Tularemia of the head and neck: A possible sign of bioterrorism. (Original Article).

Abstract

Recent bioterror attacks and other world events have focused the medical community's attention on agents that might be used in biological warfare. One of these potential biological weapons is Francisella tularensis, a gram-negative coccobacillus that is one of the most infectious bacteria known. F tularensis can cause severe, even fatal, systemic tularemia. Under normal circumstances, F tularensis is transmitted by infected ticks, insects, and other animals. As a weapon of terrorism, the bacterium would likely be disseminated as an aerosol and contracted by inhalation. Because many cases of tularemia are characterized by head and neck symptoms, otolaryngologists should be familiar with the diagnosis and management of this disease. In this article, we describe a case of zoonotic tularemia that manifested as a neck mass, and we review the pathophysiology, diagnosis, and treatment of tularemia. We also summarize what is known about its potential as a biological weapon.

Introduction

In the wake of the relatively recent anthrax bioterror attacks, otolaryngologists should realize the need for an increased awareness of the possible head and neck manifestations of bodily contamination by various biological agents that could be used by terrorists. Francisella tularensis, the causative organism in tularemia and other diseases, is considered by authorities to be a dangerous potential biological weapon because of its extreme virulence, its ease of dissemination, and its capacity to cause severe illness and death. (1) Between 11 and 45% of patients with tularemia have symptoms or signs localized to the head and neck region. (2-4)

Otolaryngologists are faced with the possibility that someday they might encounter patients who seek treatment for typical ear, nose, and throat complaints who have actually been exposed to an agent of bioterrorism, including F tularensis. Therefore, we believe it is instructive to review the case of a patient who came to our clinic with conventional zoonotic tularemia.

Case report

A 36-year-old man developed headache, malaise, and fever 1 week after he returned from a hiking trip to Yosemite National Park in northern California Three days after his initial symptoms appeared, he noticed a tender right-sided neck mass. The patient was positive for human immunodeficiency virus (HIV), but he had no history of opportunistic infections. He recalled no specific tick or insect bite, and he denied any knowledge of contact with rabbits or rabbit meat, the primary vectors in zoonotic transmission. He said that he had owned two cats for several years.

The patient first sought treatment from his primary care physician, who prescribed oral amoxicillin/clavulanate and referred him to our institution. By the time he came to our clinic, he had completed 5 days of his 7-day antibiotic regimen but showed no sign of improvement. Physical examination revealed that he had a 3 x 2-cm infra-auricular mass, which was characterized by excoriation, tenderness, and local edema; there was no sign of erythema or fluctuance. The patient's skin, scalp, and oropharynx exhibited no sign of ulceration. Findings on the remainder of the physical examination were unremarkable.

We initially diagnosed the patient's condition as catscratch fever, and we prescribed another week of amoxicillin/clavulanate. However, at the completion of the second week of antibiotic therapy, the patient had still not shown any improvement. We then performed fine-needle aspiration of the neck mass, which yielded 1.5 to 2 ml of serosanguineous fluid. Cytology demonstrated only abscess fluid; the aspirate was negative for acid-fast bacilli. The patient's white blood cell count was 7.9/[mm.sup.3] and his CD4 count was 814/[mm.sup.3].

Two days later, cytology again demonstrated abscess-type fluid. Gram's staining identified numerous neutrophils but no organisms. Bacterial culture of the fine-needle aspirate grew gram-negative rods. Meanwhile, the persistent neck mass began to exhibit overlying skin erythema and fluctuance. We performed incision and drainage of the abscess and packed the cavity. We then prescribed empiric ciprofloxacin at 500 mg orally twice a day. Within several days, all the patient's symptoms completely resolved.

Culture later identified the gram-negative bacteria as F tularensis type B. The patient completed a 4-week course of oral ciprofloxacin without complication or further symptoms. At the 6-month follow-up, he showed no sign of recurrence.

Discussion

F tularensis is a gram-negative coccobacillus that can cause a variety of diseases in humans, ranging from simple lymphadenopathy to rapidly progressive and fatal systemic illness. Two strains of F tularensis have been identified: type A and type B. In the United States, type A is the more common and more virulent strain.

Tularemia was first identified during an outbreak in Tulare County, Calif., in 1911. It was subsequently studied extensively by Francis, who first described it in 1928. (5) While the overall incidence of tularemia is low, sporadic outbreaks and epidemics have occurred in the United States and worldwide. (2) Despite the fact that between 11 and 45% of infections result in head and neck symptoms, (2-4) our search of the English-language otolaryngology literature since 1982 turned up only three journal articles that focused on tularemia. (3,4,6) Most ENT patients who are eventually found to have tularemia were originally referred to otolaryngologists for evaluation of head and neck signs and symptoms (e.g., pharyngitis, fever, and cervical lymphadenopathy) that had not responded to initial antibiotic therapy. (2,6)

Two distinct clinical forms of tularemia have been described: typhoidal and ulcero glandular. (1,7,8) The typhoidal form manifests as a systemic disease, and patients typically develop pneumonia and sepsis. The typhoidal form has fewer focal signs and a more ominous prognosis than does the ulceroglandular form. The ulceroglandular form is more common. Its hallmarks are a primary skin or pharyngeal mucosal ulceration and local lymphadenopathy; only rarely does it progress to systemic disease.

Transmission. The skin is the primary portal of entry for this virulent pathogen, which can cause disease with an inoculation of fewer than 50 organisms. The pathogen often penetrates the skin via a tick or insect bite. Infection can also occur following direct contact with the tissue of an infected animal, usually a rabbit. If used as a biological weapon, F tularensis would most likely be disseminated as an aerosol. Inhalation of the airborne particles would primarily lead to pleuropulmonary infection 3 to 5 days following exposure; only a small number of infections would occur as a result of exposures to the eye, skin, and oropharynx. (2,8)

Once zoonotic F tularensis penetrates the skin or mucosa, it usually incubates for 3 or 4 days (range: 2 to 14). (3) Patients typically develop a fever and a skin papule. The papule usually evolves into an ulcer, which is accompanied by regional lymphadenopathy. Otolaryngologists sometimes see patients whose only symptoms are fever and swelling of an isolated lymph node; in these cases, it is probable that the ulcer subsided without being noticed or that it quickly resolved following antibiotic treatment. (3) When F tularensis is acquired by eating undercooked contaminated meat, patients can develop oropharyngeal ulcers, sore throat, and pharyngeal erythema and exudate. With the oropharyngeal form, intestinal ulceration and mesenteric adenopathy can lead to additional symptoms, such as abdominal pain, nausea, vomiting, diarrhea, and even sepsis. (2-4)

Diagnosis. The diagnosis of tularemia is frequently delayed because of its relative rarity and the inconsistency of its characteristics (i.e., signs, symptoms, and laboratory test results). The most difficult cases that otolaryngologists encounter occur in those patients whose initial complaints are simply a neck mass and fever, with or without a resolution of skin or pharyngeal ulceration. (3,4,6) The differential diagnosis can be complicated by a positive HIV status and by the possibility of a bioterror attack.

Tularemia is usually diagnosed on the basis of elevated antibody agglutination titers. A result is positive when there is a four-fold increase in tularemia agglutination titers or when there is a single titer of 1:160 or greater. The white blood count is usually normal. Histopathology of lymph node tissues can demonstrate a variety of findings, from an acute abscess to chronic granulomatosis. Culture, however, is rarely useful because the intracellular pathogens grow poorly in standard culture media. Additionally, clinical laboratories are reluctant to isolate the pathogen because of the risk of accidentally infecting laboratory personnel. (2)

Treatment. The current treatment recommendations call for antibiotic therapy with an aminoglycoside (either streptomycin or gentamicin) or tetracycline. The fluoroquinolone ciprofloxacin has also been shown to be effective in patients who were treated empirically prior to diagnostic confirmation of tularemia. In two reports of a combined 16 cases over a 15-year period, a 100% cure rate was documented without evidence of relapse, albeit after highly variable treatment courses. (9,10) Ciprofloxacin has also been demonstrated to be highly effective against F tularensis both in vitro and in severely bacteremic animals, although some relapses occurred in the latter. (9,11) Another advantage of ciprofloxacin is that, unlike the other effective antimicrobials previously mentioned, it can be dosed orally and maintain good bioavailability. Most authors agree that a prolonged course (>10 days) of ciprofloxacin is necessary to prevent relapse. Surgical drainage of any fluctuant abscess is also indicated, as it was for o ur patient. (2)

Our HIV-positive patient had a mild infection, with a normal CD4 count and no history of opportunistic infection. Limaye and Hooper suggested that HIV-related immunosuppression in patients with tularemia increases the risk that patients will develop the more serious systemic (typhoidal) form of tularemia--even those patients who have the less virulent type B strain. (10) This increased risk again illustrates the importance of early diagnosis and treatment. Limaye and Hooper also found that ciprofloxacin was effective in treating tularemia in immunosuppressed patients. (10)

In conclusion, tularemia should be considered early in the differential diagnosis of patients with fever and cervical lymphadenopathy (particularly infra-auricular). Early diagnosis and treatment is especially important in potentially immunosuppressed patients. Although an isolated case of tularemia would not be particularly noteworthy, a substantial cluster of inhalational or pharyngeal tularemia might represent the consequences of a bioterror attack and warrant the notification of appropriate authorities.' Although clinical evidence is quite limited, the literature supports the use of an oral quinolone as an effective agent in the treatment of tularemia when intravenous antibiotics are not required or not tolerated and as an empiric agent when F tularensis is among the pathogens under consideration. More extensive testing of quinolones as a treatment for tularemia might become necessary in the future.

References

(1.) Dennis DT, Inglesby TV, Henderson DA, et al. Tularemia as a biological weapon: Medical and public health management. JAMA 2001;285:2763-73.

(2.) Evans ME, Gregory DW, Schaffner W, McGee ZA. Tularemia: A 30-year experience with 88 cases. Medicine (Baltimore) 1985;64:251-69.

(3.) Luotonen J, Syrjala H, Jokinen K, et al. Tularemia in otolaryngologic practice. An analysis of 127 cases. Arch Otolaryngol Head Neck Surg 1986;112:77-80.

(4.) Nordahl SH, Hod T, Scheel O, Olofsson J. Tularemia: A differential diagnosis in oto-rhino-laryngology, J Laryngol Otol 1993; 107:127-9.

(5.) Francis E. A summary of present knowledge of tularemia. Medicine (Baltimore) 1928;7:411-32.

(6.) Wills PI, Gedosh EA, Nichols DR. Head and neck manifestations of tularemia. Laryngoscope 1982;92:770-3.

(7.) Uhari M, Syrjala H, Salminen A. Tularemia in children caused by Francisella tularensis biovar palaearctica. Pediatr Infect Dis J 1990;9:80-3.

(8.) Richtsmeier WJ, Johns ME. Bacterial causes of granulomatous diseases. Otolaryngol Clin North Am 1982;15:473-92.

(9.) Scheel O, Reiersen R, Hod T. Treatment of tularemia with ciprofloxacin. Eur J Clin Microbiol Infect Dis 1992;11:447-8.

(10.) Limaye AP, Hooper CJ. Treatment of tularemia with fluoroquinolones: Two cases and review. Clin Infect Dis 1999:29:922-4.

(11.) Russell P, Eley SM, Fulop MJ, et al. The efficacy of ciprofloxacin and doxycycline against experimental tularaemia. J Antimicrob Chemother 1998;41:461-5.

From the Department of Otolaryngology--Head and Neck Surgery, University of California, San Francisco.

Reprint requests: Howard D. Stupak, MD, Department of Otolaryngology--Head and Neck Surgery, University of California, 400 Parnassus Ave., Suite A717, San Francisco, CA 94143. Phone: [phone]; fax: [phone]; e-mail: [e-mail]