STREPTOCOCCI: THEIR TOXINS AND ANTITOXINS. 167

in dermatology site of predilection is an unreliablecriterion.

All three diseases may attack the mucousmembranes of the mouth and eyes, but inE. bullosum the chief distribution of the eruptionfalls on the backs and palms of the hands andsimilar situations on the feet and the extensorsurfaces of the knees and elbows. In Dermatitisherpetiformis the eruption may come anywhere,with perhaps a special liability to attack the axillaeand groins, and Pemphigus vulgaris has, as faras my experience goes, no favourite sites. Sub-jectively, E. bullosum is usually associated withburning and tingling, and D. herpetiformis nearlyalways with maddening pruritus. Pemphigus mayeither give rise to a sense of soreness or of itching,though it is fair to admit that some observersclassify all pruriginous pemphigoid eruptions withD. herpetiformis.

Finally, I should like to refer to two other formsof generalised acute eruption. Dermatologistshave generally taken the suffix "ide " as a con-venient term to denote that the eruption is ofhkematogenous spread-e.g., syphilide, tuberculide.Of recent years it has been observed on the con-tinent, where the occurrence is fairly common,and also in this country, where it is, I think, rare,that in certain cases of ringworm of the scalp ageneralised, non-progressive eruption of minutescaling papules, occurring either singly or in ringedgroups, may appear on the trunk. Without goinginto controversial detail, I may say that thedoctrine brought forward is that this eruption isdue to the entry of particles of the fungus into theblood stream, and the subsequent depositiontherefrom into the skin. Hence it has been named" Trichophytide." It somewhat resembles theeruption commonly called dry seborrhceic eczemaof the trunk.The second form is analogous to this, and was

described by me. In certain cases of impetigo ofthe scalp in children one finds also a similar eruptionof minute follicular scaly papules occurring singlyor in groups and coming out acutely on the trunk.It is not bullous or even vesicular, and just as the" Trichophytide " does not resemble the original,local inoculation of ringworm of the scalp, in likemanner this eruption, secondary to the impetigo,does not resemble the true bullous lesion of inocu-lated impetigo. By analogy with the "Tricho-phytide " I have called this the " Streptococcide."It is far from uncommon in England, and the onlything that surprises me is that it had not beendescribed before I called attention to it. Thediagnosis in both cases is, of course, simple, providedthat due attention is paid to the general examina-tion of the patient's skin.

All Lectures and other contributions for thePOST-GRADUATE MEDICAL JOURNAL should besent to the Editors, Fellowship of Medicine,1, Wimpole-street, W. 1.

STREPTOCOCCI :THEIR TOXINS AND ANTITOXINS.*

BY

R. A. O'BRIEN, M.D. MELB.,WELLCOMIE PHYSIOLOGICAL RESEARCH LABORATORIES.

BECKENHAMI, KENT.

OUR time will be spent mainly in considering thestreptococci, and chiefly the pathogenic ones,under the headings of classification and pathology-i.e., what the streptococci are and what they do.It is probably fair to say that the attention ofbacteriologists has recently, and more fruitfully,become more centred on what these organismsdo than on what they are.

CLASSIFICATION.In all scientific work accurate classification is

of fundamental importance, and many attemptshave been made in the past to classify thesestreptococci by the careful investigations of eminentworkers in bacteriology; light has graduallydawned, and we are to-day almost in sight of arational view of the group.We may for the sake of clearness take some

historical liberties and consider each of theseattempts in sequence.The first attempts were naturally based on

morphology from the time when Pasteur drew hishistorical chain of cocci on the blackboard at ameeting in Paris, and soon such names as longusand brevis arose. Throughout all this work attemptswere constantly being made to link these variousgroupings with the various diseases produced bythe cocci. Thus, Streptococcus longus was thoughtby von Lingelsheim, 1899, to be pathogenic, andthe short-chained variety, brevis, much less so.

Next, cultural characters were carefully exploredand groupings were arranged on the basis offermentation of carbohydrates, &c; now arosethe names pyogenes, fcecalis, &c. This work islargely due to English bacteriologists-Gordon,Andrewes, and Horder (1902-1906).

Blood plates were next (Schottmiiller, 1903,Th. Smith and Brown, 1915) extensively used anda division was made into: (1) the non-haemolyticgroup; (2) those giving a green ring, the viridansgroup; and finally (3) the haemolytic group, whichproduce a clear ring around the colony, a so-called"hsemolysis," though the appearance suggeststhat there has been also decolorisation. Thislatter group gives hsemolysis of red blood cells insuspension in a test-tube. It was clearly pointedout by these workers that there was a transitionfrom cocci giving rapid and complete haemolysisto those with feeble hoemolytic power, but the

* Lecture delivered at St. Mary's Hospital, May, 1927.

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168 STREPTOCOCCI: THEIR TOXINS AND ANTITOXINS.

grouping "haemolytic" and "non-haemolytic"is convenient.

If one requires a bird's-eye view of the resultsup to this period, that given by Park and Williams 1is perhaps one of the most convenient, with itsdivision into hoemolytic and non-haemolytic groups.The beta group of Smith and Brown includesS. pyogenes, anginosus, and equi; the alpha groupis divided into two groups: those producingmethaemoglobin-e.g., fecalis and salivarius-andthose not producing methaemoglobin-e.g., thegamma type, anhcemolyticus, &c.The next attack during the immediate past has

been by agglutination and absorption methods(Dochez, 1919, Gordon, &c., and recently by Smith,Griffith, and James, &c.). The technical difficultieswere great, and only within the past few yearshas it proved practicable by various methods ofagglutination in buffered broth, rapid subculturing,or rapid microscopic testing, to work withsufficiently stable emulsions to give reasonablyconsistent results. It was at first thought that byagglutination we might be able to separateclearly the pathologically defined groups-e.g.,scarlet fever, erysipelas, puerperal fever, &c.,but later work has shown that by careful agglutina-tion and absorption work the streptococci can besubdivided into a number of nmain groups andprobably a considerable number of subgroups.

OVERLAPPING OF GROUPS.The groups definitely overlap. Thus, the scarlet

fever strains can be fairly clearly divided intothree main groups and an unknown number ofsmaller groups, but some cultures derived frompuerperal fever and erysipelas are indistinguishablefrom those in the main scarlet fever groups.

Finally, since the use by the Dicks (1924) ofthe intradermic method in human beings, theattempts have been mainly directed to seeingwhat the pathogenic actions of the variousstreptococci are, and whether any classificationcan be based thereon. But here again we arefaced with great confusion. At first it was thoughtthat the scarlet fever streptococcus would producea scarlet fever toxin and would on injection intoanimals cause the production of a scarlet feverantitoxin; similarly it was thought that thepuerperal streptococcus would give a characteristictoxin and antitoxin, that " cellulitis " and" septicoemic " strains would similarly give clearlydistinguishable toxins and antitoxins.Amoss and Birkhaug concluded as the result of

their work that the erysipelas streptococcus hadclearly specific toxin-antitoxin relationships quiteindependent of the scarlet fever streptococcus.It is not certain that further experience will confirmthis clear specificity.

It is already clear that there is some overlapamongst the main groups. How much is notyet determined. Some workers go so far as to

'Pathogenic Micro-organisms, 1925, p. 303.

conjecture that there is one antigen only-i.e.,that the toxins of the streptococci causing scarletfever "septic sore-throat," erysipelas, puerperalfever, cellulitis, &c., are all one and the same toxin,and that whatever toxin be used the same antitoxinis obtained.

METHODS OF INVESTIGATION.There are several methods of investigating this

problem, and they are all being actively pursuedat the present time. If we take the S. scarlatinceof Dochez and the Dicks and make a toxin from it,we find that when the toxin is injected in suitabledoses intradermally into human beings, some givea positive red reaction, and others give no response-the so-called negative reaction. A group ofpeople who have had scarlet fever will have amuch higher percentage of negative reactions thanthose who have never had scarlet fever or beenin contact with it.

(1) If we can obtain large groups of people whohave had, e.g., " septic sore-throat" or puerperalfever, we can test them with the scarlet fever toxinand with a culture filtrate or " toxin " made fromcultures of streptococcus obtained from puerperalfever or tonsillitis. If we end by finding that allthe people who give negative reactions to thescarlet fever toxin also give negative reactions tothe tonsillitis and puerperal fever toxins, and thosegiving a positive reaction to one toxin give a positiveto the other two, we shall be justified in assumingthat there is a close antigenic relationship betweenthe three toxins and presumably between the threediseases. The results from this line of researchare at present too meagre to justify any confidentconclusion, but apparently there is a considerabledegree of agreement in the groups-i.e., the majorityof people who give a positive response to theDick scarlet fever test will also probably give apositive response to the injection of the othertoxins, and " Dick negative reactors " will usuallybe "negative" to the other toxins.

(2) We may test the hypothesis in anotherway-make an antitoxin to one of the streptococci-e.g., scarlet fever antitoxin, and test its effect onstreptococci obtained from the other diseases andon their toxins. Parish and Okell have shownthat, in the rabbit test, scarlet fever antitoxinhas a significant protective action against a numberof hsemolytic streptococci obtained from otherdiseases.

(3) We may mix the scarlet fever antitoxin withthe toxin of, e.g., puerperal fever, and injectthe mixture into the skin of subjects who give apositive response to the injection of " puerperaltoxin." It is found in practice (Eagles, McLaughlin)that a considerable degree of overlap occurs;thus scarlet fever antitoxin will neutralise tonsillitistoxin or puerperal toxin in a considerable numberof instances.

(4) We may use one antitoxin for the treatment ofthe other diseases-e.g., scarlet fever antitoxin fortonsillitis, puerperal fever, &c. Here again the

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STREPTOCOCCI: THEIR TOXINS AND ANTITOXINS. 169

results are too few to justify any definite conclusion,but evidence giving some support to the " unitarian"hypothesis is beginning to accumulate.

(5) We may find a dose of the culture of-e.g.,scarlet fever streptococcus that will kill laboratoryanimals--e.g., rabbits, and see if the otherantitoxins give any protection. The table whichmy colleagues Parish and Okell have kindly allowedme to use shows that these other antitoxins haveconsiderable protective effect against the scarletfever streptococcus and other heterologous haemo-lytic streptococci.

(6) We may inject intradermally into a scarletfever rash, antitoxins made from cultures of-e.g.,puerperal or cellulitis strains, to see if theSchuitz-Charlton blanching results. We havereports showing that in a few recent observationsdefinite blanching was so produced.

(7) We may inquire whether people who areimmunised with scarlet fever toxin until they givea negative reaction to the Dick test will be immuneagainst tonsillitis or puerperal fevers, &c.

THE "UNITARIAN" VIEW.Where the story will lead us we shall not know

for a year or two. But it is of extraordinaryinterest that at present an amount (though notall-cf. Park, Blake, and co-workers, &c.) of recentimmunological evidence seems to be almost leaningtowards the hypothesis that all pathogenicstreptococci are identical in their pathogenic and" toxic " action. But if the implications of this"unitarian " hypothesis conflict with the very largebody of evidence enshrined in clinical medicine, wemust be very hesitant to adopt the hypothesis.If immunology hints that follicular tonsillitis andpuerperal fever, for example, are caused by thesame organism as scarlet fever, we must inquirewhat clinical evidence there is in support ofthis view. With regard to tonsillitis, variousclinicians, after a lifelong experience of theexanthemata, have inclined to the view thatone may have scarlet-fever-without-rash-i.e.,"septic sore-throat" or follicular tonsillitis; andothers have maintained that there is a closerelationship between puerperal fever and scarletfever. Goodall and Washburn 2 wrote thus:"Nurses suffering from erysipelas have conveyedpuerperal fever to lying-in women; and medicalmen and nurses have contracted erysipelas whenin attendance upon cases of puerperal fever."

So far we may account the clinicians on the sideof the hypothesis. But if these diseases areessentially identical, one disease should give riseto the other. Can epidemiology help us here ?Can we on the one hand find communities inwhich one of these diseases was common and yetnever gave rise to the other diseases ?

In the old military epidemics of "septic sore-throat" in former times, did the introduction ofthis disease into a new batch of troops lead to the

2 Infectious Disease, 1896, p. 330.

outbreak of sore-throat or also of scarlet fever anderysipelas, &c. ? When puerperal fever raged acentury ago, so that midwifery hospitals had to beclosed, did erysipelas and scarlet fever ragesimultaneously in those hospitals ? I have beenunable to discover the evidence dealing with thesepoints which almost certainly exists in medicalliterature. Can we find clear instances in whichan isolated community free of these diseasesbecame infected with, say, scarlet fever throughthe introduction of one case of tonsillitis, puerperalfever, erysipelas, or cellulitis into its midst ?

I lived for some years in a rather isolated smalltown overseas, in which I saw puerperal feverand follicular tonsillitis from time to time, butnever a case of scarlet fever, nor had one beenrecorded in the history of the town so far as Icould find.

It may be that a streptococcal disease of anykind requires the streptococcus plus anotherfactor. It will be remembered that for yearsthe B. suipestifer was thought to be the cause ofswine fever in pigs, for by the injection of thisorganism a disease apparently identical with swinefever can be produced. .Dorsett in his masterlywork showed that only one feature was lacking-i.e.,infectivity. The pigs injected with the culturedeveloped what appeared to be the typical disease,but his great discovery was that these pigs did notinfect others, whereas the natural disease was highlyinfectious. Further investigation showed that afilterable virus was the cause of the naturallyoccurring highly infectious swine fever, and that theother bacillus was so common in pigs that, when thereal swine fever disease occurred, the bacillusinfected the animal's body and produced thecharacteristic intestinal lesions. It is possibleto have a herd of pigs infected with the virus-i.e.,true highly infectious swine fever, and another herdinfected only with the B. suipestifer, showingfever and intestinal lesions. So close is the allianceand so universal is the bacillus that it is to-daysafe in England for administrative purposes todiagnose the presence of swine fever becauseintestinal lesions produced by another infectingagent-the B. sutipestifer-are present.The Dicks have described in human volunteers

the production of true clinical scarlet fever followingthe application of their culture of streptococcus.The crucial experiment is lacking. Would thepatient have infected other people ? In otherwords, had he the natural infectious disease ?It is doubtful if this experiment will ever be done.In its absence we must depend on the collaterallines of evidence above referred to.We may sum up by saying that some of the lines

of investigation at present being pursued pointto the suggestion that all the ordinary diseasescaused by heemolytic streptococci are differentmanifestations of the same disease. It is by nomeans certain that clinical and epidemiologicalevidence will support this hypothesis. For themoment, however, we must keep an open mind,

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170 STREPTOCOCCI: THEIR TOXINS AND ANTITOXIN'S.

and, in the treatment of the diseases caused by thehaemolytic streptococci, be prepared to use whateverserum is on reasonable clinical evidence found tocure the given disease.

PRESENT KNOWLEDGE.It would perhaps be useful at this stage to take

a general view of our knowledge in this field.Where the ground is shifting under our feet fromday to day, it is of some service to consider whichlandmarks are so firmly established as to beprobably permanent, which have been set up orare in process of being erected, and which mayprobably not stand the stress of time.

Streptococci mainly of the hsemolytic variety,and with various fermentation reactions, areconstantly present in various " septic " conditions.It is practically c6rtain that they are the realcause, for we know from experiment on humanvolunteers that with cultures of S. erysipelatischaracteristic erysipelas has been produced. Theproduction of experimental erysipelas with culturesof streptococci obtained from lesions of erysipelas,or from septic ones (presumably S. pyogenes),was for some time a method of " treatment " ofinoperable cancer. (In this connexion an oldexperiment by Koch and Petruschky records thatin a volunteer erysipelas was produced by theinjection of streptococci isolated from erysipelas.After recovery, experimental erysipelas was pro-duced again on the same area. The experimentwas repeated ten times.)The many unfortunate infections of pathologists,

after accidental finger-pricks while doing autopsiesor while handling cultures of streptococci, leavelittle doubt that the streptococci are the real causeof these various manifestations of lymphangitis,cellulitis, and even septicaemia. Similarly, we areentitled to believe that streptococci are the causeof severe puerperal fever with septicaemia.With regard to the viridans group of hsemolytic

streptococci, they are so frequently found incertain pathological conditions, notably subacuteendocarditis with bacterisemia, that it is reasonableto believe that they are the cause thereof.With regard to scarlet fever, the Dicks and Nicolle

believe that they produced typical scarlet feverin human subjects by the inoculation of culturesof the S. scarlatince. They have not shown,what from a coldly scientific point of view would beinteresting and valuable, that the disease soproduced is infectious to others and therefore inevery respect resembles natural scarlet fever.

It is further reasonable to believe that most ofthe symptoms at least of uncomplicated scarletfever are due to the " toxin " of the S. scarlatince,for, by the injection of sterile filtrate made froma culture of the streptococcus, subcultured perhapshundreds of times since its isolation from thehuman subject, one can produce pyrexia, headache,"strawberry tongue," the characteristic throatcondition, albuminuria and rash followed bypeeling-in other words, a pathological condition

indistinguishable from naturally ocurring scarletfever. It is practically certain that this so-called"scarlatinoid syndrome " is non-infectious.

It appears to be established beyond doubt thatthe response to the Dick test is related to immunityagainst scarlet fever, and that scarlet fever antitoxinis effective in the treatment of uncomplicatedscarlet fever; it is probably without effect on thelate septic or pyogenic conditions occurring inscarlet fever. Further, by immunising with Dicktoxin one can make positive reactors negative tothe Dick test, and this negative reaction indicatesa reasonably high immunity against scarlet fever.When we consider the more recent work, we

find a distinct suggestion that the toxins andantitoxins of all the haemolytic streptococci areso closely related as almost to amount to identity.But whether this view will be entitled to a " landmark," time and further experience alone cantell. Current clinical views may be summarisedunder some such headings as the following:-

(a) Experimental evidence.--(1) S. pyogenes wheninjected has caused at least local septic conditions. (2)S. erysipelatis when injected has caused erysipelas.(3) S. scarlatince when rubbed on the tonsils has causedscarlet fever.

(b) Conclusions reasonably based on much clinicalobservation.-Streptococci, usually hsemolytic, are thecause of puerperal fever, mastoiditis, septic pneumonia,&c. S. viridans is the usual cause of subacute infectiousendocarditis.

(c) Current hypotheses.-Truth dependent on experiencein the future. Because streptococci occur in dental septicconditions, they cause constitutional symptoms. Becausestreptococci (enterococci, &c.), occur in the bowel in largenumbers they cause diarrhoea, &c.

Although the title of our prescribed subjectdeals with the toxins and antitoxins of thestreptococci, I may be permitted to refer to theother aspect of streptococcal attack, the so-called" septic " manifestations. A hypothesis which wemight use for the moment for the sake of clearnessis that the S. scarlatince has two modes of attack-the "toxic" and the "septic." In violentepidemics, it is the early acute toxic attack whichkills most patients; in mild epidemics it is thelater " pyogenic " or " septic " manifestations, inwhich the living organisms settle down locally inthe glands, joints, mastoid, &c., that cause thegreatest harm.

It is a curious thing that in the Parish-Okellrabbit method, scarlet fever antitoxin gives completeprotection against the first " toxic " attack of thestreptococcus, which is rapidly fatal to unprotectedrabbits, but that this antitoxin apparently givesbut small or no protection against the developmentof the later septic lesions in joints, &c. Similarly,it is probable that no scarlet fever antiserumnow available has any direct effect on the lateseptic complications of scarlet fever. It is probablethat the solutions of this difficult part of the problemwill be found in the investigation of cellular

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RHEUMATISM. 171

immunity with which the Medical School of St.Mary's. Hospital has been for so long identified,and that future work may lead to a convergenceof the "cellular" and "humoral" aspects ofimmunological research of the activities of thestreptococci.

SUMMARY.The examination of agglutination, toxin and

antitoxin relationships of the various " pathogenic "streptococci suggests that there is a very closerelationship between all the members of thegroup. The further analysis of this close relationshipis the problem before us.

RH EUMATISM.*BY

CHARLES SUNDELL, M.D. LOND.,PHYSICIAN IN CHARGE OF THE CHILDREN S DEPARTMIENT, PRINCE

OF ~WALES'S GENERAL HOSPITAL; SENIOR PHYSICIANto THE SEAMIEN'S HOSPITAL, GREENWVICH.

FOR the purpose of this lecture it is proposed toconfine the conception of rheumatism within definitelimits excluding both osteo-arthritis with itsatrophic and hypertrophic bone changes andrheumatoid arthritis with its rarefaction of bone,muscular atrophy, and its undoubted relation toabsorption from septic foci obvious or occult.When these diseases are excluded there remainsa large group of rheumatic conditions with whichalone it is proposed to deal to-day.Rheumatism is met with in two forms, acute

and chronic. There is evidence that these arevariations of one underlying state differing onlyin the mode and intensity of the response of thetissues to the irritation of a single morbid cause.At first sight it is, perhaps, surprising that the

dramatic signs and symptoms of rheumatic feverin a child should be regarded as identical in originwith the lumbago of his grandparent. But experi-ence has much support to lead to this view.Careful inquiry into past history will again andagain reveal the fact that an adult sufferer fromfibrositis or " neuritis " has been marked as theprey of rheumatism during the years of his earlychildhood by growing pains, tonsillitis, or acutefibrile arthritis. It is not uncommon for theprogress of a definite acute rheumatic fever intoa siow crippling chronic rheumatic process tooccur, or for alternations of acute joint affectionsand attacks of chronic fibrositic and muscularpains to be seen in the same individual. Suchobservations emphasise the latency of the rheu-matic state, the chronicity of the disease, and itssimilarity in this particular to gout.

In connexion with the latency of this diseasemention may be made of its frequent appearance

* A Lecture delivered at the North-East London Post-Graduate College.

in an occult form, sapping energy and destroyingthe sense of well-being. Children are particularlyprone to this manifestation; they may sufferfor weeks or months from fatigue before definitelimb pains or joint swelling make their appearance.Delayed or restless sleep at night may be followedby intense sleepiness in the morning and lack ofenergy during the day. Such symptoms of ill-health in a child should always arouse the suspicionof rheumatism and the call for extra rest begenerously answered. In the adult a very similarstate of affairs is often seen. For weeks or monthsbefore the appearance of undoubted rheumaticsigns there may exist a lowering of mental andphysical vitality that makes work and playburdensome and clouds all joy in life. Underappropriate antirheumatic treatment these un-pleasant symptoms are among the earliest todisappear.Rheumatism may be described as a chronic

state of the body characterised by certain chemicaland physiological stigmata, essentially chronicin its course, liable to periods of great activity,marked by long periods of latency and by slowlyprogressing phases of slight activity, influencingparticularly fibrous and synovial and muscletissues, and producing a definite lowering ofvitality both physical and nervous.

CAUSES OF RHEUMATISMI.Infection with germs from mucous surface:, is

for many a satisfactory explanation of the originof this disease. The supporters of this view must,however, explain why: (1) case-to-case infectionis unknown; (2) why members of certain familiesare peculiarly prone to the disease in successivegenerations; (3) why the great antirheumaticspecific, salicylate, so powerful in rheumatism isso powerless in other infections with the same orclosely allied organisms.

Careful considerations of problems such asthese force one to the conclusion that theupholders of the infection theory see only partof the truth. If germs play a part in rheumatism,as they undoubtedly do in rheumatoid arthritis,may it not be that their role is a subsidiary oneand that the real fundamental cause of the diseaseis to be sought in some aberration of body chemistryand physiology that renders the tissues vulnerableto germ attack ?

Three features of the rheumatic state are of greatinterest and importance: (1) During periods oflatency, quiescence, or merely fibrositic pain theskin is abnormally dry. (2) During such periodsthe temperature is always abnormally low.(3) During spontaneous active rheumatism andunder the influence of artificially induced feversweating is profuse and strongly acid in reaction.These points merit a little elaboration. The dryskin of the rheumatic is sometimes obvious;sometimes questioning is necessary to elicit thefact that sweating is always very slight or that

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