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Chapter VI

Contents

CHAPTER VI

Bullis Fever

John C. Woodland, M.D.

During World War II, early in the spring of 1942, medical officers on duty in the Contagious Disease Section, Brooke General Hospital, Fort Sam Houston, Tex., first recognized that a disease entity1 with which they were dealing defied definite identification. There were several outstanding clinical features characterizing the illness: An initial chill followed by fever, an unusually low leukocyte count with an associated neutropenia, a severe postorbital and occipital headache, and lymphadenopathy. In all cases, there was evidence of multiple tick bites. All the patients comprising this group were soldiers of the Army Ground Forces of Fort Sam Houston who had been on maneuvers at Camp Bullis, Tex., a training area located some 20 miles from San Antonio.

When it became apparent that a condition existed presenting a problem in diagnosis, The Surgeon General was requested to furnish consultants especially qualified in that field of medicine which was related to the problem. In response to the request, three members of the Board for the Investigation and Control of Influenza and Other Epidemic Diseases in the Army arrived at Fort Sam Houston on 8 July 1942. After examining a number of the patients in the hospital suffering from the disease and after a minute scrutiny of the clinical records of those who had been under observation and treatment, the consultants agreed that this was a definite disease found only in those soldiers who had been on duty at Camp Bullis and who had been bitten by ticks.2 It was the Board's opinion that the epidemiological evidence associating this illness with the bite of the tick was highly suggestive but that the causative agent had not been conclusively identified nor could it be definitely shown at that time that the disease was transmitted to man through the tick as vector.

1It is not often that a new disease entity, including the causative infectious agent, and its insect vector are revealed with such clarity and in such short space of time. Consequently, this account of the discovery of "Bullis Fever," and the research studies conducted, will be read with intense interest. The author, Dr. John C. Woodland, in collaboration with Drs. M. M. McDowell and J. T. Richards, wrote the original article (see footnote 3, p. 158), calling attention to the new disease, while Army medical officers stationed at Brooke General Hospital, Fort Sam Houston, Tex., in 1943.-A. L. A.
2Letter, Kenneth F. Maxcy, M.D., Consultant to the Secretary of War, to The Surgeon General, 10 Aug. 1942, enclosure thereto, subject: Investigation of Cases of the Typhus-Spotted Fever Group, Station Hospital, Fort Sam Houston, Texas, July 18-25, 1942.


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CLINICAL MANIFESTATIONS

Woodland, McDowell, and Richards, in the original article on Bullis fever,3 described it briefly, as follows:

The illness was usually ushered in with an initial chill or a chilly sensation, which was soon followed by fever, the temperature ranging from 102 to 105 F. A great majority of the patients complained of severe headache located in the postorbital and occipital regions. Pronounced lassitude, prostration, anorexia, and general weakness were noted during the febrile stage of the disease, and occasionally there was nausea and vomiting. The fever lasted from 4 to 14 days and subsided by lysis. In the average case, the temperature remained elevated for 5 days. Convalescence was protracted, especially in the more severe cases. Loss of weight was observed in many of the patients, one patient losing as much as 20 pounds (9 kg.) within a fortnight. It has been established that the incubation period in Bullis fever is from 7 to 10 days.

PHYSICAL FINDINGS

There was usually a paucity of physical findings in patients with Bullis fever; however, enlargement of the lymph glands was characteristic. At times, only a regional group of glands were involved, but commonly there was general lymphadenopathy. The glandular involvement persisted throughout the acute stage of the illness and disappeared rather promptly with the clearing of the symptoms. The throat at times was slightly red and injected, but symptoms referable to the respiratory tract were notably absent. In the more severe forms of the disease, a maculopapular rash, involving the trunk and, later, the extremities, appeared during the febrile stage and usually disappeared completely within 48 hours. This fleeting eruption was similar to the rash seen in endemic typhus. In all instances, examination revealed multiple tick bites. Enlargement of the spleen was also noted in the more severe forms of the disease. Subconjunctival hemorrhage was found in the more seriously ill patients.

LABORATORY FINDINGS

A constant laboratory finding was a definite leukopenia occurring on or about the second or third day of illness, the leukocyte count dropping to 3,000 cells per cubic millimeter or less. With the abrupt drop in the total number of leukocytes, there was an associated neutropenia, the differential count showing polymorphonuclears as low as 23 percent. During the period

3Woodland, J. C., McDowell, M. M., and Richards, J. T.: Bullis Fever (Lone Star Fever-Tick Fever). An Endemic Disease Observed at Brooke General Hospital, Fort Sam Houston, Tex. J.A.M.A. 122: 1156-1160, 21 Aug. 1943.


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of convalescence, the leukopenia gradually disappeared and the differential count approached normal. All other laboratory procedures commonly performed showed no abnormal findings in Bullis fever. Complement fixation tests for Q fever, Rocky Mountain spotted fever, and endemic typhus fever yielded negative results. The Weil-Felix test, using Proteus X-19, X-2, and OX-K, was consistently negative. Agglutination determinations were uniformly negative for undulant fever, tularemia, typhoid fever, and paratyphoid fever. The heterophile antibody reaction was negative. Cultures of the blood were sterile. The spinal fluid was normal. Biopsy of enlarged lymph glands disclosed only lymphoid hyperplasia.

CLINICAL COURSE

The disease is self-limited in nature and varies from a mild febrile illness of short duration to a severe, debilitating, prolonged disease with a protracted convalescence. There have been two deaths attributed to Bullis fever. No form of therapy appears to affect the duration or severity of the illness. The sulfonamide drugs and penicillin have been used in a number of cases without apparent benefit.

EXPERIMENTAL LABORATORY STUDIES

During the spring and summer of 1943, about 485 cases of Bullis fever were observed at Brooke General Hospital. Livesay and Pollard,4 after exhaustive laboratory investigation of the disease, concluded-

1. That the clinical syndrome referred to as "Bullis Fever" has no immunological relationship to Rocky Mountain Spotted Fever.

2. That the disease does not appear to be typhus, based on guinea pig reactions, Weil-Felix reactions, and complement-fixation tests; nor "Q" fever, based on clinical syndrome and complement-fixation tests.

3. That a Rickettsia-like agent from clinical cases has thus far been passaged through three and five series of guinea pigs, inducing mild febrile reactions on the ninth to twelfth days, without orchitis.

4. That Rickettsia-like bodies have been observed in hyperplastic lymph nodes from men ill with this disease, and in guinea pigs killed during the febrile stage of the reaction.

5. That "Bullis Fever" is a previously undescribed syndrome in which Rickettsiae appear to be the etiological agent, without the development of a significant Weil-Felix reaction.

6. That it may be associated with an arthropod vector, the tick or Trombicular, in the Camp Bullis area.

7. Epidemiologically it appears that this disease is more severe and more prevalent in 1943 than in 1942. This maybe interpreted with qualifications as follows:

a. Either the agent is increasing in virulence as a result of repeated passage, or,

4Livesay, J. R., and Pollard, M.: Laboratory Report on a Clinical Syndrome Referred to as "Bullis Fever." Am. J. Trop. Med. 23: 475-479, September 1943.


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b. The human population being exposed to this disease is more susceptible: in the past the troops occupying this area have been largely local troops who perhaps had developed some degree of immunity. The latest exposures, and those in whom the disease has been rather severe and highly prevalent, are new troops, for the most part originating in relatively tick-free parts of the country such as Chicago or New York.

Shortly after this, Anigstein and Bader, working in their laboratories at the University of Texas, in Galveston, Tex., recovered a rickettsialike micro-organism from guinea pigs inoculated with Lone Star ticks (Amblyomma americanum) that had been collected at Camp Bullis.5 This micro-organism resembled the one found in patients by Livesay and Pollard, with regard to morphology, cultural characteristics, and behavior in laboratory animals.

The next laboratory work of importance which aided in establishing Bullis fever as a distinct entity was accomplished by Livesay and Pollard in the spring and summer of 1944.6 In this work, they attempted the serologic identification of Bullis fever and its differentiation from some of the known rickettsial agents. The lack of relationship between the agents of Bullis fever and those of Rocky Mountain spotted fever had already been demonstrated by a guinea pig challenge experiment. A suggestion of similarity in the clinical picture between Bullis fever and Q fever was then investigated and was not confirmed.

Serum specimens were collected from patients in whom the clinical diagnosis of Bullis fever was made. In addition, specimens of serum were collected from cases of unrelated diseases and from normal individuals as controls. Several species of animals from Camp Bullis were killed and serum specimens collected for examination. These included 40 deer, 7 rabbits, 2 raccoons, and 1 armadillo. All serum specimens were tested for Weil-Felix agglutination reaction and by the complement fixation test for endemic typhus, American Q fever, and Bullis fever. The antigen for Bullis fever was prepared by triturating with sand enlarged spleens of mice that had been infected experimentally with a strain of the microorganism isolated from a patient.

Of 192 specimens collected from soldiers who had recovered from illness diagnosed clinically as Bullis fever, 76 percent gave positive complement fixation for this disease. So also did 4 of the 40 deer specimens and 2 of the 7 rabbits. All of 29 specimens of normal human serum, 4 of endemic typhus, 3 of Rocky Mountain spotted fever, 4 of scrub typhus, and 2 of Q fever were negative in complement fixation tests with the Bullis fever antigen. This work established the specificity of the antigen and further confirmed the original opinion that Bullis fever was a distinct entity. It was the conclusion of the authors:

5Anigstein, L., and Bader, M. N.: Investigations on Rickettsial Diseases in Texas. Part 4. Experimental Study of Bullis Fever. Texas Rep. Biol. & Med. 1: 389-409, 1943.
6
Livesay, H. R., and Pollard, M.: Serological Studies of Bullis Fever. Am. J. Trop. Med. 24: 281-284, September 1944.


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1. The Bullis fever syndrome is not characterized by a significant Proteus OX-19, OX-K, or OX-2 agglutination reaction.

2. There does not appear to be any serological relationship between the rickettsia-like agent of Bullis fever and the rickettsia of American Q fever by the complement fixation tests.

3. From the results obtained, there does appear to be some significant serological relationship between the agent isolated from a human case of Bullis fever and the serums of convalescent cases.

Following the publication of this work, two more articles appeared, one on the specificity of Bullis fever rickettsia, by Bader and Anigstein,7 and the other by Blair and Bader, on experimental Bullis fever in man.8 Blair and Bader summarized their observations, as follows:

Two strains of the infectious agent recovered from human patients and from ticks of the Camp Bullis area were used for human experiments. Both strains had been maintained in guinea pig passage for a number of generations. Fresh or lyophilic material was used for the inoculum. All of the patients save one inoculated with these strains showed the syndrome of Bullis fever as described by Woodland and associates; however, most were of a mild nature. Patients inoculated with material isolated from ticks (A. americanum) showed the same reaction as those inoculated with the BH [Bullis human] strain. These results offer further evidence that the rickettsiae isolated from human patients (Livesay and Pollard, 1943) and from ticks (Anigstein and Bader, 1943) are specific for the disease diagnosed as Bullis fever.

During the summer of 1945, further experimental studies9 were conducted by Maj. M. Pollard, VC, Col. H. R. Livesay, MC, Capt. D. J. Wilson, MC, and Col. J. C. Woodland, MC, on duty at Fort Sam Houston. This experimental work was done with a view to acquiring further information about the nature of the Bullis fever syndrome, its etiology, mode of transmission, and immunologic relationship to other virus and rickettsial diseases. Human male volunteers were inoculated with various types of inoculum, as follows:

1. Whole blood from natural cases of the disease.

2. An agent derived from the blood of a natural human case of Bullis fever and propagated on chick embryo.

3. An agent, propagated on chick embryo, that was derived from emulsion of ticks (A. americanum) collected from deer at Camp Bullis.

4. Agents, both of human and of tick origin, to determine their immunologic relationship.

5. Laboratory strains of the agent of Bullis fever, to challenge the immunity of natural cases of the disease.

6. The agent of Colorado tick fever, to study the immunologic relationship to Bullis fever.

7Bader, M. N., and Anigstein, L.: Specificity of Bullis Fever Rickettsia. Texas Rep. Biol. & Med. 2: 405-412, 1944.
8Blair, R. K., and Bader, M. N.: Observations on Experimental Bullis Fever in Man. Texas Rep. Biol. & Med. 3: 105-111, 1945.
9Pollard, M., Livesay, H. R., Wilson, D. J., and Woodland, J. C.: Experimental Studies With Bullis Fever. Am. J. Trop. Med. 26: 175-187, March 1946.


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On the basis of the information obtained from these experimental studies, it was established that Bullis fever is a transmissible clinical syndrome which can be reproduced by transferring blood from a patient with the disease to a normal individual and that it can be maintained in series. It was also established that a syndrome was produced from the agent obtained from ticks (A. americanum) gathered at Camp Bullis that was indistinguishable from the syndrome in naturally acquired cases of Bullis fever and in the disease experimentally produced by a strain of human origin.

The critical phase of the problem was to determine the response of a convalescent case of the disease, acquired naturally, to the Bullis fever strain, propagated on chick embryo. Convalescent cases were challenged with the chick embryo material and were found immune. Controls developed the disease. It was thus established that a distinct immunologic relationship exists between the agent isolated from ticks and from human cases and the agent in naturally acquired cases of Bullis fever.

Since no relationship could be detected between Bullis fever and other known rickettsial diseases, attention was directed toward Colorado tick fever, as a disease similarly transmitted by ticks and characterized by a low leukocyte count. Challenge experiments with a known strain of Colorado tick fever agent10 in human volunteers immune to Bullis fever (acquired naturally and induced experimentally) failed to demonstrate any relationship between these two diseases.

The results of this work, and the conclusions drawn from it, may be summarized as follows:

1. The Bullis fever syndrome is a distinct clinical entity which may be reproduced in human subjects by the inoculation of blood from febrile cases of the disease.

2. The Bullis fever agent from the blood of febrile cases has been propagated on the yolk sac of the developing chick embryo. After 20 serial transfers on yolk sac, the agent so propagated reproduced the Bullis fever syndrome in human subjects.

3. The Bullis fever agent has been isolated from emulsion of ticks (A. americanum) from Camp Bullis and has been propagated on the yolk sac of the developing chick embryo. After propagation for 12 generations, the agent reproduced the Bullis fever syndrome in human subjects.

4. The same immunologic responses are induced by the agent from these several sources.

5. There is no immunologic relationship between the agent of Bullis fever and the agent of Colorado tick fever.

During the months of November and December 1945, further ex-

10Obtained through the courtesy and cooperation of Dr. Edward R. Mugrage and Dr. Lloyd Floria, University of Colorado School of Medicine, Denver, Colo.


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perimental work was accomplished by medical officers11 of Fort Sam Houston in an effort to distinguish between the Bullis fever syndrome and dengue fever. On the basis of a challenge experiment in human volunteers, no relationship between Bullis fever and dengue fever could be demonstrated.12 Some clinical similarity has been noted to the anicteric form of leptospirosis; further serologic studies should therefore be made to confirm or deny the possibility that a leptospiral infection is responsible.

Whatever doubt still remains about the causative agent, the evidence appears definite that the tick is the vector. It is the opinion of all those familiar with Bullis fever that future studies will show that this syndrome is not confined to one small geographic area in Texas but that it will be observed elsewhere in the United States, in regions where the tick A. americanum abounds; namely, the Mississippi Valley and many eastern States.

11Col. H. R. Livesay, MC, Maj. M. Pollard, VC, Maj. Donald J. Wilson, MC, Maj. Choice B. Matthews, MC, and Capt. Sidney M. Cohen, MC.
12Livesay, H. R., Wilson, D. J., Pollard, M., and Woodland, J. C.: Experimental Studies of Bullis Fever and Dengue Fever. Am. J. Trop. Med. 26: 379-381, July 1946.

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