natural history of syphilis and levels ofnatural history of syphilis and levels of prevention*t by...

NATURAL HISTORY OF SYPHILIS AND LEVELSOF PREVENTION*t

BY

E. GURNEY CLARKFrom the Divisioni of Epidemiology, Faculty of Medicine, Columbia Uniiversity, New York

From the viewpoint of prevention, syphilis, likeother disease processes, has its origin before manhimself is affected. Therefore, application of pre-ventive measures need not await man's actualexposure to the causative agent. There are possibili-ties of intercepting the various related " causes "which lead to exposure, as well as of interruptingthe process after it begins in man. The completeprocess, at least for preventive purposes, may betermed the " natural history of the disease ", whichbegins with the very first forces that initiate it in theenvironment or elsewhere, and continues through theresulting changes that take place-until equilibriumis reached, or defect, disability, or death ensues.There is a " period of pre-pathogenesis " beforeman's contact with the disease agent, and one of" pathogenesis " after man harbours the Treponemapallidum. Preventive measures may be appliedthroughout these two periods. The disease may beattacked from at least five preventive points duringthese two periods:

(a) health promotion;(b) specific protection;(c) early recognition and prompt treatment;(d) disability limitation(e) rehabilitation.

These represent means of interception common toa majority of disease processes and may be utilizedon a community or on an individual basis. They arenot static or isolated phases in the natural history ofthe disease process but form more or less a con-tinuum (Leavell and Clark, 1953).The relationships of these levels to the natural

history of any disease are shown diagrammaticallyin Fig. 1 (overleaf). The natural history as defined

* Recdived for publication May 26, 1954.t Paper given before the Medical Society for the Study of Venereal

Diseases, London, June 8, 1953. Based on a concept introduced in" Textbook of Preventive Medicine " (1953) by H. R. Leavell andE. Gurney Clark.

above is shown in the upper part of the diagramand the lower part shows the levels ofprevention in relation to the various phases of thenatural history. Throughout the natural history,agent, host, and environmental factors may beoperating, and their interaction during pre-patho-genesis brings the specific agent into contact with manto initiate the process in man. After this comes thephase of increase in the agent, whether it be throughmultiplication, as in infectious disease, or throughincrements of agent, as in non-infectious disease(e.g. lead). This is followed by tissue changes,signs and symptoms, and finally by recovery, defect,disability, or death. Prevention must take intoaccount all possible causative factors, from the firstenvironmental forces which bring the host and agenttogether to those which later maintain this relation-ship. The multiple causes of disease are active longbefore the disease involves the subject. Precipitatingand predisposing forces may be continuouslyoperative in the occupational or living environmentof man. Heredity, social and economic factors, orphysical environment may be preparing the waylong before pathogenesis is initiated. Malariaillustrates how the knowledge of pathogenesis aloneis not sufficient for disease prevention. This diseaseprocess produces rather characteristic humoral andcellular changes and more or less typical signs andsymptoms, yet complete knowledge of its course inman gives no clue to its prevention. The malarialparasite, the primary specific cause, can be dis-covered in the blood of those affected. Specifictherapy in the individual may prevent subsequentattack but basic prevention is related to the moreimportant environmental causes of malaria outsidethe individual. Prevention depends upon knowledgeof climatic conditions, biologic and geographicenvironment, the habits and characteristics of theanopheline mosquito, the habits and customs of the

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BRITISH JOURNAL OF VENEREAL DISEASES

PREVENTION IS ACCOMPLISHED BY INTERCEPTING THE " CAUSES " CONTRIBUTING TO THE DISEASE PROCESS

NATURAL HISTORY OF ANY DISEASE OF MAN

DAgent Agent becomes Recovery

Host established and Tissue Signs EEnvironment increases by Chans and Disability

interacting to bring multiplication ges Symptoms Ahost and agent together or increments Defect

Pre-pathogenetic Period Period of Pathogenesis

Agent-Host Interaction influenced by Environment

HEALTHPROMOTION I

SPECIFICPROTECTION REHABILITATION

EARLY DIAGNOSISNutrition AND PROMPTHealth education TREATMENT DISABILITYHousing By immunization LIMITATION To prevent totalRecreation By sanitation against To prevent spread disability and toPersonality allergens in industry To prevent sequelae To limit disability return the patient

development By specific nutrients To shorten disability To prevent death to usefulness

LEVELS OF APPLICATION OF PREVENTIVE MEASURES

FIG. I.-Natural history of disease and levels of prevention.

human host, and the application of specific protectivedevices and prophylactic measures.The complete definition of causation of any

disorder in man must encompass a consideration ofall the agent, host, and environmental factors whichinteract to provoke or perpetuate the process. Thephilosophy of prevention can be put into a singlephrase: " To oppose or intercept a cause is toprevent or dissipate its effects" (Perkins, 1938).Prevention at any level of application in the pro-gressive natural history of any disease depends uponthe knowledge of these multiple causes relating toagent, host, or environment, and the ease with whichthese causes may be intercepted or counteracted.Prevention requires the construction and inter-position of barriers to the interaction of theseelements. The degree of success depends upon thecompleteness of knowledge and the opportunity toapply it. It is not necessary to know everything abouta disease to initiate preventive measures, though oftencomplete success cannot be achieved because currentinformation is too meagre. Nevertheless, the in-

terception of any of the causes of disease at anystage of development may affect the morbidprocess. This concept permits the inclusion ofspecific treatment in the scheme of prevention.

Application of Preventive Measures

The five levels at which preventive practices may beapplied are as follows:

(1) Health Promotion.-This is applied in the period ofpre-pathogenesis before man is involved; its aim is toachieve the best state of physical, mental, and social well-being. This includes a good standard of nutritionadjusted to the various developmental phases of life,provision for adequate housing and recreation, andagreeable conditions in the home and at work. Sexeducation and counselling before and during marriagemay have a direct effect upon the exposure to venerealdisease.

(2) Specific Protection.-This comprises measuresapplicable to a particular disease or group of diseases tointercept the causes before they involve man. Included

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NATURAL HISTORY AND PREVENTION OF SYPHILIS

PREN'ENTION IS ACCOMPLISHED BY INTERCEPTING THE " CAUSES " CONTRIBUTING TO THE DISEASE PROCESS

> > > ~ ~ ~ ~~~~~~~~>> >NATURAL HISTORY OF ACQUIRED SYPHILIS

Agent CardiovascularPrerequisite | Secondary Syphilis

moisture Syphilis NeurosyphilisHostEleme/ts Infectious

Host Elenmetits X 0 < / \Relapse BenignSexual habits Latc SyphilisEducation on sex ,, o Primary STS+prophylaxisSyhl

Personality Clinical o> SYPhilisdevelopment

EnvironmnentClimate, moisture o /-Family instability 'X ->-Spontaneous CureIncome, housing - - Early - LATENCY - LateRecreational ~ ~ ~ r x/

facilities weeks to months 4 years 5-10 years 10-20 years 15-20 yearsCommunity control 1r__Ea rlEarly Syphilis Late Syphilis

Pre-pathogenetic Period Period of Pathogenesis

Agent-Host Interaction influenced by Environment

HEALTH PROMOTION di

SPECIFIC REHABILITATIONPROTECTION

EARLY DIAGNOSISAND PROMPT TREATMENT

DISABILITY LIMITATION

Avoidance of disease- Prophylaxis - chemical, Adequate treatment to des- Fever and otherproducing micro- mechanical, and chemo- troy all T. pallida treatment to destroyorganisms by health therapeutic T. pallida in brain ofeducation in hygiene paretics

Sex education, pre- Prenatal serologic exami- Case finding for early Case finding for Preparation for blind-paration for mar- nations syphilis latent syphilis and ness in primary opticriage Avoidance of sexual Advice regarding infectious- for early signs of late atrophy

Premarital and pre- promiscuity ness, immediate and ade- syphilis Rehabilitation of blind,natal examinations quate treatment Adequate examina- tabetics, paretics,as part of general Contact investigation tion of heart and and those withcheck-up Examination of infants of C.N.S. advanced cardio-

syphilitic mothers at birth Routine examination vascular diseaseand regularly for 3 months ofcerebrospinal fluid

Routine examination of Adequate treatmentcerebrospinal fluid

General improvement Eradication of com- Educational media showing Educational media Improvement of work-of socio-economic mercialized prostitu- early symptoms and ur- showing effects of ing conditions ofconditions, and re- tion gency for early diagnosis non-treatment the disabled:creational facilities Precaution in handling Adequate diagnostic, treat- Provision for low-cost cardiac,

discharges of syphilitic ment, and contact investi- treatment facilities paralysed,infants gation facilities for complicated blind

syphilis

LEVELS OF APPLICATION OF PREVENTIVE MEASURES

FIG. 2.-Application of preventive measures in the natural history of syphilis.

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AGENT

H0ST

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R0NMENT



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BRITISH JOURNAL OF VENEREAL DISEASES

here are immunizations against infectious disease,pasteurization of milk, purification of water, wastedisposal, prevention of air contamination, protectionagainst industrial dermatitis, and control of insectvectors. The avoidance of accidents and allergicconditions would also be included under this category.

(3) Early Recognition and Prompt Treatment.-Thisaims at checking the spread of infections and effectingcure or arrest of disease processes, and hence at preventingcomplications and shortening the period of disability.The basis of the ideal disease control programmeis " case finding " in the early stages of disease, whentreatment is most effective. This has been the backbone ofmodern syphilis and tuberculosis control programmes,and now has become the watchword in the control ofchronic diseases.

(4) Disability Limitation.-Only the time factor and ourscanty knowledge of disease processes separate this phasefrom the previous one. This stage of disease developmentinvolves treatment of a more or less advanced diseaseprocess, and points to the failure of prevention at someearlier phase. The large number of persons coming formedical attention with advanced detectable diseaseemphasizes the need for medicine to apply existingpreventive knowledge on a wider scale.

(5) Rehabilitation.-This means the prevention ofcomplete disability after anatomical and physiologicalchanges are no longer reversible and its positive objectiveis to return the affected individual to a useful place insociety.

The present concept places health promotion anddisease prevention into a framework based upon thenatural history of disease. It is the first step indirecting those interested in health to a common

focus for their own specific contribution to man'shealth and welfare. Its foundations lie in the evalua-tion of health on a graded scale and in the conceptthat the decline from health to disease is a processinvolving the interaction of disease agents, man

himself, and man's environment.

Syphilis

Syphilis provides an excellent illustration. Know-ledge of the characteristics of the specific treponemalagent of syphilis and of the reactions to it of thehuman host has taught us much about this diseasepattern that has aided its prevention and control.Yet, for its ultimate eradication or its reduction tominimal importance, certain environmental factorsmust be taken into account. Some causes of syphilisinfection are in operation well before agent-hostrelationships (pathogenesis) begin. The groundworkof congenital syphilis may be laid before marriagethrough the infection of the potential mother or

father. It may be affected by absence of pre-maritalexamination, inadequacy of examination and treat-ment, the attitude of the parents to pregnancy andpre-natal care, extramarital relationships, and lack ofprophylaxis. Finally, the course of congenitalsyphilis may be related to the cost and availability ofmedical care at the time of delivery and in thesucceeding few months.The factors involved in acquiring and transmitting

syphilis are complex. They have their origin invariations of human behaviour, sexual promiscuity,marital maladjustments, and in some of the inade-quacies of our social and economic life; they arerooted in prudery, ignorance, and defeatism on thepart of the public. Such attitudes present obstaclesto the application of the usual methods of controlutilized against other types of infectious disease.

Fig. 2 shows in detail the natural history ofacquired syphilis and the levels of application ofpreventive measures by the general scheme of Fig. 1.The specific microorganism reaches the biologicorbit of man through the interaction of host andenvironmental factors during the pre-pathogeneticperiod. Whether or not man becomes infecteddepends on the biologic characteristics of themicroorganism and the habits and defence mech-anisms of man.The period of pathogenesis, after infection has

taken place, may be illustrated by a graph (Morgan,1941; see Fig. 2). The division between thesymptomatic and asymptomatic stages is designatedthe "clinical horizon ". Syphilis as it progressesmay be symptomatic (above the horizon) orasymptomatic (below); early (under 4 years'duration) or late (over 4 years); infectious (primary,secondary, and infectious relapse) or non-infectious(late). There may be " spontaneous cure" or lifelongfreedom from symptoms (clinical latency), or theinfection may terminate in death, defect, ordisability. The opportunities for prevention areshown at the bottom of the diagram.

Agent Factors.-The biologic requirements of T.pallidum explain why syphilis is a disease of intimatecontact. This organism is very fragile, unable to re-sist drying, unfavourably affected by many commonantiseptic agents, and said to be destroyed morequickly by a soap solution than by many strongdisinfectants. It dies under bloodbank conditions ina short time, but will survive rapid freezing to-76° C. for one year. It is found infective for 26hours in syphilis autopsy material. It is immobilizedat 410 C. in 2 hours. Man is a necessary host, experi-mental infections in animals are not persistent, andthe agent has not been cultivated on artificial media.

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These facts have a direct bearing on the behaviourof the organism in nature. In more primitivetreponematosis (yaws, bejel, etc.), the organismfinds widespread favourable conditions for existenceon the moist skin of persons living in tropical areasand is spread by close bodily contact as a non-venereal disease. These propitious conditions areabsent in less humid areas, and are also removed bythe advance of civilization, and the use of clothing.In such circumstances, it is only on the mucousmembranes about the genitalia and in the mouththat conditions are consistently found which permitthe survival of T. pallidum for periods long enoughfor invasion. These biologic characteristics thereforedetermine the reservoir of infection, dictate the meansof transmission, and materially affect the host-parasite interaction.

Host Factors.-In syphilis these are chieflyconcerned with the habits and customs of man andthe host-agent interaction (Fig. 2). Man is the solereservoir of syphilis infection. Infection can betransmitted artificially to certain animals but diesout spontaneously without transmission to othersof the same species. Whether man as the reservoir ofthe disease transmits it to others depends on (a) theoutcome of the complicated host-agent interactionand (b) the habits and customs of the host. In view ofthe fact that the viability of this microorganismdepends upon moisture, the chance of exposure to itis dependent upon intimacy of contact, the sexualbehaviour of the host, and the habits of the host inrespect to prophylaxis.

Host-Agent Interaction.-When the infected moistsecretion of the diseased host comes into relationshipwith a new host one of three things may happen:

(a) the organism may fail to gain access and lodgement;(b) it may gain access, lodge, multiply, and produce

infection without early clinically discemible tissuereaction (symptomless infection);

(c) it may gain access. lodge, multiply, and produce thecharacteristic discernible reactions of early syphilis.

After the treponeme has gained admission to andsettled in the tissues, reproduction occurs at theinoculation site. Dissemination from the portal ofentry by means of the lymph and blood streamsoccurs within several hours, with the result that localprophylaxis delayed longer than this time, even to theextent of excision of the inoculation site, will notprevent disease. It is apparent that syphilis is ageneralized infection almost from the beginning, theorganism being carried from the original site of entryto all tissues of the body by means of the bloodstream as a passive carrier. Thus it is possible for the

organism to be transmitted to another host by bloodtransfusion before there is any clinical or serologicevidence of infection in the infected donor. Thebloodstream spread of the treponeme during thisearly incubation period probably lays the foundationfor all the late manifestations.

After a variable incubation period ranging from 10days to 10 weeks (average 3 weeks), the first manifestlesion of the disease appears. This is portrayed inFig. 2 by the graph line reaching the clinical horizon.This is primary syphilis, and at the time of theappearance of the chancre the serologic test isusually negative. It is important to remember that,although in most instances infection is followed byvisible tissue reaction at the inoculation site, andgeneralized tissue reactions usually follow thedissemination of the organism, either or both ofthese phenomena may fail to occur or may be soslight as to evade notice. Infection may thus progresswithout any demonstrable lesions. The precisemechanism operating to suppress the visible earlyreaction is not well understood; it may depend on asingle factor or a combination of such factors as thesize of the infective dose, the site of inoculation, thepatient's age, the hormonal influence of sex orpregnancy, or the administration of penicillin duringthe incubation period either for prophylaxis or forthe therapy of some other disorder.The mild, superficial, non-destructive primary

lesion enlarges and is usually followed by a painlessswelling of the regional lymph nodes. Soon " re-agin" and perhaps more specific antibodies aredetectable in the blood, and the conventional sero-logic tests as well as treponemal immobilization testsbecome positive. Over the next 4 to 6 weeks orlonger, even without specific treatment, the chancrebegins to involute spontaneously, and the result ofthe earlier blood-stream dissemination and subse-quent reproduction of the treponeme may becomemanifest in generalized lesions on the skin andmucosal surfaces-the secondary outbreak. Duringthis secondary stage there may occur also a mild ormoderate constitutional reaction characterized bymalaise, general lymphadenopathy, or other mani-festations of toxaemia. These and the clinical lesionspersist for a variable length of time ranging from afew days to several months and in their turn dis-appear spontaneously, as is shown in Fig. 2 by theline falling below the clinical horizon. These earlylesions of syphilis are characterized by a mild tissuereaction and the presence of large numbers of T.pallidum. They are superficial, non-destructive,highly infectious lesions and usually heal withoutscarring. With healing, the treponemes usuallydisappear from the skin and mucous surfaces.

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196BRITISH JOURNAL OF VENEREAL DISEASES

Thereafter follows an indeterminable period ofclinical latency (weeks to years) without outward signsof infection, during which the infected individual isrecognized as syphilitic only by means of a positivetest of the blood. The latent period may be inter-rupted during the first few years by recurrences ofinfectious lesions in the skin, mucous membrane,eyes, or central nervous system. After an unpre-dictable number of years, late, non-infectious tissuereactions may also occur in almost any part of thebody. This agent-host interaction represents abiologic struggle between the treponeme and the host.The struggle may produce a more or less symbioticrelationship with no impairment to health, but thisdoes not mean that no effort should be made toimprove the chances of the host since it is notpossible to predict the outcome. The agent-hostrelationship may end in "spontaneous cure ",a condition of life-long latency, the only evidenceof syphilis being positive blood-tests, or, in asmaller proportion of cases, disabling syphilis ofvital organs.There is no natural immunity to syphilis in man.

The host reacts to the presence of the organism bydeveloping a state of acquired immunity or resistancewhich influences the spontaneous healing of earlylesions, protects against new organisms introducedfrom without, withstands to a variable degree theaggressiveness of the organisms present in thetissues, and in most instances maintains clinicallatency throughout life. There is some evidence thatsuch factors as sex, pregnancy, race, and constitutionaffect this host-parasite relationship.The transmission of syphilis depends on certain

conditions:(a) that the organism escapes from the infected

host in sufficient numbers;(b) that it is appropriately transmitted under

conditions which satisfy its biologic re-quirements;

(c) that it gains access by finding appropriateportals of entry in the new host.

Moist surfaces provide the avenues by whichthe organisms escape from the reservoir, andintimate contact by sexual intercourse or kissingfurnishes the condition necessary for conveyance toa corresponding portal of entry in a new host.The newly implanted microorganism becomes estab-lished under conditions of moisture and warmthlasting long enough to enable it to penetrate hostbarriers.

Infectious moist lesions are present only duringprimary, secondary, and recurrent secondary syphilis.Body fluids and secretions (saliva, semen, vaginal

discharges) from syphilitic persons in various stagesof the disease have been studied experimentally andhave been shown to contain the organism duringthe early stages of syphilis when lesions are present,but only rarely, if ever, during the later stages whenthere are no obvious lesions. Blood is a passivecarrier of the organism and appears to be infectivechiefly during the incubation period and whileprimary and secondary lesions are present. At thepresent time the accepted explanation of in uteroinfection is that occasional spirochetaemia occursand results in the circulatory transfer of organismsto the foetus, but this has not been proved experi-mentally. Intimate contact with primary andsecondary lesions provides the most favourableconditions for transmission ; yet, despite thepresence of infectious lesions, unprotected sexualintercourse does not invariably lead to infection.

Transmissibility, therefore, depends on(a) duration of infection;(b) presence of moist lesions;(c) infectiousness of secretions;(d) tissue reservoirs of organisms;(e) intimate contact with the organism in sufficient

numbers;(f) accessible portals of entry in a susceptible

individual.Environmental Factors.-For preventive purposes

these may be defined as the aggregate of all theexternal conditions (physical, social, biologic, andcconomic) and influences affecting the life anddevelopment of an organism.The influence of any one or any group of these

factors cannot be measured with precision, butenvironment plays a major role in the initiationand perpetuation of syphilis. Some of the factorsare analysed by Ennes (1948). The effect of thephysical environment (geography, weather, climate,etc.) has been shown by Hudson (1946) to havealtered the manifestations of the disease to such anextent that lesions due to morphologically indis-tinguishable treponemes are given many differentnames: endemic syphilis, yaws, bejel, pinta, etc.The social environment may be particularly con-

ducive to the spread of infection. Low income,poor housing, and inadequate recreational oppor-tunity all contribute to the perpetuation of syphilis.The success of organized community control dependson the extent and availability of public health andmedical facilities, the adequacy of case finding andcase holding, the " index of suspicion" of medicalagencies, the availability of laboratory services, theextent of contact investigation, and the applicationof premarital and prenatal examination procedures.

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The lower portion of Fig. 2 shows the details ofprevention in syphilis based upon knowledge ofnatural history. Preventive action must be directedagainst the agent, the host, and the environment ateach of the levels of prevention in so far as ourpresent knowledge will permit.The success achieved in the control of syphilis is

the result of the application of such measures asthese, despite gaps in our knowledge about thisdisease.Much has been accomplished in syphilis control

and optimism pervades medical and public healthcircles in respect to its eventual elimination. Yetthere are still many unknowns which stand in theway of complete eradication of this disease. Forexample, T. pallidum has not yet been cultivated onartificial media; we have no immunizing agent; weknow very little about the mechanisms contributingto the natural history of untreated infections, aboutthe duration of infectiousness, the mechanism ofimmunity, the mechanism of infection in utero, theselectivity of the microorganism for certain tissues,or the nature of reagin, upon which serologic testsare based. Furthermore, to those who subscribeto the concept that yaws, bejel, pinta, etc., aredifferent clinical entities of the same disease-theview of " treponematosis " put forward by Hudson(1946)-it is " an illusion to hope for a syphilis-freecivilization, while yaws remains rampant in theworld ".The gaps in our knowledge are ample warnings

that vigilance must not be relaxed. This is themoment not for the demobilization of the vastforces that have been developed to combat syphilis,as some advocate, but rather for the consolidation ofall efforts to prevent the disease in all its aspects.

Summary

(1) Measures for the prevention of syphilis can beapplied before man is affected.

(2) This requires knowledge of the " naturalhistory of syphilis ", which for preventive purposeshas its origin with the very first forces wlhich act tobring agent and man together.

(3) Such a concept provides a " period of pre-pathogenesis " and one of " pathogenesis " duringeach of which multiple causes relating to agent, hostand environment are in operation to initiate andperpetuate the disease process.

(4) There are at least five levels at which preven-tive measures may be applied:

(a) health promotion,(b) specific protection,(c) early diagnosis and treatment,(d) disability limitation,(e) rehabilitation.

(5) The relationships of agent, host, and environ-mental factors to the natural history of syphilis andits prevention are discussed.

REFERENCESEnnes, H. (1948). " The Social Control of Venereal Disease. Report

of a National Inquiry of Professional Opinion." CooperativeStudies Publication No. 2, New Haven, Conn.

Hudson, E. H. (1946). " Treponematosis." In " Oxford Loose-leafMedicine ", ed. H. A. Christian. Oxford University Press, NewYork.

Leavell, H. R., and Clark, E. G. (1953). " Textbook of PreventiveMedicine ", p. 11. McGraw-Hill, New York and London.

Morgan, H. J. (1941). Amer. J. Syph., 25, 233.Perkins, W. H. (1938). " Cause and Prevention of Disease ", p. 5.

Lea and Febiger, Philadelphia.

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