iv active immunisation by intra- cutaneous … · during an operation necessitated by prolapsus...

IV

ACTIVE IMMUNISATION BY INTRA-CUTANEOUS INJECTION OF LIVEGONOCOCCUS CULTURES AS ATHERAPEUTIC MEASURE IN CHRONICGONORRH(EA OF THE CERVIX ANDADNEXA IN WOMEN

EXPERIENCE WITH OVER IO,OOO INJECTIONS

By ALFRED A. LOESER (London), late Consulting Gynmcologist ofthe Municipal Hufeland Hospital, Berlin; late Director of theGynxcological Department of the Israelitic Hospital, Berlin;L.R.C.P. and S. Edin.; M.D. Berlin.

Short Historical Introduction.Deep-seated Infection in Chronic Gonorrhoea, Histology of Cervical

Gonorrhaea.Active Immunisation with Living Gonococci.Report of IO,102 Injections with Live Gonococcus Cultures.Complications and Possible Dangers of the Method.Geographical Influences on Gonorrhoea.Comparison of Active Immunisation with other Therapeutic Methods.Summary.Bibliography.

Other methods than the ones usually employed havebeen followed by me during the last fifteen years tocombat the incurable consequences of chronic gonor-rhoea in women. In all parts of the world chronicgonococcal infection of the female genitalia plays animportant part in national health, impairs fertility andmay remain a permanent danger for fresh infection.Only the experiences and researches of generations ofdoctors have rendered it cumulatively possible to elabor-ate a new therapy and it is my grateful duty before dis-cussing my own researches to make a brief retrospectivereview.More than IOO years ago, Ricord was the first to show

clearly the clinical difference between gonorrhoea andother venereal diseases. Later, Neisser proved that thegonococcus was the causal factor of gonorrhoea. Bumm,

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who, with Neisser, I have the honour to regard as mymentor, was the first to succeed in making cultures ofthe gonococcus, thus rendering it possible to treatgonorrhoea with a suspension of killed gonococci and toinject increasing doses of such killed gonococcus culturesinto human tissue (Bruck) in accordance with the methodsof Wright, the father of vaccine therapy. I went a stepfurther and injected live gonococcus cultures, after havingproved on myself, as a healthy individual, that livegonococci, injected into or beneath the skin, remain atthe site of injection and are more or less quickly killedby the surrounding skin tissue. This was the first steptowards an active immunisation. During the lastfifteen years my investigations have been verified sooften and found to be of use that I want here to give asummary of this extensive work and to complete theaccount with a list of the publications that have appearedin medical journals in various parts of the world.Acute and chronic gonorrhoeal infections are in women

two fundamentally different pathological processes, de-pending upon the tissue layers in which the diseasedevelops. In acute gonorrhoea there is always a super-ficial infection of the mucosa of the genital passages;and in chronic cervical and adnexal gonorrhoea always adeep-seated infection of the tissues below the mucosa.It is therefore not difficult to cure acute gonorrhcea byapplying antiseptics to the mucosa ; on the other hand, itis improbable that deep-seated processes as found inchronic gonorrhoea can be affected by medicaments whichdo not penetrate deeply into the tissues. Even if oneapplies to the cervical canal such disinfectants as Mesodin(Flavadin) which claim to have a certain penetrativepower, and even if local remedies to kill all bacteriaexisting on the surface of the cervical mucosa are em-ployed, it is doubtful if any such treatment can reach thedeeper parts of the glands where colonies of gonococci arelocalised behind barriers of inflammatory tissue. Sulph-anilamide may have the best effect in this respect.

HISTOLOGY OF CERVICAL GONORRHCEAThe histological study of uteri chronically infected with

gonococci has advanced during recent years, particularlythrough the researches of Schroeder," and Felke and

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Oettingen,12 and finally Felke in I936. Extensive inflam-matory changes take place in the gland tissue, sometimesreaching as far as the muscular regions. Periglandularinfiltrates of round cells and plasma cells may be foundat the gland terminals, and in the fundus of the glandssmall abscesses containing gonococci may form. Theglandular epithelium is metaplastically replaced by strati-fied squamous epithelium. Schroeder recorded suchchanges in 20 uteri removed by operation, and Felke andOettingen demonstrated similar deep-seated mutationsin 6 cases.

I myself am in a position to report in detail a casewhich was submitted to histological and bacteriologicalexamination. In removing a very elongated cervixduring an operation necessitated by prolapsus uteri, Icame across some yellowish spotted parts in cuttingthrough the cervix from which pus exuded. These patcheswere situated beneath the cervical mucosa. Both micro-scopical and bacteriological examination revealed gono-coccus. The patient now admitted wlhat she had beforethis denied, that about two years previously she had beeninfected with gonorrhoea, which had been treated withthe usual remedies. Histologically, cervical glands cutin serial sections were found covered with squamousepithelium. This squamous epithelium was arranged inmanifold strata so that the examining pathologist (Pro-fessor Pick, Berlin) at first suspected incipient carcinoma.The musculature showed infiltration of round cells andplasma cells and at the gland terminals small deep-lying abscesses were situated. Sexual intercourse duringtwo years had not passed the infection to her partner.In the cervical canal itself no gonococci were found. Doesnot this case suggest that locally applied medicamentscause the gonococci to disappear from the surface withoutcuring the infection, which persists behind a barrier ofmetaplastic epithelium and inflammatory infiltrates, thegonococci remaining alive and able to break the barrieron the occasion of any tissue stimulation, menstruationor pregnancy, and become, once again, a source of infec-tion ? It even strikes me that by applying local remediestoo frequently and too freely a fillip is given to thedevelopment of chronic gonorrhoea. That graduallythese deep-seated foci are destroyed by natural tissueresistance is possible, and well known. To combat these

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deep-seated foci effectively it is necessary to have recourseto vaccines. The gonococcus vaccines found in com-merce lose their potency unless very recently prepared.Old killed vaccines have only a very limited activity andmany injections stretching over a number of weeks arenecessary. In previous contributions I have shownthat freshly made vaccines are more effective, but unfor-tunately they evoke very high temperatures and un-pleasant sequele. I was the first to recommend theinjection of killed vaccines direct into the cervical tissuein the neighbourhood of the deep-seated gonococcalprocesses. The results thus obtained are far superiorto those when the injection is made at a distance awayfrom the infection. Bucura: 4 5 6 7 also used thistechnique in his later investigations and it has erro-neously been ascribed to him. From this, Basset andPoincloux developed their vaccination a' la porte d'entree,which is nothing more than to inject round the infectedtissues; a modification of my technique described inI922 (Loeser 27).

Nevertheless, such treatment carried out locally at thesite of infection, was not satisfactory. A true immunisa-tion is obtained only by implanting living and activeorganisms, the site of injection being the intracutaneoustissue.

TECHNIQUE OF INJECTING LIVE GONOCOCCIThe gonococci which I use must originate from a fresh

and, if possible, untreated male or female gonococcalinfection; this is the first condition. These gonococciare grown on ascites agar but must not go beyond threeto .four subcultures, that is, after remaining for forty-eight hours on such a plate, the gonococci must beinjected as pure culture within ten days of their removalfrom the human body. The longer the gonococci arecultured away from human tissue, the more avirulentthey become and the less useful for our purpose. Gono-cocci which have been subcultured for a long time in thelaboratory are so mutated that they can no longer beregarded as able to stimulate sufficient antibodies.Freshly growrn gonococcus strains of this kind may beproduced with ease in every bacteriological laboratory.It is advisable to grow various strains and, finally, to

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pool these, in order, if possible, to give the physician apolyvalent living vaccine.Up to this point the work belonged to the realm of the

bacteriologist, but now the technical application of theliving gonococcus vaccine so produced is within thesphere of the physician.To the tube containing the mixed, fresh, forty-eight

hour old gonococcus culture on ascites agar, the dilutionof which, according to repeated counts, varies between8,ooo to 12,000 million, 3 c.c. of sterile physiological saltsolution are added from a sterile syringe. The tube isshaken, by which action most of the culture becomessuspended in the salt solution and with the help of agood platinum needle previously sterilised by thoroughheating, the remaining culture is scraped from thenutrient medium. One notices how the culture separatesfrom the medium in the form of slimy threads. Theseslimy cultures are better than the flaky cultures occa-sionally met with. After the culture has been suspendedin the salt solution, I-5 c.c. of this suspension is trans-ferred to a sterile syringe by inclining the tube and thenit is slowly injected intracutaneously into the left upperarm. It is not advisable first to pour the culture fromthe tube into another vessel, and then syphon off with thesyringe, since this takes too long and the culture mightdie or become impaired, moreover, it militates against astrictly aseptic technique.One may simplify the whole procedure by ordering

from the bacteriologist a fresh, forty-eight hour ascitesculture and injecting I-5 c.c. of this bouillon aftervigorous shaking.The injection is carried out in the same way as

one proceeds in infiltrating tissue for anaesthetisation.The needle is slowly and gently inserted obliquelybeneath the skin, remaining dimly visible to the eye,and the injection of the suspended culture is madeslowly into the skin with the formation of two to threewheals.

This procedure causes no pain. Each patient received4,000-5,000 million organisms and two patients may betreated from each tube.To prevent any small rise in temperature after the

injection (the patient may be treated as an out-patientand need not remain in the hospital), salicylates are

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given. The local reaction with this treatment is greaterthan with killed gonococcus vaccines, but the generalreaction is much weaker, comparing similar doses.

WHAT ARE THE EFFECTS UPON THE LATENT GONOR-RHEAL FocI AFTER THE INJECTION ?

In many cases the injection causes the gonococci todisappear suddenly from the discharge, which becomesless and poorer in leucocytes. Sometimes the gonococciremained permanently absent.Whereas in some cases the gonococci disappear immedi-

ately after the injection, in others a very marked increaseof gonococci is noticed and the discharge is more profuse;but these conditions abate after some days and a per-manent absence of gonococci follows.

In the great majority of cases the gonococcus contentof the discharge gradually diminishes, to cease entirelyafter eight to twenty-one days.The injection, which to-day I carry out only intra-

cutaneously should be repeated after seven days, evenwhen no more gonococci can be found in the discharge.One often notices that the site of the first injectionagain reddens, even swells, for a short time after thesecond injection. A third injection is given again afterseven days, this treatment for active immunisation takingtwenty-one days to complete.

It has been justly objected by some investigators thatit is difficult to obtain live fresh gonococcus cultures asrequired. A live vaccine is available on the marketunder the name of Gonovitan (Saechsische Serumwerke,Dresden, Germany), which represents to a certain extenta substitute for the live fresh culture. An ampoule ofGonovitan contains a living gonococcus culture which isinjected in the same way as the fresh culture; it keepson the average three months. This preparation is to beregarded as an attenuated culture which I myself havenot used, since naturally the results cannot be so goodas with fresh culture. The reactions produced by it arenot less than these called forth by a fresh culture. Asmany later investigators have used Gonovitan, it isincluded in the table given below.

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STATISTICS OF INJECTIONS OF LIVE GONOGOCCUS CUL-TURES, REPORTED IN INTERNATIONAI LITERATURE

The statistics divide into two sections. Under sec-tion I are again included the I,900 injections whichwere reported by seventeen different authors during theyears I922-3I and which I discussed together with myown experiences- (Loester 36). In sections 2-23 theinjections of other authors during the period betweenI93I and April ist, I937, are classed together.

Name of Author.

I. Collective statistics I922-3I (sevenauthors), Loeser 26

2. Abraham 13. Bertoloty 34. Edel 85. Feilchenfeld, I,96. Feilchenfeld, ii,107. Felke and Oettingen 128. Friboes 149. Hussel 19:o. Jarecki 20:I. Jacobsohn (personal report):2. Kahn 21:3. Linde254. Linde and Timochina 265. Langer 226. Loeser, I93I-377. Popescu 4 . . .:8. Schroeder 45 46, Schwab 47 Thomson 52:9. Schultz 4 . . .to. Smirnow 48

'i. Sommer49 . . .2. Waldeyer 57 . . .3. WTOlff, I93I-37 (personal report) and 58

.teen

ca.-64

Total

No. of Injections.

I,90030

2222492740

200250250324IOO237200204i8oI89I90I753007337230

4)000

IO,I02

IO,IO2 injections are thus involved which have beenadministered during the last fifteen years to more than3,000 men and women suffering from gonorrhoea. Theseinjections include patients treated by Wolff, Sommer,

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Abraham and Feilchenfeld as well as 20 of Schroeder'spatients, with attenuated live vaccine (Gonovitan).The methods adopted by the above-mentioned authors

were not always the same. Some injected subcutaneously,some intracutaneously, Schroeder 47intramuscularly. Theindications, also, varied greatly. Some of the cases wereof a chronic nature and had been treated unsuccessfullyby other methods-. Others again represented acute andsubacute types of female and male gonorrhaea. Poly-valent gonococcus cultures (Linde2G) were also used.The results were particularly satisfactory in all cases ofgonorrhceal arthritis. All authors are in agreement thatin early gonorrhoeal arthritis live vaccine treatment isthe method of choice-there was not a single failure,Hussel 19 even obtained successes in more chronic artic-ular cases. Bier stresses in particular the rapid analgesiceffect of the injection. Most authors observed thatthe vaccine had no effect upon superficial mucosalgonorrhoea of the urethra and of the rectum, whichfindings were in accordance with my own observations.Most of the authors administered two or three injectionsof various, generally increasing, strengths and in mostcases urethra and cervix were treated also locally.

The average percentage of complete cures amounted to8o -85 per cent., and with some investigators reached asmuch as 95 per cent. Waldeyer was the sole exception, whoreported ornly 50 per cent. This author deals with only20 cases.

MY OWN CASES;In a previous article (Loeser 35) I reported on i68 cases

of chronic gonorrhoea in women, of which II3 were curedwith only one injection of live virulent gonococcusculture. The technique then used differs from the one Inow adopt. Moreover, at that time, I preferred to giveone injection only. During the period I93I-37 I wasunable owing to outside circumstances to treat and sub-sequently examine more than 63 women, to whom I89injections were administered. The following changeshave been made in my previous method of procedure.On principle, three injections at intervals of seven daysare now always given; IP5 c.c. of salt solution in whichthe culture is suspended constitutes the first dose, thiscorresponding to about 4,000-5,000 million organisms,

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the second and third doses are raised to 3 c.c. cor-responding to a culture of 8,ooo to I2,000 million orga-nisms. Whereas I previously restricted mvself to chroniccases, I now also include cases of cervical gonorrhoeawith acute ascending infection. Hussel 19 describes acase in which an acute gonorrhceal exudate into thepouch of Douglas or acute gonorrhceal parametritis aswell as acute salpingitis following upon cervical gonor-rhoea was successfully treated with intracutaneous livevaccine. I have since observed in 8 cases of ascendinggonorrhoea with high temperatures instant arrest ofpathological processes accompanied by an immediatefeeling of well-being, and I would now, contrary to myprevious convictions, always recommend injections inthis condition. In 3 cases an auto-vaccine was prepared.It should further be mentioned that amongst the 63patients, 2 were pregnant. Particularly in pregnancy,where drastic methods of all kinds, even local, are pro-hibited, the injections are effective and free from danger.I would like to stress the good results in affectionsconnected with the joints and tendon sheaths. Contraryto Bertoloty 3 I have not observed an effect in reallyacute cases of urethral gonorrhoea. The striking changesoccurring in adnexal gonorrheea treated in this way arethe rapid cessation of pain and of the feeling of con-tinual discomfort in the abdomen; further, the palpablyevident return to normal size of the adnexa which hadbeen very large and adherent. Of the 63 cases, 49 werecured by three injections, i.e., 76 per cent. My percentageof cures therefore increased with my new technique,although I have not yet obtained such high percentagesas other investigators. This brings me to the questionof the permanency of the cure and of the specificity ofthe treatment.

PERMANENCY OF THE CURE AND SPECIFICITY OF THEVACCINE TREATMENT

I consider a permanent cure one in which subsequentexaminations during a period of six months, carried outafter or during menstruation, prove negative for gono-cocci. I proceed as follows. As soon as the last injec-tion has been given, a control test is made during thenext menstrual period, or, if preferred, immediately

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following. Gonococci are more frequently found duringmenstruation than just after. If one wishes to examineafter the period, it is desirable to insert a thin soundcovered with cotton-wool on the evening before examina-tion, in order to produce some local mechanical irritation.Such mechanical irritation is far preferable to chemicalirritation with Lugols solution. I have also tried toproduce hyperemia with the combined injection ofanterior and follicular hormones with the intent ofbringing to light any gonococci that might still bepresent. This method has no advantage.

In respect of the specificity of the vaccine treatment,it should be stressed that often a single injection leadsto a permanent cure of the disease. Of no other form oftreatment hitherto used can this be said, be it fevertherapy with malarial infection, killed vaccines or asingle application of a local remedy. The engenderingof febrile conditions during treatment with live vaccinesis considered undesirable and possible rises in tempera-ture should be anticipated by prophylactic doses ofsalicylates. The only factors which could be so markedlyeffective in such a single treatment are the proteins andtoxins liberated by the breaking down of the gonococciinjected into the skin. These are the specific antibodies.The gonococcus is implanted into tissue-skin-which

normally it is not in the habit of entering, being unableof itself to ensconse there. In the skin it is as a rule killedwithin a comparatively short time. The following testshave been made by me. Three, six and twelve hoursafter the intracutaneous injections, serum was removedfrom the skin by scarifying the tissue, in order to makea culture on ascites agar plates. As the tissue encirclingthe site of injection is very inflamed this may be donequite easily. Gonococci could no longer be grown fromthis serum and it would appear therefore that the gono-cocci had been killed off very quickly in the tissues.After excision of these skin portions, two to three monthsafter treatment, histological examinations were carriedout (Professor Robert Mayer, Universitats-Frauenklinik,Berlin) without gonococci being found. There have beencases in which gonococci have continued to live forfourteen days, causing an abscess to form at the site ofinjection, but this will be discussed later. The moribundgonococci throw off into the tissues their endo- and

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ecto-toxins such as are found also in old gonococcalcultures and gonococcal filtrates, thus producing a con-dition of immunisation. A comparison of the serum ofwomen treated with injections of live vaccine and that ofhealthy women, when mixed with nutrient agar, showedno difference in their behaviour. We evoke in the humantissues all these antibodies which can be extraneouslyintroduced by the injection of gonococcus toxins, anti-toxins and other products found in the filtrate of a gono-coccus culture. But there is one important difference inthe case of our active immunisation, namely, that allthese antibodies are produced in statu nascendi and inmuch larger and lasting quantities than would be avail-able by injecting similar artificial agents pre)ared out-side the body.

Henlce it follows that the skin plays a pouwerful part inthe development of immunising bodies which are producedin increasing abundance and attain increasing efficacy pro-portional to the length and intensity of the battle ragingbetween tissue and bacteria.One may truly sav that the fresher the implanted organism

the more intense and immediate will be the immnunisationthat results.

It is therefore a very satisfactory sign when theorganism is sufficiently virulent to produce a smallabscess, as the gonococci will then remain alive for sometime, setting up a permanent process of immunisationwhich will the more rapidly bring about a cure. Thisexplains why investigators like Schroeder and his col-laborators, Heyn 16, Schwab 4, Thomsen 52 obtained thebest results when abscesses formed. Jadassohn alsohas reported that these types of gonorrhoeal prostatisheal best, where, in the course of treatment an abscessforms on the prostate. Vohwinkel 54, 55 has describedother observations of abscess formation following gono-coccal vaccination.

Desirable as it is to evoke strong local reactions at thesite of injection in order to assure immunisation, thereare nevertheless cases which show scarcely any reactionat that site. Such cases are parallel to those observed insmallpox vaccination, where children are sometimestreated three or four times without a local reactionbeing produced; there are other cases again in which areaction is characterised by a markedly strong purulent

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breaking-down of tissue and high fever. The reason forthese, as for all reactions in active immunisation, is tobe found in the constitution of the patient as well as inthe nature of the vaccine. This brings us to the prin-cipal question.

CAN INTRACUTANEOUS VACCINATION OF LIVE GONO-COCCI CAUSE DAMAGE ?

No general infection nor dangerous complications wereobserved in the i0,102 cases in which live gonococcus cul-tures were injected into the skin. Amongst the cases in theabove table onlv six complications were reported, i.e., o-o6per cent., whereas it is well known that in Ioo cases ofgonorrhcea treated only locally, o027 per cent. show meta-static developments.The following complications have been noticed up to

the present after live gonococcus treatment.Felke 11-in one case myositis of the extensor muscle

of the upper arm developed and also a case of ulcusgonorrhoicum serpiginosum. The author ascribes theseconditions to certain gonococcus strains having " tissueaffinities" and recommends that strains originatingfrom abscesses or metastatic gonorrhoea should not beused, but he adds that in spite of such occurrences, treat-ment with live gonococcus injections should not beabandoned since it, particularly in severe cases of chronicgonorrhoea, is superior to any other therapy. Waldeyer 57treated in all only 27 cases of chronic gonorrhoea; heobserved complications in 2 cases, once a deep abscessat the site of injection, in another case, metastatic articularinfection. It is rather curious that in such a small numberof cases two complications should have arisen. Since thereport of Waldeyer gives no particulars respecting thenature of the original organisms nor of the methodsemployed in making the cultures, it is difficult to voicean opinion. It should be emphasised, however, thatafter injection of killed gonococcus vaccines as well asafter live vaccines articular swellings are often observed,which soon disappear and are of an allergic nature,similar to those which develop after serum injections.

Finally, Thomsen 52 reported a deep-seated abscess inthe thigh after intramuscular injection and amongst theprivate cases reported to me I was informed by Jacobsohn

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of a large abscess in the upper arm. This makes in allsix complications.

In regard to cases of large local abscess formation, thepossibility would have to be excluded that no con-tamination was present when the gonococcus culture wasinjected. In the cases of articular swelling, it should beremembered that even if metastatic articular affections dodevelop, such temporary metastases are produced duringevery other form of treatment.

It has frequently been noticed that a regional lymphan-gitis or lymphadenitis develops, which clears up after afew days' treatment. No complications are reportedfollowing injections with attenuated gonococcus cultures(Gonovitan).

COULD COMPLICATIONS OF EVERY KIND BE PREVENTED,THUS RENDERING THE THERAPY QUITE HARMLESS ?

The weak point of the treatment is the uncertainty ofthe constitution of the original material. In the absenceof tests upon animals, we cannot know in advancewhether we are in possession of a very virulent or, if Imay put it so, more harmless gonococcus. When Felkeadvises the avoidance of strains with tissue affinities,we do not know which strains are of this nature andmight thus be likely to produce complications. If weknow that amongst io,ooo cases of gonorrhoea i caseof gonorrhceal sepsis occurs which had not been treatedotherwise than with local remedies, and no other caseof gonorrhceal sepsis has been observed amongst all theseIO,I02 cases, one may say that this method of treatmentis as harmless as any other form.

Should one wish, however, to avoid even the theo-retical possibility of a complication, I suggest the follow-ing precaution which I applied in the last series of mycases. Before administering the first dose of I-5 c.c. ofthe suspension, i.e., before giving the first therapeuticdose, o03 c.c. is injected intracutaneously and one waitsto see if any articular pains follow or deep phlegmonousinflammation of the subcutical tissues is visible. Shouldsuch happen, one must consider the strain or strains ofgonococci used for the cultures as too virulent and there-fore unsuitable. I carry out this preliminary injection

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because I like to use strong strains of metastatic gonor-rhoea.

GEOGRAPHICAL CONDITIONS INFLUENCING GONORRHCeAThe same gonococci act differently upon different races

in different lands. It has been shown, for instance, thatgonorrhoea in negroes leads to a much higher percentageof gonorrhceal sepsis than in white races and that thenegro often develops disorders of the cardiac valves.Bacteriologically, we can distinguish about four differentvarieties of gonococci and we can deduce the virulenceof the strains from the macroscopical growth. Respect-ing the latter, I would mention that in my experiencethe tough slimy type of strains are the most virulentand the most certain to achieve therapeutic results.Japanese who become infected with gonorrhoea inEurope show a worse prognosis than Europeans. Euro-peans again catching the disease outside Europe are moreseriously affected than when they become infected intheir own country. By way of illustration I should liketo describe the following case.

I was treating gonorrhoea in a negress who had beeninfected by a negro. This infection took its course inthe urethra and cervix without complications. But thesame strain of gonococcus produced in two white womena severe febrile condition of the adnexa. In one of thesepatients two intracutaneous injections of a strain fromherself yielded a quick cure and similar treatment wasabout to be applied to the other patient when generalgonococcal sepsis set in. Two different articular meta-stases developed and one metastasis on the meningeswhich was of a type which I had not previously noticedand which resulted in temporary blindness of the eye.This condition was diagnosed by the attendant ophthal-mologist (Professor Krueckmann, Berlin) as an cedemacaused by gonococci which congested the cerebralmeninges surrounding the optic nerve. This case ofgonorrhoea, even when the complications had all sub-slded, remained very obstinate and a cure was eventuallvslowly brought about in Vienna by one of the mostexperienced specialists in the field of gonococcal vaccines-Bacura. It was a mere chance that I had not appliedtreatment with live vaccine earlier; had I done so, the

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development of gonorrhceal sepsis would assuredly havebeen ascribed to my treatment.The severity of gonorrhoea is, however, not only

dependent upon the virulence of the strains, but it differsalso according to the season. In my fifteen years ofexperience, I have found that the virulence of theoriginal strain from which the gonococcus cultures aremade is the only varying and uncertain factor in thetreatment. It lhappens that a strain used in a certainseries of patients will produce good results, the samestrain, injected a week later barely evokes a reaction.The dependence of gonococcus strains upon temperature,longevity and culture media affects the virulence and,consequently, the therapeutical results achieved byintracutaneous injections of live cultures.

If in spite of this uncertainty attached to the conditionof the original material, such good results were obtainedby almost all investigators, it is worth while to comparethese results with those obtained from other forms oftreatment.

COMPARISON OF RESULTS WITH VARIOUS OTHER FORMSOF TREATMENT USED IN CHRONIC GONORRHoEA

Artificial malarial infection is claimed to be an idealform of treatment for all obstinate types of gonorrhcea.One hundred per cent. cures are reported by variousauthors. One must, however, bear in mind that thistreatment cannot be given in the out-patient's depart-ment and that it represents a very severe attack uponthe general health of the patient. Apart from the manycomplications which may occur during the course of it,complications which with live vaccine therapy could nothappen, such conditions as serious anmemia, immediatecollapse, circulatory disturbances, loss of weight mayensue which can be rectified only very slowly. The timetaken for this treatment is twice that needed for livevaccine therapy. I believe that only in totally refractorycases should treatment of this kind be decided upon.Treatment with killed gonococcus vaccines produces

more serious general and cardiac reactions than that withlive vaccine, it takes longer and does not give betterpercentage results; indeed, according to available statis-tics, the successes are less than those with live vaccine,

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even Bucara, who is much in favour of treatment withkilled vaccines ascribes better results to the former.

Similar arguments apply to the treatment of chronicgonorrhoea in women with fever-producing proteins, milkinjections or injections with the patient's own blood.Recently it has been tried, by means of apparatus, toraise the body temperature to I04° F. and more(Warren 56). The reports are not explicit in statingwhether such hyperthermic methods produce adequateand permanent results in chronic gonorrhoea. In mytests with Walinsky, I proved that patients with chronicgonorrhoea become temporarily and not permanentlyfree from gonococci when their temperature is raised toI04° F. or more.

Similarly the production of high local temperatures asexemplified in diathermy and heat rods has produced noappreciable results. Short-wave treatment has beenabandoned.What success can be credited to local treatment ? As

I said at the beginning, locally applied medicaments areunable to reach deep-seated foci. Intramuscular andintravenous agents have not shown equally good results.Medicaments which partly penetrate the surface whenapplied locally to the cervical canal, may as in the caseof Flavadin cause necrosis of that part and the per-centage of cures claimed for it is not higher, particularlyin cases of purely chronic gonorrhoea with constantlyrecurring relapses. It is just these severe cases whichare difficult to influence in which the live vaccine is indi-cated. That local treatment may also be applied inaddition to live vaccines to kill off the gonococci existingon the surface of the mucosa is, of course, reasonable.What causes most investigators to give live vaccine

thereby the preference over other forms of treatment isthe advantage that it may be carried out in the out-patients' department, that the time taken for the treat-ment is three to four weeks, a shorter time than thatneeded for other treatments, and that the percentageof cures is higher than that of other methods with theexception of the risky malarial treatment. It must bementioned that recently (I937) the treatment of gonor-rhoea with oral Sulphanilamide (Prontosil) showed avery good therapeutic effect. A derivative of Prontosil"Uliron " seems to be still better, especially in chronic

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gonorrhoea. Two-thirds of the cases treated in this wayreacted favourably.

Live vaccine has achieved unsurpassed success inacute gonorrhoeal arthritis.

INDICATIONS FOR THE TREATMENT WITH LIvEGONOCOCCUS VACCINE

Primarily, it has been selected as the method of choiceby all authors in acute and subacute gonorrhceal arth-ritis. Also in all chronic and obstinate gonorrhceal infec-tions of the cervix, uteri and adnexa. In acute ascendinginfection the live vaccine may cut short the ascendingprocess. Affections of the ligaments and tendons as wellas of muscles which show themselves as due to gonor-rhoeal rheumatism always respond well. Some authors,as Hussel 10, have reported good results in acute processesand in vulvo-vaginitis in girls. Other authors again haveused the vaccine successfully in pure acute gonorrhoeafor the purpose of avoiding complications and with adefinite percentage of cures (Bertoloty). I have not hadsufficient experience in this field to recommend treat-ment for such conditions.My recommendation is to use the live vaccine in all

such cases where a gonorrhceal infection of cervix oradnexa of over three months' standing is making noprogress in spite of other treatment or where in cervicalgonorrhoea acute ascending infection sets in. It shouldbe always used when there is gonococcal infection of thecervix complicated by pregnancy and in acute gonor-rhoeal arthritis; tentatively in cervical and adnexalgonorrhoea of more than four weeks' standing. Thistreatment may always be given in the out-patient depart-ment accompanied by prophylactic doses of salicylates.If it is not possible to obtain fresh gonococcus cultures,live attenuated vaccines, as presented in Gonovitan, orany other laboratory culture may be used.

CRITICAL CONSIDERATIONS AND FINAI NOTESOften chronic gonorrhoeal infection finally cures itself,

usually after irreparable damage has been caused. Thlegradual liberation of antigens produced by latent gono-cocci embedded in the tissues and a process of auto-

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immunisation developed during the course of years,brings this about. Unfortunately, until this happensmuch permanent damage is done of which the mostserious for the woman is sterility. What then was ourtherapeutic aim, if my understanding of the problem iscorrect, in order to further such processes of self-immunisation and not allow serious injuries to ensue.?

It was to accelerate the long protracted processes ofimmunisation caused by latent gonococci embedded inthe tissues by implanting a focus of active organisms ofsimilar type. The skin offers a solution to this thera-peutic problem.

In view of the IO,OOO injections of living gonococcuscultures which have been reported up till now and of myfifteen years of investigations supported by the pains-taking researches of so many other investigators I feeljustified to-day in asking whether this treatment byactive immunisation through the injection of livinggonococcus vaccines has established itself as a thera-peutic measure against gonorrhoea.

Active immunisation with live vaccine surely nowpresents a mode of treatment for all deep-seated gono-coccal infections, whether these are of an acute or chronictype. These deep-seated foci are -present in cervicalgonorrhoea of not too early origin (in early cervicalgonorrhcea there are no deep-seated foci) as well as inadnexal infections of all kinds in man. Further, in acutearthritis, in gonococcal tendovaginitis, neuritis andmyositis.That a vaccine of this kind which can work only in

conjunction with the body's power of resistance and issubject to the ever varying character of living immunisingorganisms, may not always be successful, will be readilyunderstood by all who have studied the nature ofvaccines.

(i) In treatments involving over io,ooo injections oflive gonococcus cultures 80-85 per cent. cures wereeffected.

(2) These injections are free from danger. Complica-tions to the extent of only o-o6 per cent. were observedfollowing upon the injections, whereas it is usual foro027 per cent. complications to occur in gonorrhcealinfections.

(3) The injection of live gonococcus cultures represents59

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an active immunisation whiclh is indicated in the treat-ment of every deep-seated gonococcal focus, acute orchronic in character.

(4) The treatment may be carried out in the out-patient department and as the sequelx are slight and ofshort duration it is superior to every other form oftherapy, especially when it is accompanied with mildlocal treatment.

BIBLIOGRAPHY(i) ABRAHAM, ERNST G: "On Treatment of Chronic Adnex Gonor-

rhoea with Gonovitan," Med. Kli., I932, 2, S. iio8-iiii.(2) ANTOINE: Wien. Kli., 36, ii., pp. 883-885.(3) BERTOLOTY, RICARDO, and LEOPOLD HERRAIZ: "Active

Immunisation in Gonorrhoea by Means of Living Gonococci," UrologicRev., 1936, 40, 88-93.

(4) BucuRA: " Gonorrhoeal Infection of the Female GenitalOrgans," Handbook, Veit-Stoeckel, I934, 8.

(5) BUCURA, C.: " Serodiagnose und Vaccinetherapie," Zbl. f.Gyn., I929, Pp. I693-I700.

(6) BUCURA: " Ueber Gonokokkenmischvaccinen," Wien. Klin.Wochen., I933, PP. I4I-I42.

(7) BUCURA: " Richtlinien zur Behandlung des weiblichen Trip-pers," Wien. Med. Wochen., I928, 2, 987 and I042.

(8) EDEL, WALTER: "On Treatment of Gonorrhoea with LiveGonococci Vaccine," Dermat. Zeit., 64, I67-I72.

(g) FEILCHENFELD: "Treatment of Chronic Gonorrhoea withGonovitan," Med. Klinik., I932, P. 78I.

(Io) FEILCHENFELD: Dermatolog. Wochenschrift., I933, 2, I47I-I480.(ii) FELKE: " Zwischenfielle bei der Go. lebendvaccination,"

Med. Klinik., I932, 1, 644-645.(I2) FELKE UND V. OETTINGEN: "Zur Anatomie, Immunbiologie

und Therapie der Cervixgonorrhea," Dtsch. med. Woch., I932, 2,I52I-1523, and I936.

(I3) FRANZ, R.: "Handbuch der Haut und Geschlechtskran-kheiten Jadassohn," 21, Jahrgang, I934.

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p. 6I3.(i8) HOFSTAETTER, R.: " Ueber die Behandlung durch die Vacci-

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Peritoneums gonorrhoischer LEtiologie mit lebenden Gonokokken-kulturen," Ginek, Nr. 4, I934 S10.-22. Russisch.

(22) LANGER: Dtsch. Med. Woch. und Kli. Woch., I93I, Nr. I4.Sitzungsbericht Berl. Med. Cesellsch., February 26th, I93I.

(23) LEVINE UND PINK: Ann Dermat et Syphilis, I933, s. 855."Sur la valeur diagnostique des injections intracutanees de culturesvivantes et mortes de gonocoques," Sovietsky Vestnik Ve'nerologieDumet, I932.

(24) LEVINTHAL, W.: On Bacteriology of Gonovitan," Dtsch.Med. Woch., I929, 2, I793-I794.

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(28) LOESER: " The Cure for Chronic Female Gonorrhcea withFresh Vaccines and Live Vaccines," Medicinische Kli., I926, Nr. 35.

(29) LOESER: " Session of the Berlin Urological Society," April27th, 1926, Zeitschrift fuer Urologie, 20, I926.

(30) LOESER: "The Cure of Chronic Uterus and Adnex Gonor-rhcea with Subcutaneous Injections of Live Gonococci (Live Vaccines),"Med. Kli., I928, Nr. 25.

(3i) LOESER: "On Gonorrhcea Treatment," Kli. WVochenschrift,1929, Nr. 29.

(32) LOESER: "Further Experiences in the Treatment of ChronicGonorrhcea in Females with Live Vaccines (Gonococci Cultures)under Special Consideration of Lasting Results," Med. Kli., I929,Nr. 3.

(33) LOESER: " The Cure of Chronic Gonorrhoea in the Female bymeans of a single Subcutaneous Injection of Live Gonococci," TheAmerican Journal of Obstetrics and Gynecology," St. Louis, I927,Nr. 3.

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(36) LOESER: " The Rational Treatment of Chronic Cervix andAdnex Gonorrhoea with Live Vaccines," Mlled. Kli., I93I, Nr. 22.

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(43) POPESCU, BUZEN M.: "Zur Gonorrhcebehandlung durchlebende Gonokokken," Rev. rom. Urol., 1934, 1, S. 50, 58, Rumenisch.

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weiblichen chron. Go." Deutsch. Med. Woch., I933, 2, i86I-i865.(58) WVOLFF, FRIEDRICH: "Zur Biologie des Gonococcus und zur

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Gonovitans und der Gonokokkenlebendvaccine," Klin. Woch., I929,PP. I496-I497.

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iv active immunisation by intra- cutaneous … · during an operation necessitated by prolapsus...

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