WORLD HEALTH ORGANIZATION
ORGANISATION MONDIALE DE LA SANn: WHO/VDT/RES/63.64 \ ORIGINAL: SPANISH ~ ~·
t' c,·,
REACTIONS PRODUCED IN PINTA, YAWS OR SYPHILIS PATIENTS 1 ON INOCULATION WITH TREPONEMA PERTENUE CASTELIANI 1905 Its possible application to the test of cure of these treponematoses by Rafael Medina, M.D. 2
(/
Introduction - Purpose of the experiments There has for a long time been great interest in research on the relationship between syphilis, yaws and pinta. Because of their close etiological, clinico-
serological and therapeutic relationships, particularly in syphilis and yaws, extensive controversy has arisen as to v1hether these diseases should be considered as a single entity or as two entirely separate diseases. The present report gives the results of experimental inoculation with known strains of Treponema pertenue of different groups of patients suffering from pinta, yaws or syphilis in various stages of clinical evolution. In addition, another group of
patients with the same diseases who had first received what was considered adequate treatment with arsenic and bismuth, penicillin alone, or a combination of these drugs, 1tlere also inoculated. with
rr.
pertenue.
The purpose of these experiments was to make
a careful study of the dermctological, serological and histological reactions to the inoculation and to determine the degree of defence or allergy which might have been developed as a result of these treponematoses. Subsequently, after a certain number
of observations had been made, it was decided to apply the inoculation test to cases which were obscure from the clinical or serological viewpoint, in order to see if any light could be throw.n on them.
Originally issued as WHO/VDT/251 (2 January 1958). revised and brought up to date by the author. 2
1
The document has been
~search Department, National Institute of Venereology, Ministry of Health and Social Welfare, Caracas; Professor of Tropical Pathology, Central University, Caracas.
WHO/VDT/RES/63.64 page 2
Difficulty often
aris~s
in th0 diagnosis of patients with positive serological
t<.:sts who, after thorough clinical and other '_examinations (X-ray of tht; htoart and aorta, spinal fluid tests, eye-tests, 8tc.) appear normal. In some cases these are
adults with an ill-.defined venereal disease history, who have come from or lived in parts of the country whe;re yaws or pinta are endomic. Sometimes they are children
with craniofacial or dental deformities (some of which have been ascribed to congenital syphilis) and a suspected history of maternal syphilis. The qw::stion then arises y.s
to whether thes'-' patients havo2 late yaws, latent asymptomatic syphilis or are merely giving false positive serological reactions. On other occasions the problem is that of patiE:nts who have previously received anti-syphilitic treatment but nevertheless continue to b<:: seroreactive for months or years afterwards. The dilemma then arises of deciding whether this is a failure of
therapy, calling for a new and more intensive treatment to counter the threat of future complications, or whether in reality the person is cured and the persistent seroreactivity is only of that obscure, unchangeable and residual type so frequently observed in venereal disease practice. The fact that the three treponematoses coexist only in certain countries of the Americas (including Venezuela) and the possibility of applying the knowledge derived from the observations made to practical diagnosis, led us to undertake the investigations reported in this paper. The experiments were carried out at the Research Department, National Institute of Venereology, attached to the Ministry of Public Health and Social Welfare., over a. period of 12-l/2 years, during v-;hich 515 inoculations were made in patients suffering from treponematoses and in suspected casc.:s, the validity of results b.:.;jng confirmed 1 by comparison with 233 controls dcfini t·cly known to be heal thy.
We take this opportunity of expressing our thanks to Drs A. Gil Izaquirre, P. M. Itriago, M. Vegas, Jacinto Convit, to Mr Eugenio del Vecchio, Mrs Graciela and Mrs Esther de Gonzalez, who all in one \vay or another - in discussions and periodic analyses of the work, rcvil'w of tr1e histological and serological material. supervision of the patients - gave valuable assistance.
1
WHO/VDT/RES/6.3. 64 P~'.gc
3
I.
Reactions in
h~althy
controls
II. III. IV. V.
Reactions in pinta patients Reac~ions
in yaws patients
Reactions in syphiliti_r· pati.t:l<e,'3 Application or tb•~
r<'SUl ts ob-c;ained to tlL di J.&iOS is of, ::md
~'.S
0.
tcs t for
the VI.
cur~
of, the
trupon~matoscs
Suw.mary and conclw3ions
I •
REAC'riONS IN HEJ\LTHY CONTROLS
It was first made CC;rto.in tho.t no risk or diso.bility wo.s o.ssociatcd with the inoculation of. Treponema pcrtl-nuc. selection of the test subjects; This w.as '--nsurcd by:
(1)
thE: careful
(2)
the knowledge that T. pcrt~nuc causes no visceral
complic.ations nor any serious lesions wh,::n the: p::ctie:nts :trC; carefully watchC;d and the course of the: disease is h<ed by treatment at an -.::o.rly s~agc;
(3)
the C<..;rtainty
that, wh<::n desired, the: disease could be rapidly cured v1it.i1 p"nicillin. but li ttlc r:Lsk of bringing about fixed scro-rcacti vi ty, sinc0 the longest period of observation, in ::::. few cases, '.-I:..ts on0 year. A total of 233 controls was used; syphilis, yaws, or pinta, with n~gativ8
tlky vkrc young p8oplLC serological tGsts, who
~dthout agrc~J
cmy history of to collaborate
in the experiments and :1cccpt th•e: neccsso.ry disciplin"'.
Th\.; inoculation of oach
group of 10 pa th:nts with Treponema pertcnue from o. s ingll3 source >vs.s accompanicd by th~ SimultaneoUS inoculo.tion
Of thrt:8.0r rDOrG controls,
Stro.ins Five strains of T. pcrt,nuc were usc:d: thc first two cam~
from boys with of e;volution.
frambe:sides D.nd tlk other three from young o.dults Ln the same
stilg~_;
It was CC;rt:.dn that none of thcs0 five CCtScs ';Ets suffering from r;yphilis or pinta. The strains were ma:i.nt::~incd
by monthly passages in h~mst2rs,
h<..:::~lthy
subj<;cts.
Al thou3h
'!VC
had
infected available rabbits o.nd
wc prefcrrcd to maintain thu strain in lrumo.n
beings (infected controls) u1d(;i.cVour"lnr:~ in this w-:-y to obtc::.in ;1lso rettetions which Hould give a bctt,__r ~md
more :'.ccur1.tc
plctur~
of tl-tc nat'lral course of the disease::.
WHO;Vm'/RES/63. 64 page 4 Serological changes Various types of serological test were used: Kahn, Wassermann, Mazzini, Most
Rein-Bossak, "Sitolipina", Kline, Meinicke, Eagle, Hinton, VDRL and Kolmer.
of the cases were studied by the VDRL and Kolmer tests, and during the last four years the RPCF was added. Many of the tests were made personally by Dr Eugenio Del
Vecchio, PASB serological expert. The serological tests started to be positive between 16 and 85 days after the inoculation. In most cases the Reiter test was the first to obtain reaction. It
was noted that the Kolmer quantitative units and the VDRL dilutions remained low for a considerable period. After the subjects were treated (6oo 000-2 4oo 000 units of
penicillin procaine G in oil with two per cent. aluminium monostearate) it was found that the Reitc-r test was the first to become negative. Serological study of the controls revealed many interesting facts. One group
of five individuals who had been treated with 6oo 000 units of pencillin when the Kahn and Wassermann tests were strongly positive were re-inoculated when the titres were as follows: Case l Kahn 32 units, Wassermann 4+ Case 2 Case 3 Case 4 Case 5 11
4 0 0 0
11
11
4+ 4+ 4+ 4+
11
11
11
11
11
11
11
11
lt
The re-inoculation was carried out 17, 36, 44, 69 and 72 days respectively after penicillin treatment. In all cases the disease followed the same course as
on the first occasion, which seems to show that there is no close relationship betwe positive blood tests and the degree of immunity of the individual. As regards yaws
infections, this differs from the statement by Botreau-Roussel, v<ho believE:s that a fall in seroreactivity is a sign of decreased immunity in the yaws patient. Some controls treated 25-35 days after the infection had "taken", a period during which the Kahn and VDRL tests gave very low titres or were negative and the Wassermann test was weakly positive, became positive and about a month later reac
WHO/VDT/RES/63.64 page 5 un~t~ Kah~
32
for the
test, 64 dilutions for the VDRL and 4+ for the Wassermann test,
just as if the treatment had not interfered with the normalmechanism for the production of reagins. Finally, some peculiarities observed in the course of the Kal:m and \1/assermann reactions should be mentioned. A small group of inoculated subjects gave Kahn
reactions which were increasingly positive, reaching a titre of 128 units after an average period of 56 days; on the other hand, the Wassermann test remained completely
negative. throughout this time. It was also interesting to note that in a few cases the Kahn and VDRL reactions first became positive and then spontaneously became negative for a certain time, some months after which these subjects again commenced to react and gradually to show the usual reagin titres.
II.
·REACTIONS IN PINTA PATIENTS
It was extremely interesting to observe the behaviour of pinta patients inoculated with T. pertenue, since no mention was found in the literature of this type of experiment. DuriP6 inquiries in certain rural areas of Venezuela where individuals were freqw:::ntly met vJith a history
pinta and yaws coexist l:Pd'-'micrllly,
of yaws and late lesions of pinta, but it could not be determined which of these complaints had been the ;~irst
to develop.
With respect to sypLilis and pinta, Leon Blanco, in an admirable paper describing clinical experiments, showed that syphilitics could be at various stages of the disease. inoculat~d
vJith T. carateum
In these patients the pinta infection developed
independently of syphilis, as if there were no immunity of any kind. Our pinta subjects consisted of 28 individuals, classified as follows: In the early stage (the 11
pintids" of Leon Blanco) unev~n
7 12
In the late dyschromic stage, with
presence of treponemes
In the late stage, previously treated with various doses of bismuth or penicillin 9 28
\VHO;VD'I'/RES/63. 6l~ page 6
It was found that untreated pinta patients in the early stage as well as those in the late stage were completely resistant to inoculation with T. pertenue, i.e. there was no change at the site of the inoculation. The inoculation "took" in four of the nine pinta subjects in the late stage who had previously beeri treated. The first, a girl of 15, who had been treated with
adequate quantities of bismuth and arsenic about nine years previously, showed only some residual dyschromia and gave repeatedly negative serological tests. developed a typical mother yaw after 36 days. the infection followed a very similar course. She
The second was a young woman in whom The third was a woman aged 50, who She had been treated some two
had suffered from pinta from about 15 years of age.
years previously with six million units of penicillin, followed by 20 doses of bismuth: her blood tests had become permanently negative. The course followed by
the infection in this patient was very curious:
the incubation period was lengthened
to 32 days, during which a papule developed and very slowly increased in area, although never taking on the appearance of a frambesioma. After four months there was an erythematous hypochromic plaque some 6 cm in diameter, without infiltration but with treponemes in the lymph. This plaque commenced to clear up slowly from the The Kahn
centre outwards, healing being complete after six months and twenty days.
test became positive late with a very low titre - after seven months it was only two units. The whole course of the infection was very slow as if reflecting great The fourth case was a woman aged about 40 who, some 15
resistance to the disease.
years before, had been treated vlith a considerable quantity of neosalvarsan and bismuth; although the incubation period was long - 30 days - a typical frambesioma
subsequently developed. Of the remaining five patients in this group, two were absolutely resistant and in the remaining three a hypochromic plaquE.: 0•. 5-2 cm in dia.mc:;ter n.ppcared at the site of inoculation, with very little infiltration. In the lymph from these plaques
obtained by scarification, repeated examination failed to reveal the 9resence of treponemes. The serological tests showed no changes and the patients continued to give the same reagin titres. In conclusion, attempts to inoculate untrcatcd pinta patients in the tarly or late stages with T. pertenue were unsuccessful.
-----· WHO/VDT/RES/63.64 page 7
I
III.
REACTIONS IN YAWS PATIENTS
70 subjects were inoculated as follows: In the early stage (secondary ~ruption)
5 36 29
In the late stage .(of these, eight had complications osteoperiostitis or plantar hyperkeratosis) In the late stage, previously treated
70 Of the five subjects in the early stage, whose ages ranged from 8 to 22 years, four responded to inoculation in 18-30 days, d~veloping
a frambesiform ulceration One, a boy aged
similar to that caused in them by the natural infection.
17
with
frambesiomas of some ten months' duration, showed no change during 42 days' observation. We believe that this failure was due to his having Eontered the stage where cutaneous resistance develops, which, according to our observations, commences in most cases between the sixth and eighth months. Of the 36 persons in the late stage, who had had the disease from
5 to 45 years
and who had not received any treatment, 31 (86 per cent.), 15 to 25 days after inoculation, developed a group of small flat papules which then coalesced to form a plaque some 2 to 2.5 cm by l to 1.5 cm. The plaques were hypochromic, moderately After persisting for a
infiltrated, not pruretic and slightly desquamative.
considerable time wJ..th the same appearance and dimensions, they gradually regressed and disappeared in the course of four to six months, after which the infection came to a standstill in most cases. It was curious to note th..:; great similarity between
many of these cases and the hypochromic desquamative plaques (pianids) which some ya•-:~s
patients show during the secondary stage and which ar.:; considered to be allergic
in nature. In one of the 31 patii:.;nts who responded to tl1(
inoculation, the plaqul. continued By this
to develop until at the end of 10 months and 24 days it was 9 cm by 5 cm.
tim8 the plaque had an extensive c.rythe:matous hypochromic bas;:; with a ft;w central points of a delicate bluish or grey colour; and desquamative papules. the edges were; formed by confluent, dry
The: circinate appearance of this lattt:r lesion closely
WHO /VDT/RES /63. 64
page 8
resembled that of certain secondary pinta lesions, in particular that named by Leon Blanco "thE: erythemato-squamous variety of pintids 11 • Ten selected controls, who were inoc:·Jlatc.:d with thE: lymph from these plaqut::s, showed no cutaneous reaction during 50 to 6o days' observation. Some days later,
the same controls all responded to inoculation with lymph containing treponemes. For these reasons, it is considered that the lesions which appeared in the inoculated yaws patients are entirely allergic and non-infective. In a group of these patients who werE: given one or hro doses of 6oo 000 units of penicillin, the hypochromic plaque disappe.ared very rapidly, in 5 to 10 days. Of the 29 inoculated yaws· patients who had been previously treated, only two "took" the inoculation. From the serological viewpoint, no changes of any importance occurred. majority continued to give high Kahn and Wassermann titres. The
In a fvw cases, where
the period of observation was prolonged for about a year, the Kahn reaction decreased in titre or became negativ<-', as seems to be the natural course of the response in certain types of patient. In brief, yaws patients after the secondary stage, whether treated or untreated, were completely resistant to fresh infection with T. pertenue.
IV.
REACTIONS IN SYPHILITIC PATIENTS
Many valuable experiments, both on human beings andon animals, have already been carried out to determine the immunological relationship between syphilis and yaws, whose close connexion as regards some of their clinical aspects and serological reactions as well as their causative agents- morphologically indistinguishaqle under· the ultra microscope - has led some authorities (Hutchinson, Butler and Goodman among others) to put forward a unitary theory of these diseases. Hoffmann, Iturbi and Manson-Bahr among others, suppose that the two diseases have :c:t
common origin, which idea th:.:y express. c::s follows:
"Under the more primitive· p~;;;rson
conditions in the tropics, T. pertunue spreads from person to
as a result of·
close contact, whereas under more civilized conditions, in which such contact is not possible, T. pallidum came to be: communica tt:d vcnc:rcally and, in this vmy, acquiri:.:d a more virulent character".
WHO ;\JDT/RES /63•. 64 page 9
Schobl concludes that T. pallidum is panblasto.tropic with a tendency to multiply in all the tissues and to produce lesi·ons of the mesoblast in particular, whereas T. pertenue is epiblastotropic and invades specific tissues, especially the skin and bones. At present, a dualist theory is in vogue, based on observational data, to which the work of Turner and Saunders has made a fundamental contribution. Nowadays, it
is agreed that only syphilis can bring about visceral changes, particularly of the n8rvous system and the aorta, and can establish itself in the placenta, thus giving rise to congenital syphilis. Yaws can never bring about these pathological conditions.
Returning to the exclusively experimental field of inoculations, we may mention the early work of Charlouis who, in 1881, infected a negro suffering from yaws with the agent of syphilis, thus producing a syphilitic chancre at the site of inoculation. Levadi ti and Na ttan Larrier obtained positive results ·.by inoculating monkeys infected with yaws with syphilis, but failed when they syphilitic monkeys with T. pertenue. Schobl demonstrated that monkeys with high yaws immunity, produced by repeated inoculation with T. pertenue, Jahnel & Lange subsequ~ntly ~ndeavoured
to inoculate
became resistant to syphilis.
(1926 to 1928) inoculated a group of general paralytics with
T. pertenue from rabbit passages (Nichols strain) and another group with the Pearce and Brown strain, without obtaining positive results. In 1933, van der Shaar inoculated 4o patients suffering from progressive general paralysis with T. pertenue. The results v1erc negative with one exception, a case
whose cerebrospinal fluid gave a negative Wassermann reaction. Finally, we may mention the valuable experimental work carried out on animals by Castellani, Nichols, Takahasi, and Ferris & Turner. However, their results or
conclusions cannot be applied to man, in whom the clinical course of syphilis and yaws is very different from the_ course followed in monkeys and rabbits, the animals chosen for the experiments mentioned.
WHO;'vn?'/RES/63. 64 page 10
For the inoculation of T. pcrtcnue, a group of syphi1itics was selected which included patients in most stages of the disease, so as to detcrmin0 as far as the extent of the immunity which could be dsvcloped. possibl~
In the relevant literature
consulted, no information r0lating to inoculation of patients suffering from early syphilis was found. The syphilitic patients inoculated can be grouped as follows: Chancre in the pre-serological stage Chancre in the serological stage Secondary syphilis Early latent Late latent Cardiovascular complications Late, with cutaneous and mucous complications Nervous, asymptomatic General paralysis Tabes dorsalis Optic atrophy Recent congtnital Late congenital
3
5
5 20 21
15 2 4
5
7 5 3
38 133 Oj
- ar In only one of these subjects was the result of the inoculation positive (chancre in serological stag'-); the rest were.all negative.
. (l Of ·wet
Subsequently, 214 syphilitics who had previously received what was regarded as adequate treatment (6-10 million units PAM) were inoculated. The group comprised
148 subjects treated for acquired syphilis, 4 treate:d for c:arly congenital syphilis and 63 for late congenital syphilis. treated in the early phase. 11
·;SUp .,
.
Of the first 148, 41 "took", most of them
'J:>J:>e1
4
carly congenitals 11 ,
Of the 63 "late congenitals 11 , 17 wc::re: positive, and of the 11Se1:'c 3 were positive. J
WHO/VDT/RES/63. 64 page 11
The syphilitics with cardiovascular complications, those with nervous system lesions, and threc patients with congenital syphilis, were rc-inoculatcd with T. pertenue; they had all previously received large doses of penicillin, and in
three general paralytics, this trca tmen t had been supple:mentt::d by malaria therapy. The results were all negative, except for a very interesting case of a person aged
33 with asymptomatic neurosyphilis, in whom the inoculation did not at first "take"; after he had received 20 million units of penicillin, 30 doses of mapharside and 40 of bismuth subsalicylatc, ht: became infected and the infection coincided with return to normal of tht.- cerebrospinal fluid. Some subjects responded dark-field examination; \·li th
plaques in which no treponemes were found on
the plaques regressed spontaneously and rapidly, in the same
way as described in the chapter relating to yaws. Summing up: of 133 subjects suffering from syphilis in various stages, it was
only possible to infect with T. pcrtenue onc individual with recent symptoms of syphilis, which leads to the conclusion that syphilitics are protected .::tgainst yaws.
V.
APPLICATION OF THE RESULTS OBTAINED TO THE DIAGNOSIS OF, AND AS A TEST FOR THE CURE OF, THE TREPONEMATOSES
In the light of the results obtained in the t-Xp<:rimcnts describcd above, which indicated that it was impossible to inoculate T. pertenue in patients, particularly those with syphilis, ~ho
had not been cured.of their treponematosis, t<:st inoculations
were carried out on n number of persons whose diagnosis wns doubtful. Th<: results so far obtained seem most promising and continue to confirm the value
of this te:st.
As it would be too lengthy to give all the detnils of each cas<;, they
are summarized as follows: (1) A group of 45 children from the Child Syphilis Service ·:--f the National Institute t~sted.
of Venereology was
Some of those (with
positiv~
serological reactions) who
were negative to inoculation, had b<.:en brought to the Service by outside persons or referred to it by Welfare Institutes, and no epidemiological information could be supplied. Later thi.j parents, when inturrogatsd, confirmed that the children had Others, apparently h~.::althy
previously suffered from yaws.
and with weak positive
serological rEoactions, were also ne:gntive to inoculation with T. pcrtE:nu<c.
WHO /VDT/RES /63. 64 page 12
Extensive inquiries revealed that during pregnancy the mothers had bcE:n infected and thus the childr<:;n 'tJere actually latent (congenital) syphilitics. On the other hand 1
in a group which rt:actcd positively toT. pe:rtenue; inoculation 1 close supervision by periodic examinations appeared to infection. In this conn~xion,
l~ave
no doubt that they were really free from
an interesting case is that of a girl of six whose
father was suff8ring from aortic insufficiency caused by dilatation and gavt:. a persistently positive reaction, despite massiv<:: trc:c:tment. The child had a curious
appearance, a "bird face" vJith delay in the eruption of some of the teeth, which were malerupted; the motht::r had not been treated during pr0gmmcy. The appearance
mentioned, in conjunction with the family history, indicated congenital syphilis, but the child was seronegative. ThE.. inoculation rapidly "took 11 and her blood This was surprising and we
bec::tme reactive just as if she Here a healthy subject. examined the mother (a fairly yow1g woman): healthy.
she was clinically and serologically
\ihen she was inoculated, the disc:ase developed as in a first infection.
On the contrary 1 the inoculation of the father was negative on three occasions. It \vas therefore concluded that the mother and daughter wor0 free from syphilis because the union of the paronts had taken place after the syphilis in the husband had become non-infectious. (2) Seven ndults who had been trE.:ated three or four ye.:trs previously for late
asymptomatic syphilis continued to give positive Wassermann and VDRL reactions, the latter ranging from 16 to 64 dilutions. Inoculation •.-Ti th T. pertenue was positive
in all seven cases and when some time: later they d(;veloped syphilitic chancres, this was fortunate and sufficient proof thc'lt the first infe:ction had bcE.:n really cured.
(3)
Two women who, as in th0 above cnses, had b0cn treat.:;d vd th large quanti ties
of penic illinJ were negc, ti vc to inoculation with T. P•Jrt<.mue;
18 months and
tv10
years afterwards respectively aortitis appeared, which was diagnos(;d clinicnlly and confirmed by radiological examination. A number of people vi'ith nn obscure diagnosis arc now being kept under observation, some of them being negative and others positive to inoculation with T. pcrtenuc. on these cases. 1\t some future time it will be possible to give a definite decision
WHO /VpT/RES /63. 64 page 13
In
conclusion~
it is be;licvcd th'lt tl1c experiments reported have opened up an
extensive field of investigation in relation to diagnosis and cure of human treponematoses, based on the correct intcrpr8tation of the dermatological response to~
and perhaps also on
::1
histologicJ.l study of the lesions C3.USed by T. pertenue.
Many more cases must be VC;ry c2.refully analysed before: 2. final Vl.'rdict on the value of these tests can be given.
VI.
SUMl\'1'\.RY AND CONCLUSIONS ckrmc~tologic:ll,
The present r8port describes the
histopathological and serological
results obtained by tne inoculation of yarious groups of subjects suffering from_yaws, pinta or syphilis with T. pertunu~
Castcllani 1905.
The purpose of this was to
dctc:rmine the degree of immuni cy or allergy vihicrc they might h::we developc::d to this organism. Five hundred and fifteen inoculations were carried out on patients, and the rosul ts compared with those from 233 contrr;l'S, known to be lleal thy. when the results v:c::rc obscure clinical and :.:vailablc.;~
Subsequently,
the procedure was rcpplicd to cc group of subjects with diagnoses: it was also tried out us n test of cur0
sorologic~l
of syphilis, yaws or pinta.
This is UK true practical ilpplication of thG t.:XpcrimentsJ oft~_..n
above D.ll as concerns syphilis, since physici:ms been obtainLd, or not. The· work is set out in th0.: follmdng order: I. II. III. IV. V. Reactions in hu1l thy controls Reactions in pinta patients Reactions in yaws patients Reactions in syphilitic patients
cannot decide whether. cure has
Applico.tion of the rE:sults. obt:tinc:d to the diagnosis of, :md as o. t<c:st for the cure of, the treponematoses
I.
The controls consisted of young subjects, completely i'ret- from syphilis, y:J.t·m For !.)Very 10 path:nts inoculD. ted, four controls f],(;
and pintc::,
•t~crc
also inoculilted.
The rco.c tions gi V8n by tU~ m, from
c llnical :,s ;,,_ll c.cs tllG histological and
serological vic'.,;point, ,;ere comph:tcly uniform. hy a series of photogr<:tplls.
This :lspcct eLl L1lt.O 1vork is illustro.tcd
WHO /VDT/RES /63. 64
page 14
since as far as is known, they had not been attempted by any other workers. concerns syphilis and pinta, the eXC(O:llent work by Lean Blanco has shown that T. carateum can be-inoculated into syphilitics at any phase of the disease.
As
Nineteen pinta patients were inoculated (four in the Garly stage and 11 in the late stage). The inoculation was negative in all cases. Four pinta patients who Nevertheless,
had previously receivc;d int8nsivL: treatment were successfully infected. the course of the infection was slowed up, giving the resistance to the disease. III, impr~ssion
of a certain
Sev0nty yaws patients w0rL inoculatbd, fiVG in the early period - with
rrai'nbesiomas - 36 in th8 late stage and 29 in the late stage who had previously been treated. Four of the five in the early stage were successfully infected; this was
because the defence mechanism had not yet been established. whether treated or not - were completely resistant to IV. th~
All the others -
new infection.
A group of 133 syphiE tic pcctients in the most di v.:::rgc.mt stc.c.gc:s of thC;; disease they included chancres in the pre-serological and serological
was inoculated;
stage, secondary syphilidcs, early latent, late latent, late with cardiovascular complications, asymptomatic nervous and congenital syphilis, with ocular and bone symptoms. In only one case (chancre at serological stage) was it possible to infect with T. pcrtenuc. V. In view of the above facts, which seem to indicate the definite impossibility
of inoculating with T. pcrtunue patients who have not been cured of their treponematosis, it was decided to apply the (a) t~st
to the following subjects:
A group of children, in whom th~.;; diagnosis could not be established the. results here fully agreed with findings
clinically or by blood tests:
obtained by careful periodicQl examinations. (b) Seven adults treQtci for L'ltcnt late syphilis 1Nho had continued to give
positive blood reactions for months afterwards, ranging b"'tween 32 and 64 dilutions (VDRL): th<-.:se gave positive; responses to the inoculation and some
time aftE:rwards developed primary syphilitic infections (chancres) which indicated beyond cmy doubt that the first infection had be.Sn cured.
WHO ;VI)T/RES /E). 64 pagL
15
(c)
Two subjt_;cts - previously tre:atC:d for o.symptomatic late syphilis - who
were: cons ider,;d to bL cured bc;cc.us e: the blood te:s ts wer.___ p"rmancn tly negative: inoculTtion vli th T. pcrtcnue: go.vc ncga ti Vl: rcsul ts. Two and three years confi~mud
aftt_;rwurds respectivLly there Wl;rc symptoms of aortitis which were radiologicetlly.
The imprcssi vc rcsul L:; obt:tin,;d in tll.cse: LXpcrimcnts ll:ad us to conclude that: Inoculation v1ith T. pt.Ort:..,.:nuc- o. S"-nsitivc and s~.L.:
test- constituh:s "'
valuable o.id to tltc cL.widrttion of obscurC; c::csLS of yaws, pinta or syphilis.
i/Hv/'JDT/I-hlS/6). b4
page 16
REFERENCES Becker, S. W. & Obermayer, M. E. (1945) Dcrmatologin y Sifilografia Modernas Botreau-Roussel, P •. (1938) Cliniquc Chirurgicnle del Pays Chauds, Paris, Masson Briceno Rossi, A. L. & Iriarte, D. (1943) Breves notas sobre las ultimas investigaciones verificadas en las Zonas pintogenas d~ Venezuela, Mem. Ias. Jor. Venezolanas de Dermatologia y Venereologia, Marzo; Rev. Sanid. Asist. soc., ~~ 1001-13 Butler, Hutchinson & Van Den Shaar. Goodman, H. Cited by Iturbe Cited by Stitt's
Guthe, T. & Reynolds, F. (1951) World health and treponematoses, Brit. J. vener. Dis., 27, 1-19 Guthe, T. et al. (1952) Mass treatment of treponemal diseases with particular reference to syphilis and yaws, Tenth International Congress of Dermatology and Syphilis, London (subsequently published in Brit. med. J. 1953, No. 4810, 594 (digest)) Itriago, P. M. & Medina, R. (1949) Contribucion al estudio de la buba en Venezuela, Arch. venez. Pat. trop., ~~ 193-214 Iturbe, J. (1943) Comunidad del origen americano de las bubas y la sifilis, Mem. d~:: las Ias. Jorn. Venezolanas de Dermatologia y Venereologin, Caracas, Marzo; Rev. Sanid. Asist. soc., 8, 1095-1106 Jahmd, F. & Lange, J. (1926) Zur Kenntniss dl-'r Frambosie Inmunitat der Parnlytiker, Klin. vJschr., 5, 2118 Joyeux,
c. & Sice,
A. Precis de Medicine Colonialc, troisieme edition
Lean Blanco, F. (1940) La h:sion inicinl en el mal del pinto, R;:;v. tJ!cd. Trop. parasitologia, 6, 21-37 Leon Blanco, F. (1942) El Mal del Pinto, pintn o carate, Mexico, Cia General Editora, 77-78 Lesser, E. D. & Jadassohn, J. (1936) Tratado de las enfermedndes venereas Proce~dings
of the Fourth International Congresses on Tropical Medicine nnd Malarin, 1948, \vashington
Rein, C., Kitchen, B. K., Marqu'"z, F. & Varela, G. (1951) Le tr::titment de la pinta par l:1 penicilline-retard dans les rcgiones rurales du Mexique, Document I·JID/VD/77 (subseqm::ntly published in English in J. inve:st. Derm. 1952, 18, 137
WHO;VDT/RE9 /63. 64 page 17 Reynard, R. & Stout, G. (1951) Rapport sur la Primiere Enquete Serologique Effectuc en Amerique Centrale, Document WHD/VD/SER0/11 Shobl et al. Cited by Stitt's
Stokes, J. H. (1934) Modern clinical syphilology, 2nd ed., Philadelphia, W. B. Saunders Stokes, J. H., Beerman, M. & Ingra.ham, N. R. (1944) Syphilology, Philadelphia, W. B. Saunders Strong, R. P. (1942) Stitt's diagnosis, prevention and treatment of tropical diseases, 1, 6th ed., Philadelphia, Blakiston Co. Transactions of the International Symposium on the Study of Syphilis, Helsinki, 1950, (1951) Acta derm.-venereol. (Stockh.), 31, suppl. 24 Turner, T. B. (1937) Studies on the relationship between yaws and syphilis, Amer. J. Hyg., 25, 477 Turner, T. B. & Chesney, A. (1934) Experimental yaws; 2. Comparison of the infection with experimental syphilis, Bull. Johns Hopk. Hasp., 54, 174 Turn~r,
T. B. & MeLee~, C. P. (1942) Cross immunity in experimental syphilis and yaws, Trans. Ass. Amer. Phycns, 57, 265 Grun~
Urbach, E. & Gottlieb, P. M. (1943) Allergy, New York,
& Stratton
World Health Organization, Factcurs epidemiologiques intervenant dans les Campagnes collectives systematiques, Document WHD/VD/90
Fig. 1. Small papules appearing 12 days after inoculation. This is Few the earliest and mildest modification of the skin obtained. treponemes.
Fig. 2. tending
to
After 21 days the papules become infiltrated and erythematous, coalesce.
Fig. 3. After 25 days the papules are confluent, and have formed a plaque. More treponemes are visible in the dark field.
Fig. 4. After 31 days the lesion, which is erythematous and very infiltrated, 1s about to become eroded. Treponemes are plentiful.
Fig. 5. After 38 days superficial erosion is commencing in the lesion.
Fig. &. After 4a days the typical •mother yaw• has developed. It is a papilloma, readily bleeding, very exudative. causing little pain. whose surlace becomes covered with a thick scab.
Fig. 7. Smallsatellitepapules(daughter yaws) stantoappeararound the mother ya w; they are more easily detected by touch than by sight.
Fig. 8. After 58 daysagroupofinfiltrated papulescan be seen around the circumference of the lesion. The daughter papules contain large numbers of treponemes.
Fig. 9. After 82 days healing starts in the centre and a clear halo appears around the lesion. The number of tre ponemes begins to diminish.
Fig. 10. The lesion is regressing. The surrounding area becomes hypochromic and finally desquamative. The daughter papules have partly disappeared. There are ve._ry few treponemes.
Fig. 11. Lesion after 28 days. Epidermis: irregularly alternating areas of acanthosis and atrophy. Dermis: vascular dilatation and hyperplasia. Lympho-histiocytic infiltration in the upper dermis.
Fig. 12. Initial lesion after 39 days. Epidermis: erosion partially involving the mucous layer; in the deeper part of the latter spongiosis can be seen. Dermis: extensive oedema of the collagen. Moderate oedema of the vascular walls with swelling of the intima. Perivascular lymphoplasmocytic infiltration. Presence of pigment in certain sites.
Fig. 13. Eroded initial lesion after 54 days. Epidermis: pseudotumoral hyperplasia of the epithelium and acute inflammation, which in cenain places forms small abscesses and in others is diffuse. Dermis: granuloma very rich in vessels, formed by histiocytes and round cells •
Fig. 14. Hypochromic plaque with slight infiltration following inoculation with T. penenue of a patient with late pinta. There arenotreponemesinthelymph. Photographtakenvery close to the skin.
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Fig. 15. Cross-secdon of a plaque in a pinta patient 35 days after inoculation. Epidermis: irregular. atrophied in places. Areas of hyperkeratosis, predominantly follicular. Dermis : perivascular infiltration consisting of round cells. Increase in the connective tissue cells and in the density of the collagen.
Fig. U. Section of a plaque (32 days) in a patient with late pinta 32 days after inoculation. Epidermis : irregular with areas of spongiosis; mild hyperkeratosis. Dermis: cellular proliferation and perivascular infiltration in the upper dermis.
Fig. 1 7. Hypochromic-desquamative plaque following inoculation of a yaws patient. It shows great cllnlcal similarity to the •ptantds• sometimes seen in the secondary stage of the natural infection. There were no treponemes.
Fig. 18. Section of the plaque in the previous figure. Epidermis: areas of hyperkeratosis: discreet parakeratosis. Dermis: cellular proliferation and perivascular infiltration in the upper dermis. The resemblance to Fig. U is obvious.
Fig. 19. Infiltrated plaque following inoculadon of a patient with tabes. There were no treponemes in the lymph.
Fig. 20. Secdon of the plaque in the previous photograph. Epidermis: slight acanthosis in certain sites invaded by dermal cells. Dermis: slight oedema, vascular dilatadon. Perivascular infiltradon of round cells and histiocytes.
Fig. 21. Curious skin reaction obtained on inoculation of a subject previously treated for asymptomatic neurosyphilis; although the inoculation was positive the course followed was very irregular.
Fig. 22. Section of the lesion shown in the previous figure. Epidermis: irregular with slight follicular hyperkeratosis. Dermis: thickening of the walls of the fine vessels; chronic perivascular infiltration of round cells.