Bullis Fever: A Vanished Infection of Unknown Etiology

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. Army and Air Force with a storied history dating back to the late 19th century. In the early 1940s, an epidemic of a seasonal tick-borne rickettsial-like illness occurred at Camp Bullis; the last case was reported in 1947. To date, the etiology of this disease has remained elusive. In an attempt to retrospectively identify the causal pathogen, we surveyed Camp Bullis for the presumed tick vector with intent to screen molecularly for Rickettsia and Ehrlichia. However, no ticks were recovered from primary dragging attempts in the spring or from harvested deer in the fall. Moreover, pathologic and microbiologic materials obtained during the epidemic are no longer extant, making them unavailable for analysis. In this study, we review potential circumstances that impact emerging and, in this case, vanishing infections. The etiology of Bullis fever will probably remain undetermined, and this once-emerging infection may have vanished into history. However, given Camp Bullis’ status as an active medical training site, awareness of and surveillance for the disease should continue. Historical Perspective ullis fever was a rickettsial-like illness that occurred in B World War II troops training at Camp Bullis, Texas, 18 miles northwest of San Antonio. This seasonal disease, first 1 noted in the spring and summer of 1941, was diagnosed in more than 1,000 U.S. Army soldiers, causing one death.2 The disease incidence peaked in 1943 with 485 cases, dropping to 18 cases in 1945 when the number of troops training was significantly curtailed.2–6 The last recognized case was reported in 1947.7 Bullis fever was characterized by a 7- to 10-day incubation period followed by 4 to 14 days of symptoms.1,2 Symptoms developed abruptly, with an initial chill followed by fevers and postorbital or postoccipital headaches. Patients often had marked, generalized lymphadenopathy that resolved once the fever abated. Up to 10% of the cases, generally those with more severe symptoms, had a maculopapular rash predominately involving the trunk. Multiple tick bites were commonly evident. A constant finding among patients with Bullis fever was leukopenia with associated neutropenia occurring on or about the second or third day of symptoms. The total white blood cell count frequently dropped to ⬃3,000/␮L and occasionally to as low as ⬃1,750/␮L. The leukopenia gradually resolved during convalescence; however, a relative lymphocytosis persisted beDepartment of Medicine, Infectious Disease Service, Brooke Army Medical Center, Fort Sam Houston, TX 78216. Reprints: MAJ Clinton K. Murray, Infectious Diseases Service, Brooke Army Medical Center, MHCE-MDI, 3851 Roger Brooke Drive, Fort Sam Houston, TX 782342000. This work was presented at the 52nd Annual Conference on Diseases in Nature Transmissible to Man, June 12–13, 2002, Houston, TX. The opinions or assertions contained herein are the personal views of the authors and should not be construed as reflecting the official positions of the Department of the Army or the Department of Defense. This manuscript was received for review in June 2003. The revised manuscript was accepted for publication in December 2003. yond discharge. Patients were not anemic. Several patients had trace albuminuria. The clinical reports did not record values for any liver-associated enzymes (not yet developed) or platelet counts. Although defervescence was abrupt, convalescence was protracted. One death occurred and was attributed to “agranulocytic angina and sepsis.”4 Treatment was mostly supportive and consisted of codeine, aspirin, ice, rest, and fluids. Thirteen of the 47 patients managed in 1944 were treated with penicillin without apparent benefit.5 One patient failed to respond to sulfa drugs and penicillin, but appeared to improve after administration of p-aminobenzoic acid, an agent then used in the treatment of rickettsial disease.7 The presence of “small intracellular (organisms) similar in morphology to Rickettsia” in patients’ blood and lymph tissue, along with epidemiological evidence supporting the Lone Star tick, Amblyomma americanum, as the vector were suggestive of tick-borne infection.2,8 However, studies performed at that time at the Brooke General Hospital and other reference laboratories were negative for Q fever, Rocky Mountain spotted fever, endemic typhus, tularemia, and rickettsialpox.2,9 Additional studies for brucellosis, typhoid fever, malaria, Epstein-Barr virus, Colorado tick fever, dengue fever, and lymphocytic choriomeningitis virus were also nondiagnostic. Additional support for the existence of a distinct, tick-borne, rickettsial-like organism as the cause of Bullis fever was provided by extensive animal, insect, and human studies conducted in the 1940s.2,9,10 A “rickettsial-like” organism was observed in emulsified A. americanum ticks and in guinea pigs inoculated with blood or lymph glands from patients with Bullis fever. Moreover, human volunteers developed a clinical illness consistent with Bullis fever after challenge with whole blood isolates from Bullis fever patients, emulsions from A. americanum ticks, or from human or tick strains of the presumptive Bullis fever organism propagated in chick embryos or mice. Despite these suggestive studies, however, analysis of more than 10,000 ticks and 2,500 mites from Camp Bullis revealed no contemporarily known pathogen in such frequency that Bullis fever could be ascribed to it. The Army drastically reduced the number of troops training at Camp Bullis by 1944 because of this disease, a process that accelerated with the military demobilization after 1945.3 Consequently, the incidence of Bullis fever plummeted, with no reported case evident after 1947. Concurrently, a major effort to eliminate ticks from infected areas of Camp Bullis with dichloridphenyltrichloroethane was undertaken.3 The disease was no longer considered a risk to the welfare of troops and because the presumptively identified agent of Bullis fever could not be further characterized by the contemporary techniques, investigations ended. Training intensified at Camp Bullis approximately 10 years later. In the interim, cases of Bullis fever were not observed in 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 Rocky Mountain spotted fever. More recent tick surveys performed in 1987 failed to reveal Lyme disease or Rocky Mountain spotted fever (J. Longfield, unpublished data). Other pathogens have since been proposed as potential agents of Bullis fever, and new technologies have invited retrospective investigation. For example, po (...truncated)