sign in sign up
<<
Home , Rickettsialpox

MILITARY MEDICINE, 169, 11:863, 2004

Bullis Fever: A Vanished Infection of Unknown Etiology

Guarantor: COL David P. Dooley, MC USA Contributors: MAJ Clinton K. Murray, MC USA; COL David P. Dooley, MC USA

Camp Bullis, Texas, is an active training facility for the U.S. yond discharge. Patients were not anemic. Several patients had Army and Air Force with a storied history dating back to the trace albuminuria. The clinical reports did not record values for late 19th century. In the early 1940s, an epidemic of a seasonal any liver-associated enzymes (not yet developed) or platelet -borne rickettsial-like illness occurred at Camp Bullis; the last case was reported in 1947. To date, the etiology of this counts. Although defervescence was abrupt, convalescence was disease has remained elusive. In an attempt to retrospectively protracted. One death occurred and was attributed to “agranu- Downloaded from https://academic.oup.com/milmed/article/169/11/863/4283599 by guest on 30 September 2021 identify the causal pathogen, we surveyed Camp Bullis for the locytic angina and sepsis.”4 Treatment was mostly supportive presumed tick vector with intent to screen molecularly for and consisted of codeine, aspirin, ice, rest, and fluids. Thirteen and Ehrlichia. However, no were recovered of the 47 patients managed in 1944 were treated with penicillin from primary dragging attempts in the spring or from har- without apparent benefit.5 One patient failed to respond to sulfa vested deer in the fall. Moreover, pathologic and microbiologic drugs and penicillin, but appeared to improve after administra- materials obtained during the epidemic are no longer extant, making them unavailable for analysis. In this study, we review tion of p-aminobenzoic acid, an agent then used in the treat- 7 potential circumstances that impact emerging and, in this ment of rickettsial disease. case, vanishing infections. The etiology of Bullis fever will The presence of “small intracellular (organisms) similar in probably remain undetermined, and this once-emerging infec- morphology to Rickettsia” in patients’ blood and lymph tissue, tion may have vanished into history. However, given Camp along with epidemiological evidence supporting the Lone Star Bullis’ status as an active medical training site, awareness of tick, , as the vector were suggestive of and surveillance for the disease should continue. tick-borne infection.2,8 However, studies performed at that time Historical Perspective at the Brooke General Hospital and other reference laboratories were negative for , Rocky Mountain , en- ullis fever was a rickettsial-like illness that occurred in demic , , and rickettsialpox.2,9 Additional stud- B World War II troops training at Camp Bullis, Texas, 18 ies for , , malaria, Epstein-Barr virus, miles northwest of San Antonio.1 This seasonal disease, first , dengue fever, and lymphocytic choriomen- noted in the spring and summer of 1941, was diagnosed in more ingitis virus were also nondiagnostic. than 1,000 U.S. Army soldiers, causing one death.2 The disease Additional support for the existence of a distinct, tick-borne, incidence peaked in 1943 with 485 cases, dropping to 18 cases rickettsial-like organism as the cause of Bullis fever was pro- in 1945 when the number of troops training was significantly vided by extensive animal, insect, and human studies con- curtailed.2–6 The last recognized case was reported in 1947.7 ducted in the 1940s.2,9,10 A “rickettsial-like” organism was ob- Bullis fever was characterized by a 7- to 10-day incubation served in emulsified A. americanum ticks and in guinea pigs period followed by 4 to 14 days of symptoms.1,2 Symptoms de- inoculated with blood or lymph glands from patients with Bullis veloped abruptly, with an initial chill followed by fevers and fever. Moreover, human volunteers developed a clinical illness postorbital or postoccipital headaches. Patients often had consistent with Bullis fever after challenge with whole blood marked, generalized that resolved once the isolates from Bullis fever patients, emulsions from A. america- fever abated. Up to 10% of the cases, generally those with more num ticks, or from human or tick strains of the presumptive severe symptoms, had a maculopapular rash predominately Bullis fever organism propagated in chick embryos or mice. involving the trunk. Multiple tick bites were commonly evident. Despite these suggestive studies, however, analysis of more A constant finding among patients with Bullis fever was leu- than 10,000 ticks and 2,500 from Camp Bullis revealed kopenia with associated neutropenia occurring on or about the no contemporarily known pathogen in such frequency that Bul- second or third day of symptoms. The total white blood cell lis fever could be ascribed to it. count frequently dropped to ϳ3,000/␮L and occasionally to as The Army drastically reduced the number of troops training at low as ϳ1,750/␮L. The leukopenia gradually resolved during Camp Bullis by 1944 because of this disease, a process that convalescence; however, a relative lymphocytosis persisted be- accelerated with the military demobilization after 1945.3 Conse- quently, the incidence of Bullis fever plummeted, with no re- Department of Medicine, Infectious Disease Service, Brooke Army Medical Center, ported case evident after 1947. Concurrently, a major effort to Fort Sam Houston, TX 78216. eliminate ticks from infected areas of Camp Bullis with dichlo- Reprints: MAJ Clinton K. Murray, Infectious Diseases Service, Brooke Army Med- ridphenyltrichloroethane was undertaken.3 The disease was no ical Center, MHCE-MDI, 3851 Roger Brooke Drive, Fort Sam Houston, TX 78234- 2000. longer considered a risk to the welfare of troops and because the This work was presented at the 52nd Annual Conference on Diseases in Nature presumptively identified agent of Bullis fever could not be fur- Transmissible to Man, June 12–13, 2002, Houston, TX. ther characterized by the contemporary techniques, investiga- The opinions or assertions contained herein are the personal views of the authors tions ended. and should not be construed as reflecting the official positions of the Department of the Army or the Department of Defense. Training intensified at Camp Bullis approximately 10 years This manuscript was received for review in June 2003. The revised manuscript was later. In the interim, cases of Bullis fever were not observed in accepted for publication in December 2003. the few assigned caretaker military personnel. Tick and wildlife

863 Military Medicine, Vol. 169, November 2004 864 Bullis Fever surveys in 1978 showed no evidence of brucellosis, tularemia, or mammals). Ultimately, our attempts to collect ticks from varied Rocky Mountain spotted fever. More recent tick surveys per- areas on Camp Bullis using several methods over two distinct formed in 1987 failed to reveal or Rocky Mountain seasons were unsuccessful. spotted fever (J. Longfield, unpublished data). Other pathogens have since been proposed as potential Discussion agents of Bullis fever, and new technologies have invited retro- spective investigation. For example, polymerase chain reaction Bullis fever was a prototypical emerging infectious disease 60 amplification with primers specific for years ago. This disease was a remarkable harbinger of other against DNA extracts from 106 ticks collected and preserved rickettsial infections, such as , that would later be cited as examples of emerging infectious diseases. Bullis fever during the outbreak proved negative (C. Paddock and J. God- was unique among rickettsial-like diseases because of the pres- dard, unpublished data). However, these results may be ambig- ence of lymphadenopathy, lymphocytosis, and a restricted geo- uous because the ticks had been preserved in ethanol for more graphic distribution.11 However, Bullis fever was also unique Downloaded from https://academic.oup.com/milmed/article/169/11/863/4283599 by guest on 30 September 2021 than 50 years and there was evidence of DNA degradation. because of its status as a once-emerging disease that has ap- Although Camp Bullis was used as a combat training post parently vanished. when it initially opened in 1890, since the 1970s it has been Other infectious diseases, such as malaria, dengue fever, and used primarily for training medical personnel. Camp Bullis is diphtheria, have waxed and waned tremendously in prevalence, the premier training site for the Army Medical Department Cen- earning the status of emerging, diminishing, or re-emerging ter and School. Almost universally, every person in the Army entities. Only smallpox has truly vanished because of human Medical Department, and many from the Navy and Air Force intervention.12 Variations in factors such as ecology, human medical services, undergo training at Camp Bullis. Although no demography and behavior, international travel, technology and cases of Bullis fever have been reported recently, an assessment industry, microbial adaptation, and change and breakdown of was undertaken to determine what the original agent responsi- public health measures all occur with enough regularity to in- ble for the disease was and if the possibility of transmission troduce emerging infections, but they rarely cause infections to might persist today. utterly vanish.13 Camp Bullis was an underoccupied military training area until a rapid influx of troops occurred at the beginning of World Current Investigations War II. We suspect that this radical change in demographics, with the sudden proximation of a large human population with To determine whether biologic samples were still available, we a presumed tick vector, was responsible for the emergence of contacted the laboratories involved in the original investigation this unique disease. We also suspect that several of the afore- in the 1940s. Unfortunately, none of these institutions (Univer- mentioned factors then culminated in the disappearance of Bul- sity of Texas Medical Branch, Galveston, Texas; Texas Depart- lis fever. First, the unique ability of the military to entirely ment of Health; Rocky Mountain Laboratory, U.S. Public Health abandon the area at Camp Bullis for other available training Service, Hamilton, Montana; and our own institution, Brooke locations drastically changed demographics. Second, dramatic Army Medical Center [formerly Brooke General Hospital], Fort changes in vegetation and wildlife in the area resulted from a Sam Houston, Texas) had retained any specimens for the 50 prolonged drought that occurred in the 1950s in Texas,14 along years since they were collected. The Armed Forces Institute of with ongoing man-made alterations of the terrain at Camp Bul- Pathology (Washington, DC), which was recorded as having lis for the reintroduction of training. Third, there has been a been sent autopsy specimens from the single soldier who died notable decline in the presumed tick vector population at Camp from the disease, in fact never received the specimens (G. Wag- Bullis over the past six decades. Our inability to isolate a single ner, personal communication). We were also unsuccessful in tick with multiple attempts in 2001 stands in marked contrast obtaining serologic evidence of previous rickettsial or ehrlichial to, for example, the 910 adult ticks and 1,160 nymphs collected infection from volunteers who participated in the Bullis fever from two deer and the 294 ticks removed from one patient challenge trials.10 during the epidemic.2 We hypothesize that the presumed tick Because there were no residual pathologic or microbiologic vector, A. americanum, could not survive the triple pressures of samples from the initial outbreak, we attempted to define the the alteration in vegetation and wildlife,15 the appearance in etiology of Bullis fever by obtaining ticks from Camp Bullis to Texas at that time of the fire ant, a known predator of ticks,16,17 test them for agents that could conceivably cause this syn- and the use of dichloridphenyltrichloroethane.3 Finally, no ill- drome. In May 2001, we dragged for ticks and used dry ice traps ness reminiscent of Bullis fever has heretofore been described in five geographically distinct areas at Camp Bullis between and the responsible pathogen may not have existed outside of dawn and late morning. May was the month of the original the limited geographical area of south Texas; if so, this lack of epidemic when transmission was the highest. Not a single tick geographical flexibility may have limited the fitness of the patho- was harvested. Given that deer appeared to have been the prin- gen to survive severe stresses in this region. We suspect that it ciple host of the tick during the Bullis fever epidemic,2 we also was the cumulative effect of all of these factors that was respon- attempted to collect ticks from hunter-harvested deer during sible for the fate of Bullis fever—the apparent disappearance of December 2001, early in hunting season. Of 10 deer taken from the disease. Sanguinity with this result is unwarranted, how- multiple sites on Camp Bullis, not a single tick was found (al- ever, as has been demonstrated repeatedly with the reappear- though the season was possibly late enough that even in south ances of Ebola hemorrhagic fever in central Africa from reser- Texas, few adult ticks might be expected to be found on large voirs unknown.13 The absence of Bullis fever may merely reflect

Military Medicine, Vol. 169, November 2004 Bullis Fever 865 our inability to detect a very low level presence of the organism, 5. Annual Report of the Brooke General Hospital, Fort Sam Houston, TX, 1944, pp also in reservoirs unknown. We continue our educational and 21–2. surveillance efforts within our system in the anticipation of a 6. Annual Report of the Brooke General Hospital, Fort Sam Houston, TX, 1945, pp 95–8. possible resurrection of the disease. 7. Arnold WT, Van Noate HF: Bullis fever: report of a case treated with para- In summary, historical accounts support the existence of a aminobenzoic acid. Bull US Army Med Dept 1949; 9: 218–23. distinct rickettsial-like, tick-borne infection that was recognized 8. Livesay HR, Pollard M: Laboratory report on a clinical syndrome referred to as as Bullis fever. The causative agent was incompletely character- bullis fever. Am J Trop Med 1943; 23: 475–9. ized. We were unable to retrospectively implicate a pathogen by 9. Livesay HR, Pollard M: Serological studies of bullis fever. Am J Trop Med 1944; modern forensic microbiologic or pathologic techniques because 24: 281–4. 10. Pollard M, Livesay HR, Wilson DJ, Woodland JC: Experimental studies with bullis of the lack of stored contemporary samples as well as the dis- fever. Am J Trop Med Hyg 1946; 26: 175–87. appearance of the tick vector that probably served as the reser- 11. Eng TR, McDade JE, Fishbein DB: Was bullis fever actually Ehrlichiosis? In reply. voir. This infection was an excellent early example of an emerg- JAMA 1988; 260: 3006–7. ing infectious disease that is also unique for having apparently 12. Satcher D: Emerging infections: getting ahead of the curve. Emerg Infect Dis Downloaded from https://academic.oup.com/milmed/article/169/11/863/4283599 by guest on 30 September 2021 vanished. 1995; 1: 1–6. 13. Morse SS: Factors in the emergence of infectious disease. Emerg Infect Dis 1995; 1: 7–15. References 14. Bomar GW: Heat waves and drought: legacy of a Texas summer. In: Texas Weather, pp 143–56, Ed 1. Edited by Bomar GW. Austin, TX, University of Texas 1. Woodland JC, Richards JT: Bullis fever (lone star fever, tick fever). JAMA 1943; Press, 1983. 122: 1156–60. 15. Semtner PJ, Barker RW, Hair JA: The ecology and behavior of the lone star tick 2. Anigstein L, Anigstein D: A review of the evidence in retrospect for a rickettsial (Acarina:Ixodidae). II. Activity and survival in different ecological habitats. J Med etiology in bullis fever. Tex Rep Biol Med 1975; 33: 201–11. Entomol 1971; 8: 710–25. 3. Camp Bullis: Admirably Suited to All Purposes of Military Training. A history of 16. Burns EC, Melancon DG: Effect of imported fire ant (Hymenoptera:Formicidae) the Leon Springs Military Reservation, 1890–1990. Fort Sam Houston Museum, invasion on lone star tick (Acarina:Ixodidae) populations. J Med Entomol 1977; Fort Sam Houston, TX. 14: 247–9. 4. Annual Report of the Brooke General Hospital, Fort Sam Houston, TX, 1943, pp 17. Drees B: Spread of the imported fire ant. Available at http://agnews.tamu.edu/ 20–4. graphics/fireants/antspred.html; accessed May 22, 2003.

Military Medicine, Vol. 169, November 2004