CHAPTER IX
Tularemia
Raymond A. Kelser, D.V.M., Ph. D.
During World War II, the Army's experience with tularemia was relatively insignificant. From 1942 to the end of 1945, only 194 cases were reported in military personnel ; of these, 187 occurred in the continental United States, principally in the tick-infested regions of the Fourth and Eighth Service Commands, particularly in the Tennessee Maneuver Area. A few cases occurred among troops in the European, North African, and Mediterranean theaters. There were four deaths reported as being due to tularemia during the war years. With the exception of the issuance of warnings to avoid tick bites as much as possible and to avoid handling the carcasses of wild rabbits, no special control measures were applied or developed.
EPIDEMIOLOGY
The recognition of tularemia as a disease entity dates back to 1910 when McCoyl found it as a plaguelike infection of ground squirrels in Tulare County , Calif. The following year, McCoy and Chapin,2 after a number of failures, succeeded in cultivating the organism on an egg-yolk medium, reproduced the disease with the cultures, and named the organism Bacterium tularense. Initially, it was not known whether the disease might be of importance insofar as man was concerned, or whether it was limited entirely to animals, particularly rodents. As is now well known, it was later established that the organism, which is now designated Pasteurella tularensis, is capable of infecting man, frequently with serious results.
Tularemia is primarily a disease of wild animals, especially rodents. It has been found commonly in rabbits, ground squirrels, wild rats, and mice, but it also occurs occasionally in opossums, grouse, sage hens, gophers, and so forth. It can be readily transmitted to laboratory animals such as the guinea pig, rabbit, and white mouse.
In 1914, Vail3 proved the organism responsible for an eye condition
1McCoy, G. W. : A Plague-Like Disease of Rodents. Pub. Health Bull. 43 : 53-71, April 1911.
2McCoy, G. W., and Chapin, C. W.: Further Observations on a Plague-Like Disease of Rodents With a Preliminary Note on the Causative Agent, Bacterium tularense. J. Infect. Dis. 10: 61-72, January 1912.
3Vail, D. T.: A Case of "Squirrel Plague" Conjunctivitis in Man (Bacillus tularense Infection of the Eye). Ophth. Rec. 23: 487-495, October 1914.
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in man, and in the same year Wherry and Lamb4 reported the case of a young man who developed ulcers on the conjunctiva and adenitis of the regional lymph nodes which was proved to be tularemia. Edward Francis5 engaged in extensive studies of the organism and the disease it causes and contributed much to the knowledge of the subject. He demonstrated that the organism required cystine for its propagation on artificial media, and he coined the term "tularemia" to designate the several types of conditions caused by Past. tularensis.
Transmission of tularemia among lower animals most commonly occurs through the agency of arthropod vectors. While it is possible for animals to become infected by direct contact with those having the disease, insect transmission is more common. Man, on the other hand, is generally more likely to become infected through the handling of tissues from wild rabbits or other animals infected with the disease. This, of course, does not mean that arthropod vectors are of no importance in transmitting the malady to man; they are of importance and under some circumstances are of considerable importance in infecting man. It is of interest to note that for the most part the cases of tularemia which occurred among military personnel during World War II were tickborne (fig. 12).
The ticks Dermacentor andersoni and Dermacentor variabilis are well-known vectors of Past. tularensis. In these species, it is known that the organism can be passed from the adult female tick down through the eggs, larvae, and nymphs, thus giving rise to a large number of transmitting progeny. Moreover, the ticks are capable of harboring the organism of tularemia over long periods of time.
In the chief outbreaks of tularemia in military personnel in World War II, Amblyomma americanum was found to be the most predominant tick in the area in which the involved troops were bivouacked. Dr. Norman Topping, of the U.S. Public Health Service, who aided in the investigation of the outbreak in the Tennessee Maneuver Area, together with Maj. (later Lt. Col.) Ralph R. Sullivan, MC, Medical Inspector, Second U.S. Army, and Dr. Tucker, Epidemiologist for Tennessee, made an initial collection of ticks and found them to be A. americanum. Subsequently, a more extensive tick survey was made and was aided materially through the cooperation of Dr. W. C. Williams, Health Commissioner of Tennessee , and his staff. The ticks initially collected in the Tennessee Maneuver Area were examined by Dr. Edward Francis, in Washington, and subsequent lots by Dr. R. R. Parker and his group, at the Rocky Mountain Laboratory of
4Wherry, W. B., and Lamb, B. H.: Infection of Man With Bacterium tularense. J. Infect. Dis. 15 : 331-340, September 1914.
5(1) Francis, E.: Tularaemia Francis 1921. Pub. Health Rep. 36: 1731-1753, July 1921. (2) Francis, E.: Tularaemia. Pub. Health Rep. 38: 1391-1404, June 1923. (3) Francis, E.: Microscopic Changes of Tularaemia in the Tick Dermacentor andersoni and the Bedbug Climex lectularius. Pub. Health Rep. 42: 2763-2772, November 1927. (4) Lillie, R. D., and Francis, E.: Bone Marrow in Tularaemia. Pub. Health Rep. 48: 1127-1136, September 1933. (5) Francis, E.: Tularaemia Francis 1921 ; A New Disease of Man. U.S. Hyg. Lab. Bull. No. 130, March 1922.
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the U.S. Public Health Service, at Hamilton, Mont. None of the ticks collected were found to be infected with Past. tularensis.
Until the time of the Tennessee Maneuver Area outbreak, A. americanum generally was not considered a vector of the tularemia organism. However, according to a report by Parker in 1933,6 Philip had demonstrated experimentally the survival and transmission of Past. tularensis by A. americanum from the larval stage to the adult stage in one generation. Epidemiological observations and studies with tularemia since the experience with A. americanum during World War II have strengthened the concept that the Amblyomma species is a natural vector of Past. tularensis. Philip has called attention to his own experiences in Texas, Arkansas, and Oklahoma and to that of his colleague, Brennan, in Arkansas and Oklahoma, in which the evidence is strong that A. americanum is a natural vector in tularemia. Finally, Hopla7 has recently reported finding this tick in Arkansas naturally infected with Past. tularensis.
The horsefly, or deerfly, Chrysops discalis, is quite well known for its ability to transmit tularemia. A condition in man, observed years ago in Utah and associated with the bite of the deerfly, was referred to locally as "deerfly fever" but proved to be tularemia.
Aside from ticks and flies, other bloodsucking insects, such as lice and fleas, are capable of causing infection with Past. tularensis.
One of the notable characteristics of Past. tularensis is its ability to infect through the skin if there is the slightest amount of irritation of the epidermis. Indeed, the organism's capability in this respect is such that some investigators go so far as to ascribe to the bacterium the ability to infect through the unbroken skin.
Tularemia is well known as a disease which occurs in the United States, but it has also been reported from various other localities, including Mexico, Canada, several countries in Europe, and Japan. It is probably more widely distributed than published records indicate.
CLINICAL DESCRIPTION
The clinical picture of tularemia may assume one of several forms. The most common type consists of an initial local lesion which first appears as a skin papule that later ulcerates and is accompanied by enlargement, and sometimes suppuration, of the regional lymph glands. This form of the disease has been referred to as the ulceroglandular type. In some instances, tularemia infection is found to be confined to a group of lymph nodes in the area of initial entry of the organism but in which no frank, primary lesion occurs. This is generally spoken of as the glandular form of the malady. Tularemia in man may also begin as a conjunctivitis with subse-
6Parker, R. R.: Proc. Fifth Pacific Science Congress, p. 3371, 1933.
7(1) Hopla, C. E., and Downs, C. M. : The Isolation of Bacterium tularense From the Tick, Amblyomma americanum. J. Kansas Ent. Soc., Vol. 26, April 1953. (2) Hopla, C. E.: Experimental Studies on Tick Transmission of Tularemia Organisms. Am. J. Hyg. 58: 101-118, July 1953.
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quent involvement of the regional lymph nodes. This form has been designated as the oculoglandular type. The fourth type is one in which there is a general systemic infection without a primary local lesion or glandular enlargement. This is characterized as the typhoid form. Finally, there occasionally occurs a pneumonic type of tularemia which may start as an initial condition or may follow one of the other forms, especially the so-called typhoid type. Pulmonary involvement in tularemia, particularly if it is bilateral, ordinarily has a relatively high mortality rate.
INCIDENCE
There were 194 cases of tularemia recorded in the Army during the years 1942 to 1945, inclusive (table 14). For the 4-year period, the annual rates per 1,000 average strength were 0.01 for the total Army and the United States, and less than 0.005 for oversea theaters. The total Army annual rates were 0.01 for each year except 1945, which had a rate of less than 0.005. Among troops in the United States, the annual rates were 0.01 in each year except 1943, in which the rate was 0.02. All but 7 cases occurred in troops in the United States, principally in the Fourth and Eighth Service Commands. One case occurred in Alaska in 1942 and one in the Philippine Islands in 1940.
TABLE 14.-Number of cases of tularemia in the U.S. Army, by theater or area and year, 1942-45
Theater or area | 1942-45 | 1942 | 1943 | 1944 | 1945 |
Continental United States | 187 | 18 | 94 | 50 | 25 |
Overseas: |
|
|
|
|
|
| North America | 1 | 1 | --- | --- | --- |
| Europe | 5 | --- | --- | --- | 5 |
| Mediterranean | 1 | --- | --- | 1 | --- |
| Other areas | --- | --- | --- | --- | --- |
| Total overseas | 7 | 1 | --- | 1 | 5 |
| Total Army | 194 | 19 | 94 | 51 | 30 |
Tennessee Maneuver Area experience.-The largest single outbreak of tularemia in the military establishment during World War II occurred during the period from March to December 1943, in the Tennessee Maneuver Area. This outbreak consisted of 50 cases with 1 fatality. In classifying these cases, 35 were recorded as the ulceroglandular type, 11 as a pulmonic type, 3 as a glandular type, and 1 as a mixed ulceroglandular and pulmonic form.
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In 32 of the 50 cases, the patients gave a definite history of having had tick bites prior to the onset of illness. There were five who gave histories of having skinned, or otherwise had direct contact with, wild rabbits. The remaining 14 had no knowledge of having received tick bites and had no contact with wild rabbits or their tissues. It should be noted, however, that all of these men were in an area known to be highly tick infested. Consequently, it is reasonable to conclude that ticks were responsible for their infection.
Tick collections made in the Tennessee Maneuver Area in the summer of 1943 revealed that the predominating species was A. americanum. All the evidence points to this species as the important transmitting agent in this particular outbreak.
In those cases in which there were definite histories of tick bites, symptoms were reported as developing in from 1 to 21 days. The onset of the disease was acute in about one-half of the cases. Primary ulcers were recorded in 40 of the 50 cases. These were located on the arms, hands, lower extremities, buttocks, abdomen, scapular region, and perineum. Most of the patients had but one ulcer.
The symptoms characterizing these cases included fever of from 101? to 105? F.; headache; chills; generalized aching, more pronounced in the lower extremities and lumbosacral region; profuse sweats; painful lymph nodes; abdominal pains; marked weakness; severe prostration; nausea; dizziness; unproductive cough; and anorexia. Several of the more seriously ill patients had periods of delirium. In the pulmonary type, unproductive cough, chest pains, and dyspnea were prominent findings. A maculopapular eruption was present in a few of the cases. This involved the entire body but was most pronounced on the extremities. Pleural effusion developed in 9 of the 11 individuals with pulmonary cases, and, of those who had the ulceroglandular type, 2 developed a fibrinous pleurisy, and 3 developed pleural effusions. In all cases in which a local, primary lesion was found, there was enlargement of the regional lymph nodes. Adenitis was also observed in several cases in which there were no primary ulcers.
The course of the disease in these cases extended over a period of several weeks, and convalescence was protracted. A number of the patients were hospitalized for periods of from 3 to 6 months.
In the one fatal case, a soldier was admitted complaining of generalized aching, headache, sweating, fever, abdominal pain resembling colic, and diarrhea. Physical examination indicated an acutely ill but oriented individual with temperature of 103.6? F. and marked tenderness over the right costovertebral angle. The leucocyte count was 10,700, and urinalysis gave a 3+ albumin reading. Three days later, he developed an unproductive cough, pain in the right chest on inspiration, cyanosis, and dyspnea. Physical examination and radiologic study revealed evidence of consolidation in the right lower lobe and a widened mediastinum. The process rapidly pro-
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gressed and extended, involving both lungs, and a relatively large amount of pleural effusion developed in the left chest. The patient became delirious, the dyspnea and cyanosis increased, and death followed on the 10th day after onset of symptoms. Autopsy revealed extensive pneumonic involvement, with areas of necrosis and caseation. There was approximately a liter of cloudy, straw-colored fluid in the left chest. The mediastinum contained large masses of enlarged lymph nodes. These were purplish black in appearance and, while generally firm, contained areas of necrosis and caseation. The liver and spleen were greatly enlarged and contained areas of necrosis, and the liver revealed frank abscess formation.
The clinical diagnoses in the Tennessee Maneuver Area cases were confirmed by agglutination tests. Titers ranged from 1: 320 to 1: 10,240.
The treatment was symptomatic and supportive. The sulfonamides and antibiotics then available were of no demonstrable value.
The Medical Department of the Army took advantage of the occurrence of tularemia among troops in the Tennessee Maneuver Area to test, to a limited extent, various insect repellents then available, with a view to determining whether or not they were of value in preventing tickborne infections. The agents tested were dimethyl phthalate (Insect Repellent No. 612), Indalone, and the official Army louse powder. No evidence was obtained that any of these repellents were of value for the purpose.
LABORATORY DIAGNOSIS
For the specific diagnosis of tularemia, use is made of serologic tests, bacteriologic procedures, and the inoculation of guinea pigs, rabbits, or mice.
The blood agglutination test is valuable and is the procedure chiefly relied upon for diagnosis. The fact must be borne in mind, however, that serums from patients with tularemia may give cross-agglutination reactions with antigens prepared from Brucella abortus and Brucella melitensis. In tularemia, the agglutinins make their presence in the patient's blood about the second week of the infection, and the titer usually rises to its highest level between the third and eighth week. Generally, an agglutination titer of 1: 80 or higher is regarded as diagnostic of the disease, especially if the titer continues to rise as the disease progresses. Some cases develop titers ten to a hundred, or even a thousand, times that considered as the lowest for positive diagnosis. In cases of infection with Brucella species, the agglutination titer with Past. tularensis antigen is lower and the reaction occurs less rapidly, as compared to serums from individuals suffering from tularemia.
While in some instances Past. tularensis may be isolated in culture directly from the blood, local lesions, lymph nodes, pleural effusions, sputum, and so forth, of patients, failures are the common experience in these procedures.
In carrying out animal inoculation tests, guinea pigs, rabbits, or mice are inoculated subcutaneously or intraperitoneally with material from the primary
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lesion, regional lymph node, pleural effusion, sputum, or blood. In positive cases, the test animal usually succumbs within a week. Autopsy will reveal a hemorrhagic edema at the point of inoculation, enlargement and caseation of the lymph nodes, and the characteristic, small, necrotic focuses in the spleen and liver ("pepper-and-salt" liver). By use of a glucose-cystine-blood?agar culture medium, Past. tularensis may be recovered from the blood, liver, and spleen. The initial growth usually appears on the culture medium in about 3 days. Subcultures grow more rapidly and more luxuriantly.
A skin test using a detoxified preparation (Tularin) made with Past. tularensis has been reported of value for the diagnosis of tularemia. It is indicated that positive reactions can be obtained as early as the 3d or 4th day of the disease, which is several days earlier than an agglutination reaction may be expected. This intradermic test appears to be of considerable value but apparently has not been widely used.
THERAPY
As previously mentioned, the treatment of the tularemia cases which occurred in the Army during World War II was largely symptomatic and supportive. The sulfonamides and penicillin were used in a number of the cases, but there was no evidence that these agents possessed any specific value in the treatment of the disease. There is nothing in the records to indicate that specific serum, such as that developed by Foshay, was available or used in any of the cases which occurred among military personnel. Streptomycin, which is now considered specific treatment for tularemia, of course, was not available during World War II.
