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Chapter 11 - Meningococcal Meningitis

Contents

CHAPTER XI

Meningococcal Meningitis

John J. Phair, M.D.

Relationships between civilian and military medicine are well illustrated by the history of meningococcal meningitis in this country as a whole and in the United States Army. The concern of both in the prevention and treatment of the disease has been deep and constant over the years. Progress made by one has been applied also by the other. Civilian and military experts, often the same individual under different dress, have served both the civilian populations and the Armed Forces. This was notably true of the vigorous and intelligent programs of the Preventive Medicine Service, Office of the Surgeon General of the Army, and of the Commission on Meningococcal Meningitis, Army Epidemiological Board, which was established and supported by The Surgeon General.

This chapter is divided into three main sections:

1. Meningitis as a military health problem up to and including World War I. This portion covers the years from about 1805 to 1919 when it was almost impossible to control the disease.

2. Meningitis between World War I and World War II, which covers the period from 1919 to 1939; inclusive. It was during these 20 years, in 1934, that the sulfonamides came into use and completely changed the therapy, prognosis, and possibilities of at least temporary prevention of meningococcal meningitis.

3. Meningitis in the Army during World War II (1941-45). There were many advances made by the study of the disease in military personnel, the dynamics of subclinical meningococcal infections were studied, and methods of chemoprophylaxis using sulfonamides (chiefly sulfadiazine) were developed. It was a period of intense activity in this field by the Preventive Medicine Service and the Commission on Meningococcal Meningitis.

PERIOD UP TO AND INCLUDING WORLD WAR I

Meningococcal meningitis has always been one of the most serious and important of the various communicable diseases of man, insofar as the United States Army has been concerned. Apparently impossible to control in any practical sense and difficult to treat, it has been a constantly present and vexing problem for everyone responsible for the health of any of the branches of the Armed Forces. The gravity of this infection arises not because of its incidence,


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which has always been low when compared with other upper respiratory diseases, but because of the usually extraordinarily high case fatality rate. As a matter of fact, during World War I, while this disease ranked only 76th as a cause of admission to a hospital, of the cases reported approximately 40 percent were fatal, bringing it up to 6th as a cause of death among Army personnel.

The sudden onset, the striking clinical picture, and the high case fatality rate have always served to delineate cerebrospinal fever sharply for the laity as well as physicians. Other important factors which distinguished this infection were the lack of a successful therapeutic program, the usual failure to demonstrate any degree of association between the clinical cases, and the fact that quarantine or similar control measures generally have proved ineffective. Therefore, the appearance of a single case in a command or in a neighboring civilian community was, and is, followed by an unwarranted apprehension and alarm on the part of all individuals who had had any possible degree of contact with the patient. The orderly flow of training, reception and shipment of personnel, and housing was usually disrupted immediately and completely. As a consequence, few illnesses were given more attention by line and medical officers. Since the anxiety and fear of attack is always inversely related to the extent of knowledge possessed as to the modes of transmission and efficacy of preventive procedures, this interest and concern of the military was natural and excusable

. The historical record of cerebrospinal meningitis as a clinical and epidemiologic entity opens early in the 19th century with the description of an outbreak in Geneva, Switzerland, which began in March 1805, and another in Medford, Mass., during March 1806.Isolation of the causative organism by Weichselbaum1 in 1887, confirmed by the extensive studies of von Lingelsheim 2 in 1905, permitted a firm etiologic diagnosis based upon the demonstration of the causative organism in the spinal fluid.

Hirsch, 3 in his classical work, has compiled descriptions of epidemics which were published in the medical literature from 1805 to 1882. Netter and Debre 4 supplemented those accounts and completed the record up to 1911. Heiman and Feldstein 5 have cataloged outbreaks in the United States.Similar monographs were published by Dopter, 6 Sophian, 7 and Worster-Drought and Kennedy.8 From accounts gathered from these references, it is possible to piece together a partial mosaic of the frequency and extent of major epidemics

1 Weichselbaum, A.: Ueber die Aetiologie der akuten Meningitis cerebro-spinalis. Fortschr. d. Med., Berlin 5: 573-583,1887.

2 von Lingelsheim, W.: Die bakteriologischen Arbeiten der kgl. hygienischen Station zu Beuthen O.-Schles. während der Genickstarreepidemie in Oberschlesien im Winter 1904-5. Klin. Jahrgb. Jena 15: 373-488, 1906.

3 Hirsch, August: Handbook of Geographical and Historical Pathology, vol. 111, ch. 18.London: The New Sydenham Society, 1883-86.

4 Netter, A., and Debré, R.: La Méningite Cérébro-spinale. Paris: Masson et Cie, 1911.

5 Heiman, Henry, and Feldstein, Samuel: Meningococcus Meningitis. Philadelphia: J. B. Lippincott Co., 1913.

6 Dopter, C.: L'Infection Méningococcique. Paris: J. B. Baillière & Fils, 1921.

7 Sophian, Abraham: Epidemic Cerebrospinal Meningitis. St. Louis: C. V. Mosby Co., 1913.

8 Worster-Drought, Cecil C., and Kennedy, Alexander M.: Cerebro-Spinal Fever: The Etiology, Symptomatology, Diagnosis and Treatment of Epidemic Cerebro-Spinal Meningitis. New York: The Macmillan Co., 1919.


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which have occurred in Western civilizations during the 19th and beginning of the 20th century.

Granting the inadequate and chance nature of the picture which can be elicited from these historical descriptions, it is nevertheless apparent that there were periods when the disease was excessively prevalent over large geographic areas and others when it was relatively quiescent. There were at least five intervals when the disease was apparently epidemic and not limited by natural boundaries; namely, 1838-50, 1865-70, 1886-88, 1896-1905, and 1909-10.

Meningococcal meningitis became epidemic again shortly after the outbreak of World War I. In England, France, Germany, and probably in other western European countries, the crest of the epidemic wave was observed in 1915, but in Denmark it came a year later.These accounts have not been reviewed in detail since they are readily accessible in the, references which have been cited.

The military, for many reasons, has always been selected as one of the principal occupational classes on which the disease falls most heavily. Without a doubt, it has been present among personnel of the United States Army during all wars and mobilization periods. Interesting clinical reports of outbreaks are recorded in the histories of the War of 1812, the Mexican War, and the Civil War. No reasonable comparison of the incidence rates is possible because of the considerable confusion in nomenclature and the inability to make a satisfactory differential diagnosis without the demonstration of the etiologic agent. In spite of the fact that the meningococcus had been recognized as the specific cause of cerebrospinal meningitis 10 years prior to the Spanish-American War, very few cases which occurred among Army personnel during that conflict were confirmed by laboratory methods.It is more than probable, therefore, that many of the cases were confused with typhus, typhoid, and other fevers. Since the turn of the century, however, with the increased use of laboratory facilities, diagnosis became more exact, and records have included usually only those cases in which the clinical impression has been confirmed by appropriate examinations.

It is noteworthy in studying these records that the admission rates for the Army have always been negligible except during the periods of rapid and extraordinary mobilization of unseasoned personnel. For example, in 1907 at the time of the Cuban occupations, the rate increased nearly tenfold. Again in 1913, during the military activity on the Mexican border, the admission rate more than doubled. However, in contrast, it is also important to remember that the subsequent concentration of solely Regular Army troops on the Mexican border in 1911 was not accompanied by a similar rise.

For several years before the onset of World War I, meningococcal meningitis, as indicated by the weekly morbidity and mortality reports of the United States Public Health Service, had been noticeably prevalent and widely distributed among the civilian population of the United States. In 1917, the rapid mobilization of over a million raw susceptible recruits from all sections of the country was followed by the outbreaks of the disease in every camp


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and installation. The close intimate contact under unusually crowded barrack conditions provided ideal soil and opportunity for the growth and dissemination of meningococci. As a consequence, the annual admission rate among enlisted men in the United States increased rapidly to a peak of 4.6 per 1,000 in January 1918. From this crest, the number of cases fell gradually with the exception of a small rise in October 1918 to the low point of 0.07 during the months of October; November, and December, 1919. The incidence of this disease in many camps was well above 2 per 1,000 per annum; for instance, the high at Camp Beauregard, La., was recorded as 12.8, and at Camp Jackson, S. C., 25.7 per 1,000 per annum. These attack rates are far greater than those ordinarily found in adult civilian populations living under customary urban relationships.

The disease occurred sporadically in the Army Expeditionary Forces rather than in extensive epidemics and at a lower rate than that found in the continental United States. A large proportion of the European cases could be traced to contacts within receiving ports or on shipboard, and usually the morbidity rates were highest in organizations originating from training camps in the United States having an epidemic incidence. It was commonly noted that more than 50 percent of the cases in any week, during the period troops were arriving from the United States, were reported from ports, and, in most cases, it is easy to assume that the exposure occurred during the voyage to England or France.

Comparison between the monthly incidence rates of the American Expeditionary Forces and of the British and French almost always shows higher rates in the American troops for this period. The British Expeditionary Force in France was attacked with some severity, the French Army suffered less, and the German Army hardly at all.

Etiologic Agent and Mode of Transmission

Meningococcal meningitis is an infectious disease caused by an obligate parasite of man, the meningococcus, a member of the genus Neisseria (Neisseria intracellulacis, Diplococcus intracellularis meningitidis, Neisseria meningitidis).

The, diagnosis of the infection rests upon a combination of clinical and laboratory findings. In cases with frank meningitis, the causative organism is always present in the cerebrospinal fluid; in a considerable proportion of cases, it is also demonstrable in the nasopharynx. Early in the disease, blood cultures are, likewise, positive in 40 to 60 percent of the patients. The organisms can be seen in stained smears of spinal fluid and blood expressed by puncturing the petechiae. The demonstration of the etiologic agent requires, however, an adequate, meticulous technique and a thorough understanding of the pathogenesis of the disease so that specimens can be obtained from the proper sites during optimal periods.


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In 1887, Weichselbaum 9 of Vienna published his classical paper describing the finding of this organism in six patients. His work was quickly confirmed by Goldschmidt, 10 but it was not until the extensive studies of von Lingelsheim 11 during an epidemic of 1904-5 that his observations were finally confirmed. Dopter 12 described parameningococci in 1909 since some confusion had arisen over the failure of monovalent serum to agglutinate all strains of meningococci. As soon as the so-called parameningococci were found in typical clinical cases, various systems for serologic classification of this organism were, developed. These systems employed agglutination, agglutinin absorption, complement fixation, and chemical fractionation. Classification of strains into four types was generally accepted as a result of this work.

The host response originally recognized and described is similar to other types of purulent inflammation of the meninges and is characterized clinically by an intense headache, emesis, stiff neck, positive Brudzinski's signs, and in the more severe reactions by coma and convulsions.

In some of the pioneer pathologic studies, the presence of a purulent rhinitis was recorded and some workers suggested the nasopharynx as a possible portal of entry. Weichselbaum 13 in his original paper mentioned that one of his patients had a purulent sinusitis and expressed an opinion that the organisms might find their way to the meninges via the nose. Subsequently, many other investigators isolated the organism not only from the nasal passages of patients but from healty contacts and even individuals without a history of the slightest exposure to the disease. So it was generally accepted that the meningococcus could proliferate in the nasopharynx without giving rise to symptoms and that it could be transmitted from patients to healthy persons or between individuals who had no contact with the clinical disease.

While there was general agreement as to the nasopharynx as the portal of entry, there were two main views as to the possible routes traveled by the organisms in order to gain access to the meninges. The first, supported by Netter and Debré,14 suggested the direct transmission of the organism from the nose to the meninges. The second, upheld by scientific workers in Germany, America, and England,15 postulated that the organisms were carried to the meninges by the blood stream. Each group of the interested investigators marshaled evidence to support their views, but the general opinion of physicians

9See footnote 1, p. 192.

10 Goldschmidt, F.: Ein Beitrag zur Aetiologie der Meningitis cerebro-spinalis. Centralb. f. Bacteriol. u. Parasitenk., Jena 2: 649-654, 1887.

11 See footnote 2, p. 192.

12 Dopter, C.: Étude de quelques germes isolés du rhino-pharynx, voisins du méningocoque (paraméningocoques). Compt. rend. Soc. de biol. 67: 74-76, 1909.

13 See footnote 1, p. 192.

14 See footnote 4, p. 192.

15 (1) Councilman, W. T., Mallory, F. B., and Wright, J. H.: Epidemic Cerebrospinal Meningitis and Its Relation to Other Forms of Meningitis. Report of the State Board of Health of Massachusetts, 1898. (2) Elser, W. J., and Huntoon, F. M.:Studies on Meningitis. J. Med. Research 20: 371-541, June 1909. (3) Flexner, S., and Barker, L. F.: A Contribution to Our Knowledge of Epidemic Cerebro-spinal Meningitis. Am. J. M. Sc. 107: 155-172, February 1894. (4) Albrecht, H., and Ghon, A.: Ueber die Aetiologie and pathologische Anatomic der Meningitis cerebrospinalis epidemica. Wien. klin. Wehnschr. 14: 984-996, 1901.


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dealing with these patients, as summed up essentially by Topley and Wilson,16 was that the most probable sequence had to be as follows: The organisms reached the nasopharynx as an airborne parasite; here they set up a rhinopharyngitis but usually gave no trouble. In some cases, however, the organisms gained access to the meninges; whether by direct invasion or via the blood stream was not known. Meningococcemias without meningitis also occurred frequently.

Much has been written about the various factors which may play a role in determining the occurrence of this disease. Early in the recorded history, keen observers noted that the incidence was affected by crowding, poor housing, or a combination of these two factors, although they could give no reasons for this association. A low temperature, a, cold wind, and increased humidity also appeared to be predisposing agents, but, in retrospect, it seems probable that these act mainly by forcing undue crowding indoors. Fatigue was also thought to play an important role, for it was the recruits, unaccustomed to rigors of military life, who furnished the greatest number of cases.

During the war of 1914-18, many investigations were carried out in attempts to ascertain the importance of the symptomless infections of healthy individuals in the transmission of this disease. Glover noted that when the carrier rate rose above 20 percent, isolated cases would appear and, as the epidemic gained a foothold, the rate might reach as high as 88 percent. He also observed a direct relationship between the proportion of soldiers harboring the organism and the degree and type of overcrowding. He called attention to the aggregation of infections in a given but which pointed strongly toward direct transmission from one man to another. This observation brought about spacing of the men in the barracks during World War I as a control measure which seemed to give relatively good results.

Following these and many similar studies,18 it was generally recognized that the carrier infections were clearly of great importance in the propagation of meningococci and that the infection was airborne. While it was possible that indirect infections such as contaminated dust particles may play a small part in the spread of this disease, in view of the extreme susceptibility of the organism to drying and to cold, it was regarded as negligible. Neither in barracks nor in civilian households can this method of infection be compared with direct transmittal by nasal mucus sprayed by the sneezing of infected individuals, even though meningococci remain viable after drying for 10 days if protected from direct sunlight.

16Topley and Wilson's Principles of Bacteriology and Immunity. 3d ed. Baltimore: The williams and Wilkins Co., 1946, vol. II.

17 Glover, J. A.: Cerebrospinal Fever: Studies in Bacteriology, Preventive Control and Specific Treatment of Cerebrospinal Fever Among the Military Forces, 1915-19. Section 20. Observations of the Meningococcus Carrier Rate and Their Application to the Prevention of Cerebrospinal Fever. Medical Research Council of the Privy Council, Special Report Series No. 50. London: His Majesty's Stationery Office, 1920.

18 (1) Dudley, S. F., and Brennan, J. R.: High and Persistent Carrier Rates of Neisseria meningitidis Unaccompanied by Cases of Meningitis. J. Hyg. 34: 525-541, December 1934. (2) Maxey, K. F.: The Relationship of Meningococcus Carriers to the Incidence of Cerebrospinal Fever. Am. J. M. Sc. 193: 438-445, March 1937.


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Control

With usual conditions and standards of human intercourse, there were no effective methods that could be devised to prevent dissemination of the meningococcus and the consequent occurrence of cases. Immediate methods of control during the period prior to and including World War I generally included isolation of acute clinical cases until 14 days after onset of the disease and close observation of immediate contacts such as household associates, barracksmates and messmates. General procedures called for prevention of overcrowding in living quarters, working places, and conveyances, such as is common in institutional and military populations. Early in World War I, it was considered advisable to detect and isolate the symptomless infections (carriers). Later, however, it was realized that such an isolation policy, even if effective, would be impracticable if rigidly applied to either civilian or military groups. For such populations as were exposed to epidemic prevalence of the disease, the separation or spacing of individuals was increased, and the ventilation of living and sleeping quarters improved. Likewise, all possibilities of chilling, bodily fatigue, and physical strain were minimized.

Polyvalent serum which could protect mice was prepared as early as 1906 by Jochmann,19 who injected horses first with dead then living cultures. Kraus and Doerr 20 prepared antitoxic sera by injection of broth filtrates and endotoxin. Such sera were used for treatment either by intravenous or intraspinal injections. Employment of these materials with spinal lavage seemed to give satisfactory results, but this could not be proved because of the extreme variability of the case fatality rates in different areas and outbreaks.

Sophian and Black,21 Greenwood,22 and Gates 23 made early attempts to ascertain the value of prophylactic vaccination but could not obtain unequivocal results.There was and is, however, no acceptable method of determining the resistance of an individual to an infection with this parasite other than determining the incidence of disease in a vaccinated and control group. This situation prevented any adequate assay. Since the immunity conferred by a clinical attack was apparently of long duration, subclinical carrier) infections were accepted as probably explaining the resistance of most adults. This was supported by the observation that contact (secondary) cases in families or military units were very rare.

19 Jochmann, G.: Versuche zur Serodiagnostik und Serotherapie der epidemischen Genickstarre. Deutsche med. Wchnschr.. 32: 788-793, May 1906.

20 Kraus, R., and Doerr, R.: Ueber Meningokokkengifte and Gegengifte. Wien. klin. Wchnschr. 21: 12-14 January 1908.

21 Sophian, A., and Black, J.: Prophylactic Vaccination Against Epidemic Meningitis. J. A. M. A. 59: 527-532, Roy. Soc. Med., London August 1912.

22 Greenwood, M.: The Outbreak of Cerebrospinal Fever at Salisbury in 1914-15.Proc. Roy. Soc. Med. London 10: Sec. Epidemiol. and State Med., 44-55, November 1916.

23 Gates, F. L.: A Report of Antimeningitis Vaccination and Observations on Agglutinins in the Blood of Chronic Meningococcus Carriers. J. Exper. Med. 28: 449-474, October 1919.


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PERIOD BETWEEN WORLD WAR I AND WORLD WAR II

In the years between 1919 and 1939, a more exact description of the occurrence of meningitis in various population groups became possible on the basis of mortality and morbidity reports. The published records of the Health Section of the League of Nations 24 began after World War I and the number of countries from which annual reports of cases of meningococcal meningitis were received increased steadily year by year. Hedrich 25 published a careful analysis of this material for the years between 1915 and 1930. Gover and Jackson 26 have expanded and extended these studies to take in the interval up to and including the year 1945, devoting most of the discussion to a description of the occurrence of this disease in the United States but including a brief report of the experience in other countries.

Germany experienced a sharp and pronounced outbreak in 1922, and a number of other Middle European countries showed similar waves that year or the next. Incidence was high in France and Denmark in 1925, in Sweden in 1926-27, and in Poland, Czechoslovakia, the Baltic states, Germany, Italy, and Greece in 1929. From 1928 to 1931, meningococcal meningitis was excessively prevalent in Canada and, from 1931 to 1934, in the British Isles. Another epidemic spread began in 1937-38 in Germany, Italy, Poland, Czechoslovakia, Greece, and Turkey when the recent world conflict was imminent. It is not at all improbable that this increase was related to or precipitated by the extensive mobilization activities which preceded the war.

A wave began in South Africa in 1928 and spread to Southern and Northern Rhodesia in 1929 and 1930. In North Africa, it began in Morocco and Algeria in 1929-30, extended to Egypt and the Anglo-Egyptian Sudan from 1930 to 1936, reaching Uganda and Kenya in 1934 to 1938. In the Far East, epidemics were recorded in Indo-China and Hong Kong between 1931 to 1934, and in Formosa and Japan in the period 1934 to 1936. These data, gleaned from the incomplete records of the League of Nations, insofar as they go, lend substantial support to the constantly recurring impression that meningococcal meningitis becomes epidemic over large geographic regions in such a manner as to suggest a wavelike spread through populations living in essentially contiguous countries. Furthermore, it is evident that between 1919 and the beginning of World War II, most of the reporting countries experienced one, two, or perhaps three possibly related or synchronous epidemic waves.

After World War I, really beginning in 1916, coincidental with the broadening of the United States registration area, recognition, reporting, and classification of deaths and cases of meningococcal meningitis became relatively satisfactory. The area and population was sufficiently large and representative

24 League of Nations: Health Organization.Annual, monthly, and weekly epidemiological reports.

25 Hedrich, A. W.: The Movements of Epidemic Meningitis, 1915-1930. Pub. Health Rep. 46: 2709-2726, November 1931.

26 Gover, M., and Jackson, G.: Cerebrospinal Meningitis; Chronological Record of Reported Cases and Deaths Pub. Health Rep. 61: 433-450, March 1946.


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to afford a comprehensive delineation of the occurrence and movement of this disease in the United States.

For the purpose of studying the chronology and geographic extent of epidemic periods, either regional morbidity or mortality rates may be employed as indices.27 The wide variation in case fatality rates, as previously noted by many observers, is an ever-present source of error. Likewise, morbidity rates are equally unreliable because of failure to report or to make a proper diagnosis. However, after analyzing the available records from all points of view, it is apparent that the use of either the morbidity or mortality rate does not essentially change the picture that can be drawn regarding the occurrence of meningococcal meningitis.

Epidemic incidence was noted in many parts of the United States during 1917-18, but the outbreaks were so small and scattered in the Mountain and Pacific States, that they were scarcely perceptible in the regional picture. The next wave in 1928-29 apparently began in 1926 in the regions which had been spared in the earlier outbreak and gradually extended into the Mountain States. Under this impact, the area recorded the highest attack rate realized in all regions. Excessive rates were found throughout the country, but the epidemic wave was least noticeable in New England and the South Atlantic States.

After a relatively quiet period of 5 years, meningococcal meningitis became important again in 1935-36 with a noteworthy increase in rates which was reflected all over the United States but with the highest incidence, in the South Atlantic and East South Central States. Following this swing, a period of low incidence followed, lasting until 1942.

It must be kept in mind that the excessive rates for any given region may be due to a number of small foci within the area; that is, the regional picture may be only the reflection of epidemic incidence of a few localities. The data are not sufficiently detailed, the distribution of cases and deaths are not uniform, and it is impossible to analyze the occurrence in small geographic units or to attempt to trace the movement of this disease from one area to another. It is possible and interesting, however, to note the time required for an epidemic to move through the United States. When the incidence curve swings upward, it is reflected across most of the continent within a year. This is an entirely different situation from that which was found in the classical Swedish experience

28

of 1856-61. The rapid spread noted today, as compared with the slow movement found in the middle of the 19th century, probably can be attributed directly to the tremendous improvement in methods of transportation: modern railroads, paved highways, the automobile, and the airplane have all played an important part in changing the effective contact rate not only for meningococcal meningitis but all parasitic diseases in Western civilizations.

It was noted before that the use of mortality and morbidity rates could not be relied upon entirely to describe the extent and severity of epidemics. How-

27 United States Public Health Service: The Notifiable Diseases; Prevalence of Certain Important Communicable Diseases, by States: Pub. Health Rep. Supp. (issued annually).

28 See footnote 3, p. 192.


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ever, it was remarkable that the ratio of mortality to morbidity was relatively constant for all regions, the United States as a whole, and in epidemic or endemic periods prior to 1940. About that time a marked change occurred, and suddenly three or four times as many cases per death were reported than heretofore. This sudden drop in the case fatality rate was recorded throughout the United States registration area. Several explanations may be offered to explain this observation, such as a change in the strains of the meningococcas prevailing in the United States, improvement of reporting, and better diagnostic facilities.

However, it was and is generally accepted that the introduction of a much more effective therapeutic program prevented an extremely significant number of deaths. Sulfonamide drugs were made generally available to the physicians in the United States in 1934, and it was quickly demonstrated that they have an extraordinary specificity in the treatment of meningococcal infections.29 Of course, while the improvement in the case fatality rate lagged 5 or 6 years behind, it is not unexpected that this apparently long period of time was required before these compounds were used in the treatment of a sufficient number of cases to produce the improvement in recorded mortality figures. The addition of these drugs to the armamentarium of the physician was the most significant advance in medical knowledge in the 20 years between the two world conflicts. It changed completely the therapy and prognosis of classical meningococcal meningitis.

Etiologic Agent and Mode of Transmission

The several studies attempting to classify the various strains of meningococci isolated during this interval between world conflicts served to show only that no sharp line of demarcation could be drawn between the several types. Group I was the organism commonly found in the United States during the socalled epidemic episodes, while group II was isolated more frequently during the interepidemic periods. Branham and others 30 and Rake and Scherp 31 reached the broad conclusion that, on the basis of extensive clinical, chemical, and serologic observations, it was impracticable to distinguish between type I and type III and they should be classified jointly as group I. Type II is not a homogenous group serologically and was, therefore, more appropriately desig-

29 Dingle, J. H., Thomas, L., and Morton, A. R.: Treatment of Meningococcic Meningitis and Meningococcemia With Sulfadiazine. J. A. M. A. 116: 2666-2668, June 1941.

30 (

1) Branham, S. E.: Significance of Serologic Types Among Meningococci. J. A.M.A. 108: 692-696, February 1937. (2) Branham, S. E.: Value of Typing Meningococci. Am. J. Pub. Health 35: 233-238, March 1945. (3) Branham, S. E., Mitchell, R. H., and Brainin, W.: Gonococcic meningitis. J. A. M. A. 110:

1804-1806

, May 1938. (4) Branham, S. E., and Pittman, M.: A Recommended Procedure for the Mouse Protection Test in Evaluation of Antimeningococcus Serum. Pub. Health Rep. 55: 2340-2346, December 1940. (5) Branham, S. E., Pittman, M., Rake, G., and Scherp, H. W.: A Proposed Mouse Protection Unit for Antimeningococcus Serum. Proc. Soc. Exper. Biol. & Med. 39: 348-350, November 1938. (6) Branham, S. E., Taft, C. E., and Carlin, S. A.: Studies on Meningococci, Isolated in the United States, 1928-1930: Serological Classification and Geograph

ic Distribution. Pub. Health Rep. 46: 897-916, April 1931. (7) Branham, S. E., and Carlin, S. A.: Comments on a Newly Recognized Group of the Meningococcus. Proc. Soc. Exper. Biol. & Med. 49: 141-144, February 1942.

31 Rake, G., and Scherp, H. W.: Studies on Meningococcus Infection.III. The Antigenic Complex of the Meningoeoccus-A Type-specific Substance. J. Exper. Med. 58: 341-374, September 1933.


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nated as group II. A number of strains were isolated late in the thirties as distinctive members of group II and are now referred to as group IIa. Type IV has not been isolated from clinical cases in the United States since World War I, and, because it is so uncommon, it was generally accepted that maintenance of a separate classification seemed rather unwarranted.

Branham believed firmly that the meningococci classified in group I were responsible for the epidemics and those in group II for sporadic cases. She stated that "during recent years it has been possible to foresee periods of unusual incidence by the increase in the relative number of Group I strains sent in for typing, and to recognize that an outbreak was on the wane by an increased proportionate occurrence of Group II strains."

These, and similar studies were directed primarily at the development of an adequate therapeutic serum. The occasional observation could be used in control procedures, but the great interest lay in the standardization of serum treatment. The introduction of the sulfonamides completely changed the picture. For some time it was undecided whether it would be necessary to employ both serum and these drugs, but it was not long before clinical reports demonstrated that the sulfonamide alone would suffice.

Control

During this interval, efforts to develop and assay various methods of prophylactic, immunization continued apace in many countries. Zrunek and Feierabend 32 endeavored to immunize the Czechoslovakian Army. Riding and Corkill 33 in 1932 carried out a large series of vaccinations among the natives in northern Sudan. No significant protection was obtained in either of these attempts although the studies were well planned with large samples and carefully carried out by the investigators.

With the concept that meningococci produce a soluble exotoxin, Ferry 34 in the early thirties recommended that therapeutic antitoxic sera be prepared by injecting horses with the type-specific toxins. Later he developed toxoids which were employed by Kuhns 35 in studies utilizing various Civilian Conservation Corps installations. The results obtained were not sufficient to warrant serious consideration of this method of immunization. The principal obstacle encountered in all these investigations came about because there is no laboratory method by which human immunity can be gaged. Reliance always had to be

32 Zrünek, K., and Feierabend, B.: An Attempt of Active Immunisation Against Epidemic Cerebrospinal Meningitis. Trav. Inst. d'hyg. pub. de l'Etat Tchécoslovaque 2: 1-6, January 1931.

33 Riding, D., and Corkill, N. L.: Prophylactic Vaccination in Epidemic Meningococcul Meningitis. J. Hyg. 32: 258-267, April 1932.

34 (1) Ferry, N. S.: Meningococcus Antitoxin. I. Prophylactic and Therapeutic Tests on Guinea Pigs. J. Immunol. 23: 315-324, 1932. 11.Therapeutic Tests on Monkeys. Ibid. 23: 325-347, October 1932. (2) Ferry, N. S., Norton, J. F., and Steele, A. H.: Studies of the Properties of Bouillon Filtrates of Meningococcus: Production of Soluble Toxin, J. Immunol. 21: 293-312, October 1931.

35 Kuhns, D. M., Kisner, P., Williams, M. P., and Moorman, P. L.: The Control of Meningococcue Meningitis Epidemics by Active Immunization With Meningococcus Soluble Toxin: Further Studies. J. A. M. A. 110: 484-487, February 1938.


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placed upon the comparison of incidence rates and this was not at all satisfactory when dealing with a disease in which such a large proportion of the infections are subclinical.

ARMY EXPERIENCE DURING WORLD WAR II

Although meningococcal meningitis was not yet a serious problem for the Army early in 1941 and sulfonamide therapy seemed extraordinarily promising, it was believed desirable by the Preventive Medicine Service of the Surgeon General's Office to establish and support a special group of civilian workers concerned primarily with this disease. The tempo of mobilization was increasing, and the unusual susceptibility of new recruits was well recognized. For the prevention and control of meningococcal meningitis in the Army, with its shifting population, unusual environmental factors, and tactical requirements, extension of knowledge of the biology of the causative organism and the epidemiology of the disease were deemed of primary importance in the war effort.

To carry out this proposal, the Commission on Meningococcal Meningitis was organized under the Board for the Investigation and Control of Influenza and Other Epidemic Diseases in the Army. Employing their recommendations, a tentative program for study and control of meningococcal meningitis was formulated, approved by the Board, and submitted to the Office of the Surgeon General on 26 April 1941.36 This memorandum, in addition to specific immediate recommendations, defined the aims and basic procedures that would permit the coordination of the activities of all interested groups, civilian and military, and to contribute effectively in every way to the solution of this problem. Among the more important suggestions, it was recommended that a central laboratory be established at the Johns Hopkins School of Hygiene and Public Health, Baltimore, Md., to act as a center for interim laboratory studies, preparation and distribution of meningococcal typing sera, and analysis of case data for correlation with the characteristic strains isolated. An investigative team was planned to carry on the necessary field studies and to evaluate therapeutic and prophylactic measures. In addition, the importance of a specialized consultation service for the Office of the Surgeon General and commanding officers of Army posts and medical laboratories was recognized and provided.

In 1941, as previously noted, the incidence of meningococcal meningitis in the United States was low and usually sporadic. The reports to the Health Section of the League of Nations at the actual beginning of World War II in 1939, however, showed a rise in incidence in practically every European country where records are available. The disease became increasingly prevalent in the United States at the end of 1942 shortly after this country entered the war. Beginning with the fall of 1942, the number of cases began to rise among both Army personnel and civilian populations. From 1942 through 1944, the

36 Commission on Meningoeoccal Meningitis, United States Army, Preliminary Report, 1941.


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United States experienced the most severe epidemic ever recorded by the United States Public Health Service 37 (chart 19). Illustrative of the force of this outbreak, the Commission from July 1941 through June 1943 received over 5,000 case records from the various military commands stationed in the continental United States.38 Chile in 1942, likewise, had one of the largest and most severe epidemics recorded in modern times.39

CHART 19.-Meningococcal meningitis in the Army in the United States, 1910-461 and in the total United States population, 2 1916-46

In the Army, the patients with this disease were concentrated among the new unseasoned recruits. Sixty-seven percent of the 5,000 cases reported to the Commission on Meningococcal Meningitis occurred among men who had been in service 3 months or less, 82 percent with 6 months or less, 89 percent with 9 months or less, and 93 percent with 12 months or less. Although this was a time of rapid expansion in the Army, the appearance of cases in the recruits during their first 3 months of service was consistent not only throughout mobilization but was noteworthy for the entire war period. Therefore, this

37 Meningococcus Meningitis in the United States During 1943. Pub. Health Rep. 59: 469-471, April 1944.

38 Records and Cultures of Cases Received By and On File With the Commission on Meningococcal Meningitis, Army Epidemiological Board.

39 Pizzi, M.: A Severe Epidemic of Meningococcus Meningitis in Chile, 1941-1942. Am. J. Pub. Health 34: 231-238, March 1944.


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difference apparently is a valid representation of the unusual hazard or risk associated with the younger group, insofar as Army experience is concerned. The susceptibility of the very young age group has been noted repeatedly in civilian populations, and it is interesting in this respect to call attention to the Army experience with environmental age as based on a study of 1,337 cases (chart 20).40

CHART 20.-Meningococcal infections by duration of Army service, percent of 1,337 cases

Mortality from meningococcal meningitis and meningococcemia was exceedingly low, when compared with usual experience, due to widespread and intelligent use of the sulfonamides. From records received by the Commission for the period July 1941 to July 1943, 4,843 cases were classified as proved or probable clinical meningococcal infection.41 Of this group, the final disposition of 4,724 cases was recorded. The case fatality among this latter group was 3.7 percent. Disposition was usually not stated because the patient was still retained in the hospital at the time the record was forwarded to the central office. It is highly improbable that any deaths occurred among this group retained for further observation, and the case fatality among the entire group of 4,843 cases was also only 3.7 percent.

The experience with this disease in areas such as Europe, Australia, and the Mediterranean, mirrored that which was found in the continental United States. The incidence was high throughout 1942 and 1943. For instance, the disease among the first contingents to reach the British Isles reached an

40 See footnote 37, p. 203.
41 See footnote 38, p. 203.


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annual incidence of 4.56 per 1,000 per annum. Also the improvement in the case fatality rate was duplicated with the general use of the sulfonamides. The case fatality rate of 4.6 percent for United States troops stationed in Europe during this conflict was extraordinary when compared with the rate of 43.4 percent recorded in World War I.

The epidemiologic pattern, however, was much the same as has been described in the previous war, in that the disease appeared sporadically. No extensive, epidemics were reported from any theater and all groupings of cases were of a minor nature. That a goodly proportion of the infections were imported from the Zone of Interior became manifest by the frequency with which the disease was recognized on transports and the higher rates among newly arrived troops.

Etiologic Agent and Mode of Transmission

Approximately 2,488 strains from cases of meningococcemia and classical meningitis occurring in Army personnel were carefully studied in respect to colony morphology, biochemical activity, and antigenic patterns.42 The results have been summarized in table 33.

It is important to call attention to the fact that the frequency distribution of meningococcal types as isolated from cases and illustrated in this table was not duplicated when the subclinical infections were carefully studied. Typing of the strains obtained from cases throughout the Army revealed that 91 percent were group I. In a study group, 36.1 percent of the meningococci isolated from the subclinical infections were group I, 23.2 type IIa, 39.4 group II, and 1.3 polyvalent IIa-II.

It was recognized, with the careful study of the detailed clinical records of these Army cases, that meningococcal infections should be considered as having three distinct stages. The first is a localized infection of the nasopharynx; the second is a septicemia (meningococcemia) ; and the third is a purulent inflammation of the merlinges, particularly at the base of the brain. It must be noted, however, that the progression through these stages may be so rapid that the stages may not appear separate to the casual observer but to coexist.

The importance of the simple, essentially innocuous nasopharyngeal infections was difficult to ascertain because the term "infection," in its various gradations, cannot be precisely defined. Its scope includes a wide range of manifestations varying from a local reaction, so slight that only the associated antibody response of the host indicated the presence of the organism, to the gross changes which result in clinical signs and symptoms.

A study 43 was formulated, as part of the total effort of many workers, to describe the dynamics of subclinical meningococcal infections according to type

42 See footnote 38, p. 203.

43 Phair, J. J., Schoenbach, E. B., and Root, C. M.: Meningococcal Carrier Studies.Am. J. Pub. Health 34:148-154, February 1944.


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TABLE 33.-Serologic classification of case strains isolated from Army personnel and received by the Commission on Meningococcal Meningitis l

in respect to distribution, prevalence, incidence, and duration. Among 99 men in an untreated group, the average composite prevalence rate was 40 percent, but 91.9 percent were infected at some time during the study period. Of the 91 men with positive cultures, 44 had infections classified as persistent under a reasonable definition. An approximately equal number lead only transient infections. Classification of the plates according to the type and number of meningococcal colonies present did not differentiate between the persistent and transient infections.

No fixed pattern could be derived from the study of the individual records. Cultures from some men were negative throughout the study period. Spontaneous parasitic cures occurred in many. In others, infections with one type would be followed, interrupted, or accompanied by an infection with another type. No correlation could be demonstrated between the daily prevalence rates, climatic conditions, the occurrence of upper respiratory diseases, and the incidence of the common contagious diseases, including clinical meningococcal infections.


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The high proportion (91.9 percent) of the 99 men found infected extended and confirmed the concept that the spread of the meningococcus is primarily at the subclinical level. Few escaped infection during the brief study period of 68 days, indicating the extent and extraordinary rapidity of dissemination. It was quite apparent that the composite or type-specific prevalence rate for any given day is a static representation of a biologic equilibrium and does not describe the rate of transmission of the meningococcus. A dynamic process exists and must be illustrated by a dynamic equation. The number of new infections in each succeeding time period, that is, the incidence rate, is a much better index than the level of prevalence attained. If the incidence is increasing, transmission is taking place; if it is decreasing, conditions are operating against the survival of the parasite. The same prevalence may be found in two population groups, yet in one there may be a declining incidence and in the other an increasing transmission of the meningococcus. If all other factors are equal, such as group susceptibility or degree of contact, the latter situation would cause more concern.

With this concept the hypothesis of a fixed epidemic level of subclinical meningococcul infections falls. Glover 44 had concluded that there was a correlation between prevalence of these infections and the incidence of clinical cases by stating: "A carrier rate of 20 percent (without awaiting the occurrence of cases) should be regarded as a signal for prompt and effective action * * *." However, in the development of this thesis, he was actually concerned with the changes in the prevalence rather than the static level. In his report, the following inferences were drawn: "A wave of high (non-contact) carrier rates precedes and accompanies an outbreak of cerebrospinal fever. In other words there is a carrier epidemic (for the most part entirely devoid of symptoms) preceding and accompanying the much smaller case epidemic." He did not stress sufficiently the importance of this latter observation and later workers in the field of preventive medicine neglected it entirely.

These results, combined with the many similar investigations of other workers dealing with Army personnel, indicated that clinical reactions or cases of the disease must then be considered only as uncertain and irregular indicators of the dissemination of the specific micro-organism in a population. The rise or decline of the incidence of disease over long periods of time may be due alone to a change in the prevalence of a parasite, to a variation in the ratio of clinical to subclinical infections, or a combination of these. However, it is evident that the number of cases would be determined largely by the total incidence of new infections, clinical and subclinical, rather than the level of the prevalence, in any given period.

Control

These studies as described offered a reasonable explanation of the failure of control measures which have been suggested in the past. The meningococcus

44 See footnote 17. p. 196.


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must be considered as an efficient parasite which maintains itself in any human population through infections at a subclinical level. Only a very small pro-portion of the total number of infections are followed by clinical manifestations. The latter group acquire the parasite not necessarily from contact with other cases but from apparently healthy individuals who have a subclinical infection. As there are no methods for the protection of susceptibles, a reduction in the number of clinical cases can be obtained only by decreasing the probability of exposure to the meningococcus.

The formulation and application of adequate practical preventive programs for the control of such upper respiratory infections, in civilian or military populations under these circumstances, is extremely difficult. The obstacles encountered stem essentially from the fact that the host-parasite relationship is well established and apparently of long standing. The extent of this adaptation in the equilibrium between host and parasite was evidenced by (1) the relativelv small proportion of infections which present clinical manifestations; (2) a relatively prolonged infectious period; (3) a vulnerable portal of entry and all open portal of exit; (4) the antitoxic, rather than antiparasitic, immunity which usually follows au infection; and (5) the relatively transient immune period.

Attempts at nasal disinfection had been made in World War I without success. The administration of subtherapeutic doses of the sulfonamides lead been advocated for the chemoprophylaxis of certain selected, particularly upper respiratory, bacterial infections by numerous workers before World War II. Schwentker and coworkers 45 employed sulfadiazine in an attempt to influence the course of a scarlet fever epidemic among the personnel of a naval training station. Coburn, 46 Holbrook, 47 Hodges, 49 Van Ravenswaay, 49 among others, have reported oil the apparent reduction in the attack rate of streptococcal respiratory infections at Army and Navy installations following the institution of sulfadiazine prophylaxis. The experience of several investigative teams organized by the Navy at various bases and conducted through the, winter of 1943-44 has been summarized in a bulletin issued by the Bureau of Medicine and Surgery of the Navy Department. Siegel 50 reported extensively on studies for the control of acute infections of the respiratory tract with small daily doses of sulfadiazine administered to an institutional group. The effect of this regime on the nasopharyngeal flora was followed by carefully repeated nasal and throat cultures at periodic intervals.

45 Schwentker, F. F., Hodes, H. L., Kingsland, L. C., Jr., Chenoweth, B. M., and Peck, J. L.: Streptococcal Infections in a Naval Training Station. Am. J. Pub. Healtb 33:1455-1460, December 1943.

46 Coburn, A. F.: The Carrier Problem in the Dissemination of Hemolytic Streptococcus.U. S. Nav. M. Bull. 42: 325-335, February 1944.

47 Holbrook, W. P.: The Army Air Forces Rheumatic Fever Control program. J. A. M. A. 126: 84-87, September 1944.

48 Hodges, R. G.: The Use of Sulfadiazine as a Prophylactic against Respiratory Disease.New England J. Med. 231: 817-820, December 1944.

49 Van Ravenswaay, A.. C.: Use of Sulfonamides in the Army. J. Missouri M. A. 41: 29-30, February 1944.

50 Siegel, M.: Studies on the Control of Acute Infections of the Respiratory Tract. III. Results of Sulfadiazine Therapy From May 3, 1942 to May 2, 1943.Am. J. Dis. Child. 67:365-370, May 1944.


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Meehan and Merrillees, 51 Fairbrother, 52 Mueller, 53 Cheever and coworkers, 54 Kuhns and coworkers, 55 and the Commission on Meningococcal Mellingitis,56 among others,57 reported the prevention of meningococcal infections with sulfonamide prophylaxis. This has been the disease in which the greatest success has attended its use because of the unusual sensitivity of the meningococcus to these compounds. It was readily demonstrated by carefully controlled observations that even a single 2-gm. dose of sulfadiazine was followed by a rapid and complete disappearance of meliingococci from repeated subsequent nasopharyngeal cultures of the entire group.

Prophylaxis by chemotherapy, however, cannot control the incidence, of reinfections indefinitely. It must be recognized that only parasitic cure or suppression was obtained. There may be a brief refractory period following the administration of the drug, due possibly to a change in the nasopharyngeal bacterial flora. However, there are no grounds, either theoretical or experimental, for the assumption that the sulfonamides, except during the relatively brief period of their activity, confer freedom from, or eidlance resistance to, subsequent infection over any long period of time. The rapidity with which the treated groups may again attain the prevalence level of the general community will depend upon their degree of reexposure. Such exposure is the resultant of the effective contact rate between the treated and untreated groups and the incidence of meningococcal infections as contrasted to the prevalence among the latter.

The use of these chemotherapeutic drugs, however, offered a feasible and effective method of controlling the dissemination of meningococci in the vast variety of situations found in the Army, such as troop trains, troopships, training installations, and prison camps. Armed with this knowledge and fortified also with a rapid and adequate therapeutic program, the Preventive Medicine Service arranged prophylactic programs which met the urgent needs of the Army during the war period. It is impossible to determine the contribution of mass sulfadiazine prophylaxis to the decline of meningococcal meningitis in the Army as a whole, but there is no doubt as to its effectiveness in the control of specific outbreaks. However, with intelligent application of these procedures,58 fear was allayed, and the widespread shifting and deployment of troops and other personnel was not hampered or curtailed because of this disease during the remainder of World War II.

51 Meehan, J. F., and Merrillees, C. R.: An Outbreak of Cerebro-spinal Meningitis in a Foundling Hospital. The Treatment of Carriers with "M & B 693." M. J. Australia 2:84-90, July 1940.
52 Fairbrother, R. W.: Cerebrospinal Meningitis. The Use of Sulfonamide Derivatives in Prophylaxis.Brit. M. J. 2: 859-862, December 1940.
53 Mueller, J. H.: The Relation of the Carrier to Epidemic Meningitis. Ann. Int. Med. 18: 974-977, June 1943.
54 Cheever, F. S., Breese, B. B., and Upham, H C.: The Treatment of Meningococcus Carriers With Sulfadiazine. Ann. Int. Med. 19:602-608, October 1943.
55 Kuhns, D. M., Nelson, C. T., Feldman, H. A., and Kuhn, L. R.: The Prophylactic Value of Sulfadiazine in the Control of Meningococcic Meningitis. J. A. M. A. 123: 335-339, October 1943.
56 See footnote 36, p. 202.
57 Aycock, W. L., and Mueller, J. It.: Meningococcus Carrier Rates and Meningitis Incidence. Bact. Rev. 14: 115160, June 1950.
58 Circular Letter No. 170, Office of the Surgeon General, U. S. Army, 30 Sept. 1943, subject: Prophylaxis of Meningoeoccal Meningitis by Use of Sulfadiazine-