determine the variations and limitations of the reactions that
follow intradermic administration in the normal skin of man. In
the majority of normal persons, there appears, after twenty-fourhours, a very small erythematous area at and around the point of
injection. No pain or itching sensation is experienced. This reaction gradually recedes within forty-eight hours and leaves no induration. In certain individuals, the reaction may reach a stage ofsmall papule formation after twenty-four to forty-eight hours, after
which and within seventy-two hours it commences to subside. No
induration is left behind, although occasionally slight yellowish pigmentation may result from mild ecchymosis.
Positive Reactions.--According to the manner and intensity withwhich the skin of syphilitics responds to the introduction of theluetin, one may distinguish the following varieties of effects:(A) Papular Form.--A large, raised, reddish, indurated papule,
usually five to ten millimeters in diameter, makes its appearance intwenty-four to forty-eight hours. The papule may be surrounded
by a diffuse zone of redness and show marked telangiectasis. The
dimensions and the degree of induration slowly increase during thefollowing three or four days, after which the inflammatory processes begin to recede. The color of the papule gradually becomesdark bluish red. The induration disappears within one week, except in certain instances in which a trace of the reaction may
persist for a longer period. This latter effect is usually met withamong cases of secondary syphilis under regular mercurial treatment in which there are no manifest lesions at the time of making
the skin test. Cases of congenital syphilis also show this reaction.
( B ) Pustular Form.--The beginning and course of this reaction
resemble the papular form until about the fourth oi" fifth day, when

A Cutaneous Reaction in Syphilis.

562

the inflammatory processes conimence to progress. The surface of
the indurated, round papule becomes mildly edenlatous, and multiple miliary vesicles occasionally foml (figure e). At the sametime, a beginning central softening of the papule can be seen.
Within the next twenty-four hours, the papule changes into a vesicle
filled at first with a selni-opaque serum that later becomes definitely
purulent (figures ,3 and 4). Soon after this, the pustule ruptures
spontaneously or after slight friction or pressure. The margin of
the broken pustule remains indurated, while the defect caused by
the escape of the pustular content becomes quickly covered by a crustthat falls off within a few days. About this time the induration
usually disappears, leaving almost no scar after healing. There isa wide range of variation in the degree of intensity of the reaction
described in different cases, as some show rather small pustules,
while in others the pustule is much larger. This reaction was
found ahnost constantly in cases of tertiary syphilis, as well as incases of secondary or hereditary syphilis which had been treatedwith salvarsan.
(C) Torpid Form.--In rare instances, the injection sites fadeaway to almost invisible points within three or four days, so thatthey may be passed over as negative reactions. But sometimes
these spots suddenly light up again after ten days or even longer
and progress to small pustular formation. The course of this pustule is similar to that described for the preceding form.
This form of reaction has been observed in a case of primarysyphilis, in one of hereditary syphilis, and in two cases of secondarysyphilis, all being under mercurial treatment.
Neither in syphilitics nor in parasyphilitics did a marked constitutional effect follow the intradermic inoculation of the luetin.
In most positive cases, a slight rise in teniperature took place lastingfor one day. In three tertiary cases and in one hereditary case,however, general malaise, loss of appetite, and diarrhea werenoted.
THE

PECULIARITY

OF THE

SKIN" OF SYPHILITICS.

The skin of certain individuals suffering from tertiary syphilis isnoted for its susceptibility to traumatic irritations. This tendency
has been much discussed by dermatologists. To account for thisHideyo Noguchi.

563

phenomenon, Finger advanced the theory of superinfection, which
presupposes that a trauma creates a spot of weakened resistance inthe skin and that the syphilitic virus wanders thither from a hidden
focus in the interior to set up the lesion. On the other hand, Neisser maintains that it is not the spiroch~ta that produces a syphilitic
lesion after a slight trauma, because he failed to prove the presenceof any spiroch~eta or infectious agent in the lesions; but he believes
that it is due to a pathological condition of the skin itself, which hecalls " U m s t i m m u n g . " Among I77 cases of syphilis, I observednine cases (one secondary, six tertiary, and two hereditary) in
which the sites of the control emulsion reacted quite intensely.
But these reactions were always less intense than those producedby the leutin in the same persons. Furthermore, in these cases
the induration remained much longer at the sites of luetin injection than at the control sites. In view of these results and of
the additional fact that the majority of cases giving the positive
skin reactions did not react to the control emulsion, I am of thebelief that the reactions set up by the intradermic inoculation ofluetin are due not to Neisser's so-called state of "Umstimmung,"
but to a purely allergic condition. It is, of course, possible thatboth conditions may be coexistent in the same patient, although theoccurrence of " U m s t i m m u n g " appears, from my experience, to be
far less frequent than that of allergy. In carrying out the cutaneous
reaction for syphilis (as for any other infectious disease), it ishighly important to provide adequate control observations to determine whether the state of "Umstimmung" exists only in syphilis, or whether it may not also occur in other diseases.
THE RESULTS OF THE CUTANEOUS REACTION IN MAN.
In all, 400 cases, comprising 177 syphilitics, 77 parasyphilitics,
and 146 controls, have been studied. The results obtained in syphilitics are summarized in table I.
The table shows that in casesof primary and secondary syphilis, which have had either insufficient treatment or none at all, no skin reaction occurred, except ina few instances. The reaction in the positive cases was always of theindurated papular variety. In one primary case, in which the skintest was applied before regular mercurial treatment was begun, a564

A Cutaneous Reaction in Syphilis.

torpid reaction followed the administration of mercury. On theother hand, most of the secondary cases which had been mercurialized before the administration of salvarsan, and which remained
TABLE

Primar:~syphil s.

Secondarysyphilis.

I.

Tertiary syphilis.

Cerebro-I Heredispinal I tarysyphilis. ! syphilis.

_ _[ Symp-sp-

Syrup- I Symptoms / toms
)resent, J absent.

3

ISj

I I
222] 8xo 226 1I

27

prte°sX~st pl e~,era. abs, it.
t+

N o a n t i s y p h i l i t i c l ~ + ~~ treatment ......
] 2
Slight mercurialI
treatment ...... I [ 2Regularanti]
syphilitic]
treatm ent ...... i/
Salvarsan treatment ............
x 4
5

--

+

Controls.
Latentsyphilis. Normal [ Nonindivid- I luetic
uals.
cases.
ii+-- + --

J

Ii~
o

3°

5°

2

5

5
Io

22

224 6

23

3o

o

46

o
I46

I77
+ intricates a p o s i t i v e , a n d - - a n e g a t i v e c u t a n e o u s r e a c t i o n .

without symptoms for some months after the salvarsan injections,gave striking and unmistakable reactions.
Two distinct groups that give a negative or doubtful reaction
occur among the salvarsan cases. One consists of cases showing areappearance of the Wassermann reaction, but no other symptoms,
and usually gives doubtful cutaneous reactions. The other, which,however, comprised only two cases treated with salvarsan that remained without any clinical symptoms or Wassermann reaction
for many months, gave no cutaneous reaction.
To this group also belong two interesting cases that have been
under my observation since September, 191o. One was treatedfor gumma of the liver by an intramuscular injection of salvarsan by Dr. Kakels at the Lebanon Hospital. The large gumma
promptly disappeared, and the patient has remained without
symptoms up to the present. The Wassermann reaction in thispatient disappeared slowly but completely in about ten weeks. The

ioo

Hideyo Noguchi.

565

blood, tested every two months, has remained negative. The skintest with luetin, made in August, I9I I, was negative. The other caseis one of malignant syphilis, refractory to mercurial treatment.
Three intramuscular injections of salvarsan were given in September and November, I9IO , and in January, I 9 I I . The Wassermann
reaction disappeared soon after the healing of the extensive and destructive lesions, and still remains negative. A luetin test made inAugust, I 9 i i , was negative. Both patients are now in excellent
health. I have introduced these cases to illustrate the point thatthe allergic state of the skin in syphilis seems not to persist beyonda certain time after the probable complete eradication of the pallidum from the body. This point has been confirmed experimentally by rabbits treated with salvarsan.
The results in tertiary and hereditary syphilis present a striking
contrast to those observed in the earlier stages of the disease. The
skin reacts intensely to luetin in these cases. The intensity of thereaction in the tertiary cases is probably increased by the state of"Umstimmung," but the constancy with which it appears suffices
to render it a valuable clinical diagnostic aid. It is in this stage
that syphilis manifests itself in its most diverse and often mostobscure forms. A gumma or other tertiary lesion on the visible
parts of the body offers but little diagnostic difficulty; but it is notalways easy to ascertain the luetic nature of lesions of the internalorgans. In tertiary cases, moreover, the Wassermann reaction isfrequently absent, especially after specific treatment. Thus it isimportant to find that the skin reaction is more constant than the
Wassermann reaction in tertiary syphilis. Two causes for a negative V~rassermann reaction in the tertiary stage may be distinguished.
The first, which may apply also to latent syphilis, consists of therestraining power of the body upon the propagation of the pallidum
together with the neutralization of its injurious products throughthe formation of antibodies. The second cause, which also operates
in some primary and secondary cases, arises from the inability ofthe body to respond to the pallidum stimulus by the formation of
the substances on which the Wassermann reaction depends. The
results of the luetin reaction in syphilis of the central nervous
system are even less constant than is the Wassermann reaction.

566

A Cutaneous Reaction in Syphilis.

Whether a better result can be obtained by improving the luetin
can be determined only by future work. The cases of latent syphilis reported here consist chiefly of parents of the hereditary syphilitic cases reported in table I. Most of them became infected many
years before and have remained without symptoms. Many of themothers have, however, suffered miscarriages previous to or after
the birth of their syphilitic children.
The controls include 46 normal individuals, chiefly children between the ages of two and eighteen years, and Ioo individuals
suffering from various diseases of non-syphilitic nature. These
include tuberculosis, leprosy, pneumonia, typhoid fever, psoriasis,
malaria, alcoholic psychosis, dementia pr~ecox, gonorrhea, chancroid, brain tumor, eczema, epithelioma, carcinoma, etc. In none
was a positive luetin reaction obtained.
The results thus far obtained in parasyphilitic cases are unsatisfactory and call for further study with more active preparations of
the luetin. Seventy-two cases of general paralysis and five of tabes
were studied. Of the seventy-two cases of general paralysis, fortyfive reacted positively. In a few instances pustules were formed,
but twenty-seven gave no reaction. Of five cases of tabes, threereacted positively. Among thirty-five controls of this series, consisting of fir.teen cases of dementia prmcox, six of alcoholic psychosis, and fourteen of other non-syphilitic psychoses, four reacted
positively, and these were cases of dementia pr~ecox. These patientswere adults, and two of them gave positive Wassermann reactions.
I incline, therefore, to the opinion that they had suffered either
from congenital or acquired syphilis.
CONCLUSIONS.

I. I have proposed the name luetin for an emulsion or extractof pure cultures of Treponema palIidum which is designed to be
employed for obtaining, in suitable cases, a specific cutaneous reaction that may become a valuable diagnostic sign in certain stages
or forms of syphilitic infection.
2. The repeated inoculation of either living or killed pallida into
the testicles of rabbits leads to a condition in which an intradermic
injection of luetin is followed by a well marked inflammatory reac-Hideyo Noguchi.

567

tion. A corresponding reaction has been obtained neither in rabbits
suffering from active syphilitic orchitis, nor in those in which thecondition had been cured by the administration of salvarsan fourmonths previously. Normal rabbits, likewise, do not react' to theluetin.
3. The luetin produces a similar cutaneous reaction in syphilitic
and parasyphilitic patients that is most constant and severe in thetertiary and hereditary affections. In my series of cases, it waspresent constantly (IOO per cent.) in the manifest tertiary affection,in 94 per cent. of latent tertiary affection, and in 96 per cent. of
the hereditary affection.
4- During the primary and secondary stages, the reaction is infrequent, and when present it is of mild degree. An exception
has been found in cases in which energetic treatment has been or isbeing carried out and in which clinical signs of syphilis are absent.
Such cases may show a severe reaction. Apparently this is true
especially of the cases treated with salvarsan.
5. In certain cases of old infection in which no treatment has
been taken and in which no symptoms have appeared for many
years, and in the course of which miscarriages have not occurred,
the cutaneous reaction has failed to appear. But, despite the absence of symptoms, mothers who have young syphilitic children
have usually given the reaction.
6. It remains to be determined in how far the cutaneous reaction
with luetin can be used to supplement the Wassermann reaction in
determining the complete and permanent suppression of a syphilitic
affection.
7. It appears probable that the Wassermann reaction is more constant in the primary and secondary, and the cutaneous reaction in
the tertiary and latent forms of syphilis. Moreover, it appears that
the Wassermann reaction is more directly and immediately affectedby antisyphilitic treatment than is the cutaneous reaction.
8. A more active preparation of luetin can certainly be produced
by improved methods. This phase of the subject is being considered at the present time and will be reported upon in a later paper.

568

A Cutaneous Reaction in Syphilis.
E X P L A N A T I O N OF P L A T E S .
PLATE 50.

FIG. I. An actively immunized rabbit (No. 4), inoculated on June I4th,
I9II, and painted on the sixth day. Both pustules are produced by the luetino
The control site disappeared.
FIG. 2. Female, aged I6 years. Hereditary syphiIis, and interstitial keratitis
of six months' standing. Salvarsan injected five months ago without goodresults. Wassermann reactior~ positive. Inoculated on June ITth, I911, andpainted on the fifth day. Both sites of the luetin injection show a tendency topustulation. Marked telangiectasis.
PLATI~ 5 I.
FIG. 3. Male, aged 29 years. Chancre seven months ago, followed by secondaries. Six intramuscular injections of salvarsan, the last about three months
ago. Developed exudative ch0roiditis six weeks ago. The right eye shows
typical exudative choroiditis; the left eye is free from it. Wassermann reaction negative. Inoculated on June 23, I9II, and painted on the sixth day.
Between the two large luetin pustules there is a faint trace of the injection of
the control material.
PLATE 52 .
FIG. 4- Female, aged 51 years. Became infected twenty years ago, and Was
treated moderately by Lassar in Berlin. Present symptoms: exostosis andstenosis of lacrimal canal. Wassermann reaction weakly positive. Luetin teston July Ilth. The left arm shows two well marked pustules at the sites ofthe luetin injection, while the right arm shows a faintly visible trace on thecontrol site. Photographed on the sixth day, (Dr. S. Pollitzer kindly took thisphotograph for me.)THE JOURNAL OF EXPERIMENTAL MEDICINE VOL, XIV.

PLATE

50.

T H E J O U R N A L OF E X P E R I M E N T A L MEDICINE VOL. XIV.

~IG. 3.

PLATE 51.

PLATE 52.

T H E JOURNAL OF E X P E R I M E N T A L MEDICINE VOL. XIV.

LEFT.

RIGHT.
FIG. 4.