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Chapter 5, Part 4

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, where plague has been a serious problem at various times, required that this disease be given careful consideration during the Korean War. It may be stated categorically that plague did not occur in the U. N. troops during the period of military activity which followed the outbreak of hostilities in June 1950. Furthermore, at no time was the threat of plague considered sufficiently important to warrant the introduction of specific control measures. Indeed, throughout the war American troops in Korea were not even vaccinated against plague. Under the circumstances one might suppose that this disease required no discussion in a symposium devoted to medical military problems of the Korean conflict. Despite the absence of plague it was deemed worth-while to review the subject at this meeting in order to record the considerable amount of information which was brought together for use by the Armed Forces should a need for it arise.

We shall not attempt in this report to present a general review of the literature on the subject of plague, for that has been admirably accomplished in the recent and authoritative publications of Pollitzer (1) and Hirst (2). It is our purpose to discuss at some length certain aspects of 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 Board which observed the control methods employed in two areas where plague is endemic, i. e., Madagascar and the Union of South Africa, (b) the findings of two field research units sent from the Army Medical Service Graduate 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 sponsored by the Commission on Immunization. Somewhat elaborate reference will be made to the problems of plague in Madagascar because of our familiarity with the situation there and the fact that the control measures employed by the French in Madagascar provide a practical working model which could be employed with little modification by an American military group operating in an area where plague is endemic. Even the problems encountered by the French in establishing control measures would be very similar to those that would confront a task force operating outside the U. S. A. Of these, the resentment and suspicion incurred by the language barrier and the incompatibility of modern preventive medicine measures with the sociological and religious patterns of the indigenous population are particularly noteworthy. The relatively poor housing conditions and sanitation of Madagascar are also factors which would probably be encountered elsewhere.

General

Plague is a bacterial disease of rodents transmitted to man by the bite of fleas. When infection proceeds in a somewhat leisurely fashion with appreciable involvement of the lymph nodes which drain the site of the inoculation, 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 untreated bubonic type is about 50 percent and in the septicemic about 90 percent. Efficient control measures directed against the flea vector and the rodent host have immediate effects on an outbreak of bubonic and septicemic plague. In contrast to these two types of plague, which are initiated in each patient by the bite of an infected flea, pneumonic plague spreads directly from man to man via the respiratory tract, killing almost every person who develops the disease. Each outbreak of pneumonic plague stems from a bubonic or septicemic patient who develops secondary plague pneumonia during the course of his disease. Control measures which are effective against the vector and rodent reservoir only indirectly influence the occurrence of pneumonic plague and are entirely inadequate to stop an epidemic of the pneumonic disease. In addition, the therapeutic measures for flea-borne plague are more efficient than for the type transmitted directly from man to man.

The natural history of plague in Madagascar is similar in many respects to the disease found in South Africa (4), in the western United States (5) and in Java (6). In each instance, classical plague was brought into seaports; here outbreaks quickly subsided, reappearing only when infection was again introduced from elsewhere. From


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the coastal regions it spread inland, becoming established there in enzootic and endemic foci. After the introduction of plague to Madagascar in 1898 by a rice-carrying ship from India, there developed along the semi-tropical seacoast a series of epidemics of the bubonic disease with only occasional patients suffering from septicemic or pneumonic complications. In 1921, the malady appeared for the first time in the cooler high plateau central region. During the next 15 years the disease spread widely over the entire plateau and became characterized by the frequency of the pneumonic form. Certain factors were thought to be associated with an increased incidence of the pneumonic-type disease; i. e., wet summer months, environmental temperatures below 15° C., and seasons of prevalent bacterial or viral respiratory infections. Nevertheless, each circumscribed episode seemed to have its origin in an individual suffering from the bubonic or septicemic form with pneumonic complications (7, 8).

It is not possible to predict which cases of bubonic or septicemic plague will develop pulmonary involvement. Therefore, in those few parts of the world where plague is endemic and the primary pneumonic form is suspected or known to exist, the constant threat of an epidemic of pneumonic plague with its associated rapidity of transmission and high mortality, necessitates that all cases of plague, even those presenting initially as the bubonic or septicemic types, be handled as potential pneumonic plague.

Plague control measures instituted by the French on the High Plateau of Madagascar are of several types, viz, (a) case finding and isolation of contacts, (b) immunization of man against the disease, (c) elimination of the rodent reservoirs of disease, and (d) elimination of arthropod vectors.

Case Finding and Isolation of Contacts

The application of the traditional cordon sanitaire to the large endemic plague region of Madagascar was not feasible in this geographic situation. Since pneumonic plague constituted the major part of the problem, a system was developed to isolate cases and contacts in order to limit the respiratory transmission of the disease from man to man. This in itself was an heroic task, for it was necessary to train personnel, to take into account 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 investigation was imposed by law. As presently employed, a person who dies in endemic plague regions of Madagascar cannot be buried until after a representative of the Health Service has viewed the body, taken material for examination for Pasteurella pestis, and has released


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the corpse to the relatives, after the results of the examination are negative. With a needle and syringe, the hospital assistant punctures each lobe of the lungs, the liver, spleen and any enlarged lymph nodes of the cadaver, and smears the aspirated fluids on glass slides. This diagnostic method, known as "dépistage," was developed by Bouffard and Girard in 1921 (9). In addition, in suspected cases of plague a small amount of sterile physiological saline (1.0 ml.) is injected into the bubo or the visceral organ and immediately aspirated; this fluid is placed in a sterile bottle and submitted for bacteriological examination. The slides are taken to a field hospital, stained and examined microscopically by a local physician who determines the presence or absence of bacteria with the morphologic characteristics of P. pestis. The stained slides and the material in saline are forwarded to the Institut Pasteur at Tananarive for confirmatory microscopic examination and for inoculation into guinea pigs, respectively.

If plague is suspected, all contacts of the patient are collected and retained for 10 days in group isolation at the nearest field hospital or lazaret. At these small isolation units their temperatures are taken every 4 hours. If fever develops, the subject is placed under strict isolation. At the present time therapeutic measures are instituted at the onset of fever without waiting for a confirmatory laboratory diagnosis.

Although the system was simple in principle many obstacles were encountered in making it function effectively in Madagascar. The Malagaches interred their dead in family mausoleums with great ceremony and at intervals reopened the tomb, rewrapped the body and even paraded the bedecked cadaver along the original route of the funeral procession before returning it to rest for another period. The health authorities supervised the burial of those who succumbed to plague according to usual sanitary practices. Since the Malagaches 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 can be 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 many of the endemic areas the diagnostic procedures were sometimes unsuccessful and usually somewhat delayed. It may be noted that a precipitin test described by Larson, et al. (10), was recently found applicable for the detection of plague antigen in "dépistage" material (11). What part this procedure will play as an adjunct to control measures 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 ability to 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 of the pneumonic plague patient by confinement in small local units for close observation and prompt treatment if disease develops is one which has proved successful in Madagascar in limiting the spread of a given outbreak. A similar program should be instituted immediately by our Military should it encounter disease of the pneumonic type in an endemic plague area.

Immunization

Despite the benefits derived from case finding and the isolation of contacts, the problem of plague continued to be a serious one in Madagascar and the French authorities next investigated the efficacy of vaccination as an adjunct to the control program.

The history of plague vaccine goes back almost to the beginning of the science of bacteriology. During the years many kinds of vaccines have been prepared and some have been used extensively in one or another part of the world. The textbook of Pollitzer (1) may be consulted for detailed information. In Madagascar a living attenuated vaccine was developed in the early 1930's and has been extensively employed there since the middle 1930's.

It will be seen from figure 1 that the annual number of cases of plague in Madagascar was about 3,500 in 1933 and in 1934, but diminished to about 500 in 1937 (12). It was during this period that the vaccine first came into wide use in the population of the endemic area. It is of interest that the precipitous drop in number of cases came after the program had been in effect for several years.

Meyer (13) has pointed out that immunization with killed plague vaccines results in appreciable resistance to infection only after repeated injections have been administered. It cannot be stated whether the sharp reduction in plague about 1937, shown in figure 1, was dependent upon some factor such as this or whether it was not until about 1937 that a sufficient number of people in the area had been vaccinated to establish an immunological barrier.

Vaccination against plague should be employed by the American Military for its troops and its associated civilian populations during any operation carried out in an area where pneumonic plague is known to have occurred. Remembering the importance of repeated vaccination, one must assume that an immunization program begun during an epidemic of pneumonic plague would be unlikely to have any


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FIGURE 1.

beneficial effect within a matter of weeks or months. If troops are conditioned by a basic course of immunization given some months before the individual reaches the endemic area, then booster doses of vaccine administered 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 of bubonic plague was to reduce the rat population and concurrently the flea population. During World War II, the American Army in Africa emphasized control of the rodent flea by means of the newly available long-lasting insecticides (14). This practice has come into widespread use in various parts of the world.* While measures for reducing rat populations are certainly to be considered as adjunct control procedures in outbreaks of pneumonic plague, it is to be realized that even elimination of rodents would not influence the course of an epidemic which was spreading directly from man to man.

When sylvatic plague exists enzootically among the indigenous rodents of the area and the climatic conditions are suitable for the direct transmission of 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 time an individual with plague from the bite of an infected flea may develop secondary pneumonia and start an epidemic. Therefore, measures which reduce the possibility of human infection from fleas in such areas may be expected to diminish the number of flash outbreaks which must be controlled.

To return to our example, Madagascar, rat control in that area, both as regards Rattus norvegicus in the urban areas and R. rattus in the countryside, has been relatively unsuccessful, just as it has in most other areas. In contrast, the reduction of vector fleas on urban rats has been so great as a result of repeated widespread application of DDT in malaria and plague control programs that rats now trapped in the city of Tananarive are frequently without fleas.

In addition to the general use of DDT the systematic application of DDT in the control of plague is carried out in the following manner in Tenanarive Province (3). When the hospital attendant of the area inspects a corpse, he applies DDT powder with a small hand apparatus to the room occupied by the family of the deceased. If immediate laboratory studies indicate plague, a team of four men with hand-operated DDT dusters visits the home of the deceased and liberally dusts the house, outbuildings and all observed rat runs within the general area. Furthermore, at this time the dusting team treats any neighboring habitations. Over and above this application to the homes of plague victims and their immediate neighbors, the dusting team systematically circulates through the endemic areas during the 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 plague on the High Plateau for several years, 1948-51, even though vaccination was not practiced to any appreciable extent during this period. However, following a moderately severe season in 1951-52 with 291 cases the French authorities decided to strengthen the general control program by reinstating, prior to the 1952-53 season, widespread vaccination of the population of the endemic area (12). The number of cases during 1952-53 was 157 and during 1953-54 was 97.

Therapy of Plague

Significant advances in therapy of plague began in 1938 with the clinical use of the sulfonamides and continued with the advent of the antibiotics (1, 15-17). In India the sulfonamides reduced the mortality of bubonic and septicemic plague which was about 50 and 90 percent respectively, to about 5 and 20 percent respectively (18). Moreover, streptomycin elicited a more prompt response and lowered the mortality of septicemic plague 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 sulfadiazine at 4-hour intervals until the patients remained afebrile for several days.

It should be emphasized that penicillin is useless in plague-see references cited in reference 1.

Successful treatment of pneumonic plague was accomplished first with streptomycin (19) and subsequently with several of the broad-spectrum antibiotics (16, 17). Therapeutic studies carried on in Madagascar by the French, and later by French and American investigators, have provided most of our current information on treatment of pneumonic plague. However, in this instance, as in most others, the clinical use of the therapeutic regimens was preceded by extensive laboratory studies the results of which provided the incentive for the trials in man (20).

The results obtained with streptomycin, chloramphenicol and terramycin in pneumonic plague are as dramatic as those in patients with pneumococcal pneumonia who received penicillin, provided that therapy is initiated within the first 24 hours after onset of disease. When therapy is delayed beyond this period the disease terminates fatally, even though prompt bacterial control may be attained and P. pestis cannot be cultured from the autopsy tissues. It is assumed that the potent toxins of the plague organisms contribute materially to the fatal outcome in such instances.

In practice, the reduction in mortality of pneumonic plague from almost 100 percent to almost zero as a result of antibiotic therapy is limited to contacts of plague patients who develop the pneumonic disease while under observation in a medical installation. In Madagascar, at least, none of the patients survive who develop pneumonic plague outside of a lazaret for contacts. Since one would anticipate a similar experience in any other geographic area where pneumonic plague may exist, one cannot overemphasize the need for prompt institutionalization of all contacts of this form of the malady and immediate treatment of exposed persons who develop a febrile illness.

The recommended treatment for plague is as follows: Initial intramuscular injection of 1 gram of streptomycin followed by 0.5 gram every 4 hours until the temperature remains normal for 4 or 5 days. Chloramphenicol, aureomycin or terramycin may be used in the usual dosage of 2 to 4 grams daily beginning with a loading dose, preferably by a parenteral route. In the pneumonic and the fulminating septicemic forms of the disease therapy must be initiated within hours after onset if the patient is to survive. The use of sulfonamides in the treatment of plague probably has no place in military medicine. However, its use in indigenous populations for whom the Military


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must assume responsibility is indicated in bubonic and septicemic plague when adequate supplies of the specific antibiotics are unavailable.

Chemoprophylaxis

It is not surprising that chemoprophylaxis with the sulfonamides was introduced shortly after members of this group of drugs were proved to be of value in the therapy of bubonic and septicemic plague and appeared to be useful in the abortive treatment of pneumonic plague when employed within a few hours after onset of fever (21). Sulfonamides were administered to contacts by a number of groups of investigators working in widely separated geographic areas (see summary in ref. 1) and with only rare exceptions favorable results were reported. Despite this essential unanimity of opinion, it is practically impossible to evaluate the observations because of the extreme variability in communicability of pneumonic plague.

Notwithstanding the weight of opinion, we believe that chemoprophylaxis with sulfonamides, or for that matter with the specific antibiotics, has no place in American military medicine. Now that at least four antibiotics are available for effective treatment of plague, it seems to us more important to concentrate one's efforts on (a) prompt collection of exposed persons, (b) proper observations including temperature determinations at least twice daily, and (c) immediate administration of full antibiotic therapy as soon as the individual under observation develops fever or other signs of illness. Similarly, we would discourage chemoprophylaxis for medical personnel employed in the care of patients with pneumonic plague. Instead we would emphasize (a) thorough immunization, (b) careful indoctrination in isolation technics and in recognition of the early signs and symptoms of the disease, and (c) prompt institution of antibiotic treatment at the very onset of any febrile illness. Such a regimen would undoubtedly result in the unduly vigorous treatment of some minor illnesses, but even this would probably be less wasteful of medicines and less hazardous to the individual than a prolonged course of chemoprophylaxis. Furthermore, if plague were suppressed by such a regimen it would be difficult, and sometimes impossible, to establish a retrospective diagnosis on the basis of laboratory studies; however, it is better to ponder a diagnosis in a healthy person than to confirm one at autopsy.

Conclusion

As regards flea-borne plague one can add little to the recent statement of Pollitzer (1), ". . . . it is only within the last decade that treatment with sulfonamides and antibiotics, on the one hand, and the application of potent insecticides-particularly DDT-on the other,


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have rendered plague both a normally curable and a thoroughly controllable disease." Pneumonic plague which spreads directly from man to man presents additional problems as regards control and treatment.

The French, working in Madagascar where pneumonic plague occurs each year, have developed a control program which could be used, with only minor modifications, by an American military group operating in an area where pneumonic plague occurs. The essentials of the Madagascar program are (a) case finding and isolation of contacts, (b) immediate treatment with specific antibiotics of those contacts who develop signs and symptoms of plague infection, (c) annual immunization of the population at risk, 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 the evolution of epidemiology, pp. 1-455, Clarendon Press, Oxford, 1953.

3. Smadel, J. E., Woodward, T. E., and Goodner, K.: Control of Plague in Madagascar. Annual Report, Commission on Immunization, Armed Forces Epidemiological Board, Appendix 2, pp. 1-33, 1951.

4. Davis, D. H. S.: Sylvatic Plague in South Africa; History of Plague in Man 1919-1943. Ann. Trop. Med. 42 : 207-217, 1948.

5. Meyer, K. F.: Known and Unknown in Plague (Charles Franklin 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 á Madagascar. Ann. d. Med. et d. Phamarmacie coloniales 35 : 305-358, 1937.

8. Girard, G.: L'Institut Pasteur de Madagascar et la lutte contre la peste. La Revue Synthese 7 : 1-11, 1939.

9. Bouffard, G., and Girard, G.: Le dépistage de la 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 Pasteurella pestis 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 credited is summarized from various reports published in Arch. d. L'Institut Pasteur de 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 Vaccination with Dead Virulent and Living Avirulent Plague Bacilli. Proceedings of the Fourth International Cong. on Trop. Med. and Malaria 1 : 264-275, 1948.

(b) Meyer, K. F.: Recent Studies on the Immunity Response 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.: Plague in 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., and Goodner, K.: Antibiotics in the Treatment of Bubonic and Pneumonic Plague in 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 and Terramycin in the Treatment of Pneumonic Plague. Am. J. Med. 14 : 284-293, 1953.

18. Sokhey, S. S., and Wagle, P. M.: Sulfonamides and Antibiotics in the Treatment of Plague. Proceedings of the Fourth International Cong. on Trop. Med. and Malaria. U. S. Gov't Print. Office 1 : 276-282, 1948.

19. (a) Estrade, F.: Un cas de peste pulmonaire primitive traité et guéri par la streptomycine. Bull. Soc. Path. Exotique 41 : 438, 1948.

(b) Girard, G.: La streptomycine, médication héroique 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 pesteuse par les corps sulfonamides. Peste expérimentale et peste humaine. Bull. Soc. Path. Exotique 34 : 37-48, 1941.