Medical Science Publication No. 4, Volume II
THE CONTROL OF PLAGUE*
JOSEPH E. SMADEL,M. D.
KENNETH GOODNER, PH.D.
THEODORE E. WOODWARD, M. D.
Introduction
There are no confirmed reports of plague ever having occurred in Korea.Nevertheless, the proximity of Korea to Manchuria and North China, whereplague has been a serious problem at various times, required that thisdisease be given careful consideration during the Korean War. It may bestated categorically that plague did not occur in the U. N. troops duringthe period of military activity which followed the outbreak of hostilitiesin June 1950. Furthermore, at no time was the threat of plague consideredsufficiently important to warrant the introduction of specific controlmeasures. Indeed, throughout the war American troops in Korea were noteven vaccinated against plague. Under the circumstances one might supposethat this disease required no discussion in a symposium devoted to medicalmilitary problems of the Korean conflict. Despite the absence of plagueit was deemed worth-while to review the subject at this meeting in orderto record the considerable amount of information which was brought togetherfor use by the Armed Forces should a need for it arise.
We shall not attempt in this report to present a general review of theliterature on the subject of plague, for that has been admirably accomplishedin the recent and authoritative publications of Pollitzer (1) andHirst (2). It is our purpose to discuss at some length certain aspectsof problems encountered in the control and treatment of pneumonic plague.
The major portion of our own knowledge of this subject has evolved from(a) information gathered when we served as a special committee (3)of the Commission on Immunization of the Armed Forces Epidemiological Boardwhich observed the control methods employed in two areas where plague isendemic, i. e., Madagascar and the Union of South Africa, (b) thefindings of two field research units sent from the Army Medical ServiceGraduate School to study pneumonic plague
*Presented 28 April 1954, to the Course on Recent Advances in Medicine and Surgery, Army Medical Service Graduate School, Walter Reed Army Medical Center, Washington,
D. C.
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in Madagascar, and (c) certain of the work of investigators sponsoredby the Commission on Immunization. Somewhat elaborate reference will bemade to the problems of plague in Madagascar because of our familiaritywith the situation there and the fact that the control measures employedby the French in Madagascar provide a practical working model which couldbe employed with little modification by an American military group operatingin an area where plague is endemic. Even the problems encountered by theFrench in establishing control measures would be very similar to thosethat would confront a task force operating outside the U. S. A. Of these,the resentment and suspicion incurred by the language barrier and the incompatibilityof modern preventive medicine measures with the sociological and religiouspatterns of the indigenous population are particularly noteworthy. Therelatively poor housing conditions and sanitation of Madagascar are alsofactors which would probably be encountered elsewhere.
General
Plague is a bacterial disease of rodents transmitted to man by the biteof fleas. When infection proceeds in a somewhat leisurely fashion withappreciable involvement of the lymph nodes which drain the site of theinoculation, the disease is designated bubonic plague. On the other hand,when the infection progresses rapidly with early and overwhelming bacteremia,the disease is designated septicemic plague. The mortality in the untreatedbubonic type is about 50 percent and in the septicemic about 90 percent.Efficient control measures directed against the flea vector and the rodenthost have immediate effects on an outbreak of bubonic and septicemic plague.In contrast to these two types of plague, which are initiated in each patientby the bite of an infected flea, pneumonic plague spreads directly fromman to man via the respiratory tract, killing almost every person who developsthe disease. Each outbreak of pneumonic plague stems from a bubonic orsepticemic patient who develops secondary plague pneumonia during the courseof his disease. Control measures which are effective against the vectorand rodent reservoir only indirectly influence the occurrence of pneumonicplague and are entirely inadequate to stop an epidemic of the pneumonicdisease. In addition, the therapeutic measures for flea-borne plague aremore efficient than for the type transmitted directly from man to man.
The natural history of plague in Madagascar is similar in many respectsto the disease found in South Africa (4), in the western UnitedStates (5) and in Java (6). In each instance, classical plaguewas brought into seaports; here outbreaks quickly subsided, reappearingonly when infection was again introduced from elsewhere. From
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the coastal regions it spread inland, becoming established there inenzootic and endemic foci. After the introduction of plague to Madagascarin 1898 by a rice-carrying ship from India, there developed along the semi-tropicalseacoast a series of epidemics of the bubonic disease with only occasionalpatients suffering from septicemic or pneumonic complications. In 1921,the malady appeared for the first time in the cooler high plateau centralregion. During the next 15 years the disease spread widely over the entireplateau and became characterized by the frequency of the pneumonic form.Certain factors were thought to be associated with an increased incidenceof the pneumonic-type disease; i. e., wet summer months, environmentaltemperatures below 15° C., and seasons of prevalent bacterial or viralrespiratory infections. Nevertheless, each circumscribed episode seemedto have its origin in an individual suffering from the bubonic or septicemicform with pneumonic complications (7, 8).
It is not possible to predict which cases of bubonic or septicemic plaguewill develop pulmonary involvement. Therefore, in those few parts of theworld where plague is endemic and the primary pneumonic form is suspectedor known to exist, the constant threat of an epidemic of pneumonic plaguewith its associated rapidity of transmission and high mortality, necessitatesthat all cases of plague, even those presenting initially as the bubonicor septicemic types, be handled as potential pneumonic plague.
Plague control measures instituted by the French on the High Plateauof Madagascar are of several types, viz, (a) case finding and isolationof contacts, (b) immunization of man against the disease, (c)elimination of the rodent reservoirs of disease, and (d) eliminationof arthropod vectors.
Case Finding and Isolation of Contacts
The application of the traditional cordon sanitaire to the largeendemic plague region of Madagascar was not feasible in this geographicsituation. Since pneumonic plague constituted the major part of the problem,a system was developed to isolate cases and contacts in order to limitthe respiratory transmission of the disease from man to man. This in itselfwas an heroic task, for it was necessary to train personnel, to take intoaccount difficulties in transportation, the attitude of the population,and the lack of facilities for detention of contacts.
Case finding became of primary importance. A compulsory system of investigationwas imposed by law. As presently employed, a person who dies in endemicplague regions of Madagascar cannot be buried until after a representativeof the Health Service has viewed the body, taken material for examinationfor Pasteurella pestis, and has released
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the corpse to the relatives, after the results of the examination arenegative. With a needle and syringe, the hospital assistant punctures eachlobe of the lungs, the liver, spleen and any enlarged lymph nodes of thecadaver, and smears the aspirated fluids on glass slides. This diagnosticmethod, known as "dépistage," was developed by Bouffardand Girard in 1921 (9). In addition, in suspected cases of plaguea small amount of sterile physiological saline (1.0 ml.) is injected intothe bubo or the visceral organ and immediately aspirated; this fluid isplaced in a sterile bottle and submitted for bacteriological examination.The slides are taken to a field hospital, stained and examined microscopicallyby a local physician who determines the presence or absence of bacteriawith the morphologic characteristics of P. pestis. The stained slidesand the material in saline are forwarded to the Institut Pasteur at Tananarivefor confirmatory microscopic examination and for inoculation into guineapigs, respectively.
If plague is suspected, all contacts of the patient are collected andretained for 10 days in group isolation at the nearest field hospital orlazaret. At these small isolation units their temperatures are taken every4 hours. If fever develops, the subject is placed under strict isolation.At the present time therapeutic measures are instituted at the onset offever without waiting for a confirmatory laboratory diagnosis.
Although the system was simple in principle many obstacles were encounteredin making it function effectively in Madagascar. The Malagaches interredtheir dead in family mausoleums with great ceremony and at intervals reopenedthe tomb, rewrapped the body and even paraded the bedecked cadaver alongthe original route of the funeral procession before returning it to restfor another period. The health authorities supervised the burial of thosewho succumbed to plague according to usual sanitary practices. Since theMalagaches preferred their own customs, they tended to conceal those sick,or dead, of a disease suspected of being plague.
The method of diagnosis also presented difficulties. Under ideal conditions,organisms with the morphologic characteristics of P. pestis canbe recognized in stained smears of materials from plague cases and P.pestis can be recovered from the specimens taken for this purpose.However, since means of rapid transportation were not available in manyof the endemic areas the diagnostic procedures were sometimes unsuccessfuland usually somewhat delayed. It may be noted that a precipitin test describedby Larson, et al. (10), was recently found applicable forthe detection of plague antigen in "dépistage" material(11). What part this procedure will play as an adjunct to controlmeasures awaits further application.
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The successful functioning of the program depended upon: (a)proper selection of Health Service personnel who possessed the abilityto gain the confidence and cooperation of the local population; (b)adequate personnel, equipment and transportation; and finally, (c)perseverance on the part of the Chief of Medical Service of the area.
The program of diligent case finding and isolation of all contacts ofthe pneumonic plague patient by confinement in small local units for closeobservation and prompt treatment if disease develops is one which has provedsuccessful in Madagascar in limiting the spread of a given outbreak. Asimilar program should be instituted immediately by our Military shouldit encounter disease of the pneumonic type in an endemic plague area.
Immunization
Despite the benefits derived from case finding and the isolation ofcontacts, the problem of plague continued to be a serious one in Madagascarand the French authorities next investigated the efficacy of vaccinationas an adjunct to the control program.
The history of plague vaccine goes back almost to the beginning of thescience of bacteriology. During the years many kinds of vaccines have beenprepared and some have been used extensively in one or another part ofthe world. The textbook of Pollitzer (1) may be consulted for detailedinformation. In Madagascar a living attenuated vaccine was developed inthe early 1930's and has been extensively employed there since the middle1930's.
It will be seen from figure 1 that the annual number of cases of plaguein Madagascar was about 3,500 in 1933 and in 1934, but diminished to about500 in 1937 (12). It was during this period that the vaccine firstcame into wide use in the population of the endemic area. It is of interestthat the precipitous drop in number of cases came after the program hadbeen in effect for several years.
Meyer (13) has pointed out that immunization with killed plaguevaccines results in appreciable resistance to infection only after repeatedinjections have been administered. It cannot be stated whether the sharpreduction in plague about 1937, shown in figure 1, was dependent upon somefactor such as this or whether it was not until about 1937 that a sufficientnumber of people in the area had been vaccinated to establish an immunologicalbarrier.
Vaccination against plague should be employed by the American Militaryfor its troops and its associated civilian populations during any operationcarried out in an area where pneumonic plague is known to have occurred.Remembering the importance of repeated vaccination, one must assume thatan immunization program begun during an epidemic of pneumonic plague wouldbe unlikely to have any
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beneficial effect within a matter of weeks or months. If troops areconditioned by a basic course of immunization given some months beforethe individual reaches the endemic area, then booster doses of vaccineadministered at the onset of an epidemic should induce appreciable resistance.
Vector and Rodent Control
One of the classical methods of the past for controlling outbreaks ofbubonic plague was to reduce the rat population and concurrently the fleapopulation. During World War II, the American Army in Africa emphasizedcontrol of the rodent flea by means of the newly available long-lastinginsecticides (14). This practice has come into widespread use invarious parts of the world.* While measures for reducing rat populationsare certainly to be considered as adjunct control procedures in outbreaksof pneumonic plague, it is to be realized that even elimination of rodentswould not influence the course of an epidemic which was spreading directlyfrom man to man.
When sylvatic plague exists enzootically among the indigenous rodentsof the area and the climatic conditions are suitable for the direct transmissionof pneumonic plague from man to man, this situa-
*It should he noted that any extensive campaign directed against the rodent should be preceded by a program of vector eradication. The death of infested rats forces the fleas to seek other suitable hosts, including man, and a transient rise in the number of plague cases may occur.
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tion is analogous to the proverbial match and powder keg. At any timean individual with plague from the bite of an infected flea may developsecondary pneumonia and start an epidemic. Therefore, measures which reducethe possibility of human infection from fleas in such areas may be expectedto diminish the number of flash outbreaks which must be controlled.
To return to our example, Madagascar, rat control in that area, bothas regards Rattus norvegicus in the urban areas and R. rattusin the countryside, has been relatively unsuccessful, just as it hasin most other areas. In contrast, the reduction of vector fleas on urbanrats has been so great as a result of repeated widespread application ofDDT in malaria and plague control programs that rats now trapped in thecity of Tananarive are frequently without fleas.
In addition to the general use of DDT the systematic application ofDDT in the control of plague is carried out in the following manner inTenanarive Province (3). When the hospital attendant of the areainspects a corpse, he applies DDT powder with a small hand apparatus tothe room occupied by the family of the deceased. If immediate laboratorystudies indicate plague, a team of four men with hand-operated DDT dustersvisits the home of the deceased and liberally dusts the house, outbuildingsand all observed rat runs within the general area. Furthermore, at thistime the dusting team treats any neighboring habitations. Over and abovethis application to the homes of plague victims and their immediate neighbors,the dusting team systematically circulates through the endemic areas duringthe off season and applies DDT to the homes and outbuildings of the inhabitants.
This extensive use of DDT was associated with a low incidence of plagueon the High Plateau for several years, 1948-51, even though vaccinationwas not practiced to any appreciable extent during this period. However,following a moderately severe season in 1951-52 with 291 cases the Frenchauthorities decided to strengthen the general control program by reinstating,prior to the 1952-53 season, widespread vaccination of the population ofthe endemic area (12). The number of cases during 1952-53 was 157and during 1953-54 was 97.
Therapy of Plague
Significant advances in therapy of plague began in 1938 with the clinicaluse of the sulfonamides and continued with the advent of the antibiotics(1, 15-17). In India the sulfonamides reduced the mortality of bubonicand septicemic plague which was about 50 and 90 percent respectively, toabout 5 and 20 percent respectively (18). Moreover, streptomycinelicited a more prompt response and lowered the mortality of septicemicplague even further, i. e., to about 10
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percent. To attain these results the Indian investigators (18)administered to adults 0.66 gram of streptomycin or 1.0 gram of sulfadiazineat 4-hour intervals until the patients remained afebrile for several days.
It should be emphasized that penicillin is useless in plague-see referencescited in reference 1.
Successful treatment of pneumonic plague was accomplished first withstreptomycin (19) and subsequently with several of the broad-spectrumantibiotics (16, 17). Therapeutic studies carried on in Madagascarby the French, and later by French and American investigators, have providedmost of our current information on treatment of pneumonic plague. However,in this instance, as in most others, the clinical use of the therapeuticregimens was preceded by extensive laboratory studies the results of whichprovided the incentive for the trials in man (20).
The results obtained with streptomycin, chloramphenicol and terramycinin pneumonic plague are as dramatic as those in patients with pneumococcalpneumonia who received penicillin, provided that therapy is initiatedwithin the first 24 hours after onset of disease. When therapy is delayedbeyond this period the disease terminates fatally, even though prompt bacterialcontrol may be attained and P. pestis cannot be cultured from theautopsy tissues. It is assumed that the potent toxins of the plague organismscontribute materially to the fatal outcome in such instances.
In practice, the reduction in mortality of pneumonic plague from almost100 percent to almost zero as a result of antibiotic therapy is limitedto contacts of plague patients who develop the pneumonic disease whileunder observation in a medical installation. In Madagascar, at least, noneof the patients survive who develop pneumonic plague outside of a lazaretfor contacts. Since one would anticipate a similar experience in any othergeographic area where pneumonic plague may exist, one cannot overemphasizethe need for prompt institutionalization of all contacts of this form ofthe malady and immediate treatment of exposed persons who develop a febrileillness.
The recommended treatment for plague is as follows: Initial intramuscularinjection of 1 gram of streptomycin followed by 0.5 gram every 4 hoursuntil the temperature remains normal for 4 or 5 days. Chloramphenicol,aureomycin or terramycin may be used in the usual dosage of 2 to 4 gramsdaily beginning with a loading dose, preferably by a parenteral route.In the pneumonic and the fulminating septicemic forms of the disease therapymust be initiated within hours after onset if the patient is to survive.The use of sulfonamides in the treatment of plague probably has no placein military medicine. However, its use in indigenous populations for whomthe Military
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must assume responsibility is indicated in bubonic and septicemic plaguewhen adequate supplies of the specific antibiotics are unavailable.
Chemoprophylaxis
It is not surprising that chemoprophylaxis with the sulfonamides wasintroduced shortly after members of this group of drugs were proved tobe of value in the therapy of bubonic and septicemic plague and appearedto be useful in the abortive treatment of pneumonic plague when employedwithin a few hours after onset of fever (21). Sulfonamides wereadministered to contacts by a number of groups of investigators workingin widely separated geographic areas (see summary in ref. 1) and with onlyrare exceptions favorable results were reported. Despite this essentialunanimity of opinion, it is practically impossible to evaluate the observationsbecause of the extreme variability in communicability of pneumonic plague.
Notwithstanding the weight of opinion, we believe that chemoprophylaxiswith sulfonamides, or for that matter with the specific antibiotics, hasno place in American military medicine. Now that at least four antibioticsare available for effective treatment of plague, it seems to us more importantto concentrate one's efforts on (a) prompt collection of exposedpersons, (b) proper observations including temperature determinationsat least twice daily, and (c) immediate administration of full antibiotictherapy as soon as the individual under observation develops fever or othersigns of illness. Similarly, we would discourage chemoprophylaxis for medicalpersonnel employed in the care of patients with pneumonic plague. Insteadwe would emphasize (a) thorough immunization, (b) carefulindoctrination in isolation technics and in recognition of the early signsand symptoms of the disease, and (c) prompt institution of antibiotictreatment at the very onset of any febrile illness. Such a regimen wouldundoubtedly result in the unduly vigorous treatment of some minor illnesses,but even this would probably be less wasteful of medicines and less hazardousto the individual than a prolonged course of chemoprophylaxis. Furthermore,if plague were suppressed by such a regimen it would be difficult, andsometimes impossible, to establish a retrospective diagnosis on the basisof laboratory studies; however, it is better to ponder a diagnosis in ahealthy person than to confirm one at autopsy.
Conclusion
As regards flea-borne plague one can add little to the recent statementof Pollitzer (1), ". . . . it is only within the last decadethat treatment with sulfonamides and antibiotics, on the one hand, andthe application of potent insecticides-particularly DDT-on the other,
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have rendered plague both a normally curable and a thoroughly controllabledisease." Pneumonic plague which spreads directly from man to manpresents additional problems as regards control and treatment.
The French, working in Madagascar where pneumonic plague occurs eachyear, have developed a control program which could be used, with only minormodifications, by an American military group operating in an area wherepneumonic plague occurs. The essentials of the Madagascar program are (a)case finding and isolation of contacts, (b) immediate treatmentwith specific antibiotics of those contacts who develop signs and symptomsof plague infection, (c) annual immunization of the population atrisk, and (d) extensive arthropod control.
References
1. Pollitzer, R.: Plague, pp. 7-619. World Health Organization,Geneva, 1954.
2. Hirst, L. F.: The Conquest of Plague. A study of theevolution of epidemiology, pp. 1-455, Clarendon Press, Oxford, 1953.
3. Smadel, J. E., Woodward, T. E., and Goodner, K.: Controlof Plague in Madagascar. Annual Report, Commission on Immunization, ArmedForces Epidemiological Board, Appendix 2, pp. 1-33, 1951.
4. Davis, D. H. S.: Sylvatic Plague in South Africa; Historyof Plague in Man 1919-1943. Ann. Trop. Med. 42 : 207-217, 1948.
5. Meyer, K. F.: Known and Unknown in Plague (CharlesFranklin Craig lecture). Am. J. Trop. Med. 22 : 9-36, 1942.
6. Otten, L.: Plague, pp. 617-628. Far East, Ass. Trop.Med., 1922, trans., Weltevredan, Batavia, 1921.
7. Robic, J.: Les characteristiques de la peste áMadagascar. Ann. d. Med. et d. Phamarmacie coloniales 35 : 305-358,1937.
8. Girard, G.: L'Institut Pasteur de Madagascar et lalutte contre la peste. La Revue Synthese 7 : 1-11, 1939.
9. Bouffard, G., and Girard, G.: Le dépistage dela peste par la punction due foie. Son importance prophlyactique. Bull.Soc. Path. Exotique 16 : 501-524, 1923.
10. Larson, C. L., Philip, C. B., Wicht, W. C., and Hughes,L. E.: Precipitin Reactions with soluble Antigens from Suspensions of Pasteurellapestis or from Tissues of Animals Dead of Plague. J. Immunol. 67: 289-298, 1951.
11. Hoyer, B., and Courdurier, J. 1953. To be published.
12. This information and other not specifically creditedis summarized from various reports published in Arch. d. L'Institut Pasteurde Tananarive from 1933 to 1953.
13. (a) Meyer, K. F., Foster, L. E., Baker, E.E., Sommer, H., and Larson, A.: Experimental Appraisal of Antiplague Vaccinationwith Dead Virulent and Living Avirulent Plague Bacilli. Proceedings ofthe Fourth International Cong. on Trop. Med. and Malaria 1 : 264-275,1948.
(b) Meyer, K. F.: Recent Studies on the ImmunityResponse to Administration of Different Plague Vaccines. Bull. Wld. Hlth.Org. 9 : 619-636, 1953.
14. Lewis, P. M., Buehler, M. H., and Young, T. R.: Plaguein Dakar. Bull. U. S. Army Med. Dept. No. 87 : 13-16, 1945.
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15. Meyer, K. F.: Modern Therapy of Plague. J. A. M. A.144 : 982-985, 1950.
16. Smadel, J. E., Woodward, T. E., Amies, C. R., andGoodner, K.: Antibiotics in the Treatment of Bubonic and Pneumonic Plaguein Man. Ann. N. Y. Acad. Sci. 55 : 1275-1284, 1952.
17. McCrumb, F. R., Jr., Mercier, S., Robic, J., Bouillot,M., Smadel, J. E., Woodward, T. E., and Goodner, K.: Chloramphenicol andTerramycin in the Treatment of Pneumonic Plague. Am. J. Med. 14 :284-293, 1953.
18. Sokhey, S. S., and Wagle, P. M.: Sulfonamides andAntibiotics in the Treatment of Plague. Proceedings of the Fourth InternationalCong. on Trop. Med. and Malaria. U. S. Gov't Print. Office 1 : 276-282,1948.
19. (a) Estrade, F.: Un cas de peste pulmonaireprimitive traité et guéri par la streptomycine. Bull. Soc.Path. Exotique 41 : 438, 1948.
(b) Girard, G.: La streptomycine, médicationhéroique de la peste. Rev. Med. Franc. 29 : 102-104, 1948.
20. (a) Meyer, K. F., Quan, S. F., McCrumb, F.R., Jr., and Larson, A.: Effective Treatment of Plague. Ann. N. Y. Acad.Sci. 55 : 1228-1274, 1952.
(b) McCrumb, F. R., Jr., Larson, A., and Meyer,K. F.: The Chemotherapy of Experimental Plague in the Primate Host. J.Infect. Dis. 92 : 273-287, 1953.
21. Girard, G.: Le traitement de l'infection pesteusepar les corps sulfonamides. Peste expérimentale et peste humaine.Bull. Soc. Path. Exotique 34 : 37-48, 1941.
