Neck Mass: Tularemia Misdiagnosed as a Possible Malignancy

Abstract

Background:

Tularemia is a zoonotic disease of the Northern Hemisphere caused by Francisella tularensis. Given its diverse animal reservoir and wide range of transmission modes, a thorough history of potential exposure is paramount. In the right context, fever combined with skin eruption and lymphadenopathy should raise the possibility of tularemia. Additionally, health care providers should be mindful that F. tularensis is a risk group 3 pathogen and a category A bioterrorism agent and presents a risk for laboratory personnel due to its aerosolization potential, low infectious dose, and fatality rate ranging from 2% to 60%.

Method:

Retrospective single chart review.

Results:

We describe a 65-year-old man with tularemia working as a bear-hunting guide whose management was delayed despite a fairly typical presentation due to lack of awareness regarding this disease. This case also demonstrates the need for safer referral practices and improved communications with the laboratory to ensure personnel are taking the appropriate measures while handling patient samples to avoid potentially serious consequences.

Conclusion:

The diagnosis was confirmed from a neck mass biopsy and the patient made a complete recovery with appropriate antibiotic treatment.

Case Presentation

A 65-year-old man with diabetes, hypertension, and coronary artery disease presented with a 2-week history of worsening fatigue, fever, night sweats, cervical tenderness, and a 7 kg weight loss (9% of body weight). The patient had spent several weeks in the Interlake region of Manitoba (Canada) as a bear-hunting guide, but given the severity of his symptoms, he interrupted his trip to visit an emergency department in rural Manitoba. In the weeks prior to becoming symptomatic, he reported multiple tick, mosquito, and deer fly bites, and had skinned over 15 bears with only intermittent use of personal protective equipment. In addition, he was exposed to lake water while bathing and brushing his teeth; however, he denied drinking lake or river water. He reported a more remote history of hunting and eating rabbit, caribou, and moose meat.

On initial presentation to the rural hospital, he was lethargic with an oral temperature spiking up to 39.4°C. He had large and tender bilateral cervical nodes, with the left node being much larger than the right (Figure 1). A non-pruritic maculopapular skin eruption (Figure 2a and 2b) was distributed from head to toe. Leucocyte count was 17.1 × 10⁹/L. Computed axial tomographic (CT) scans of the neck and chest were remarkable for numerous bilateral enlarged necrotic cervical lymph nodes, the largest of which was 3.7 × 3.3 cm (Figure 3). There was also supraclavicular lymphadenopathy and pharyngeal mucosal enhancement with submucosal edema.

Figure 1: Bilateral lymphadenopathy, left side being more prominent and from which a fine-needle aspiration was performed.

Figure 2a and 2b: Head-to-toe non-pruritic maculopapular eruption.

Figure 3: Axial contrast-enhanced computed tomography (CT) image of the neck.

The emergency physician was concerned about an infectious process and undertook a telephone consultation with the on-call infectious diseases physician, who provided a broad differential diagnosis, including tularemia, Lyme disease, brucella, and Q fever. He recommended obtaining serologic investigations for these potential pathogens as well as immediately starting intravenous gentamicin and ceftriaxone. When the radiologist who interpreted the CT scan raised the high possibility of metastatic cancer, however, the antimicrobial therapy was stopped and the patient transferred for an otolaryngology opinion. Endoscopy showed a non-purulent, patent airway and medialization of the left oropharyngeal wall. Fine-needle aspiration of the most prominent node was performed, and specimens were submitted for cytology and culture.

Diagnosis

Following the fine-needle aspiration, cytology reported numerous mixed inflammatory cells, consistent with abscess formation. Gram stain showed a heavy amount of polymorphonuclear cells and no organisms. The microbiology requisition provided only minimal clinical information (“neck swelling” was written in the clinical section). Three days later, fine cream-colored colonies grew on chocolate agar only. The possibility of Francisella tularensis was immediately considered due to the slow-growing and fastidious nature of the organism, and a Gram stain of the colonies performed in a biosafety cabinet demonstrated gram-negative coccobacilli (Figure 4). Once F. tularensis was suspected, the culture was moved into a class II A2 biosafety cabinet. No laboratory exposures occurred as the cultures were placed into containment in accordance with laboratory protocols. F. tularensis was confirmed by Matrix Assisted Laser Desorption Ionization–Time of Flight (MALDI-TOF) (Bruker, Massachusetts, USA) following inactivation using ethanol, acetonitrite, and formic acid. No additional testing was performed on the isolate as the laboratory has abandoned the use of rapid biochemical tests (eg, oxidase, catalase) for the exclusion of Francisella sp in favour of using MALDI-TOF after chemical inactivation.

Figure 4: Gram stain showing characteristic pleomorphic coccobacillary forms of Francisella tularensis.

Following identification of F. tularensis (eventually subspeciated as holarctica), the patient was asked to return to the hospital, where he was treated with intravenous gentamicin (prescribed for 10 days) and oral doxycycline (prescribed for 3 weeks). The patient showed clinical improvement within a day. He was discharged from the hospital after 5 days of observation and completed his IV treatment as an out-patient. Upon follow-up nearly 3 months after discharge, bilateral non-tender cervical lymphadenopathy, while still present, was continuously improving in size. Most other symptoms were completely resolved, apart from mild fatigue. He was then seen in follow-up 7 months after completing his treatment. At that point, his symptoms and lymphadenopathy had completely resolved.

Discussion

Francisella tularensis is a small, fastidious, gram-negative coccobacillus causing tularemia, also known as rabbit or deer-fly fever (1). Tularemia is a zoonotic disease of the Northern Hemisphere, with over 100 vertebrates and invertebrates acting as reservoirs (1–3). Common invertebrate reservoirs include ticks, deer flies, and mosquitoes. Vertebrates such as rodents and lagomorphs, birds, fish, and bears may also serve as hosts (2,4). This large reservoir translates into multiple transmission modes, each of which is associated to a particular clinical presentation (Table 1) (1,2,5). Given the clinical presentation, the patient in this case likely had a glandular tularemia. Clinical disease usually presents after an incubation period of 3–5 days with a sudden onset of general malaise and fever, accompanied by a painful regional lymphadenopathy, with necrosis and liquefaction, that can last up to 6 weeks without treatment (1,5).

Table 1:

Overview of tularemia clinical forms (1,2,5)

Clinical form	Incidence (USA)	Transmission mode	Specific presentation	Main location of lymphadenopathy
Ulceroglandular	80%	• Arthropod bite • Direct skin contact	Ulcers at the site of inoculation, suppurative lymphadenopathy	Variable, depending on site of inoculation
Glandular	15%	• Arthropod bite • Direct skin contact	Suppurative lymphadenopathy, in the absence of identifiable skin ulcer	Variable
Oropharyngeal	<5%	• Ingestion of undercooked meat • Contaminated water	Sore throat and dysphagia	Cervical, preparotid, and retropharyngeal
Oculoglandular	1%	• Ocular inoculation of contaminated material	Conjunctival hyperemia, purulent discharge, keratitis, episcleritis, dacryocystitis, uveitis	Submandibular and pre-auricular
Typhoidal	Rare	• Ingestion of contaminated water	Mimics typhoid fever: severe fever, abdominal pain, sepsis	Mesenteric
Pneumonic	Rare	• Inhalation of contaminated aerosols • Hematogenous spreading from glandular or typhoidal infections	Pneumonia with multiple ill-defined infiltrates	Hilar

The species Francisella tularensis contains multiple subspecies. In North America, the more virulent type A (F. tularensis subsp tularensis) is the most frequently isolated subspecies, responsible for 60% to 90% of cases. Type B (F. tularensis subsp holarctica) causes a milder disease and is more frequent in Europe and Asia (1).

Secondary eruptions, such as the ones described in this report, are found in nearly half of patients with tularemia (6). They are non-specific, most often papular or maculopapular; additional cutaneous manifestations include erythema nodosum, erythema multiforme, or macular, pustular, or vesicular lesions (6,7). Nearly 20% of patients develop an erythema covering the affected lymph nodes (6). This highlights the importance of recognizing skin lesions and considering tularemia in the differential when patients living in endemic areas with compatible exposures present with a rash and acute lymphadenopathy.

Francisella tularensis presents a risk for laboratory personnel due to its aerosolization potential and low infectious dose: less than 10 organisms when inhaled or up to 10⁶ to 10⁸ when ingested (3,8). The case fatality rate for all forms is approximately 2% (8), but if not recognized and treated promptly, the mortality associated with the most severe forms (pneumonic and typhoidal) can reach up to 60% (9). These characteristics make F. tularensis worrisome enough that it is classified as a category A (of highest concern) bioterrorism agent (3,9). This emphasizes the need to warn laboratory personnel when a case is suspected so that it can be handled at the correct biosafety levels as per national guidelines and to establish clear protocols for laboratory personnel to recognize potential category A agents by their microbiological characteristics (3,9). Our case illustrates the need for increased awareness of the disease and improved communication with the laboratory. Providing additional information on the microbiology request, such as suspected pathogens or diagnosis, could enable laboratory personnel to take appropriate safety measures sufficiently early in the process to avoid potentially serious consequences.

Prevention of community-acquired tularemia can be achieved through measures targeting the diverse modes of transmission. Gloves and practising hand hygiene must be used when handling dead or sick animals (10,11). Measures to prevent tick and fly bites, such as wearing long-sleeve shirts and pants and closed shoes and using insect repellent, should be employed, as well as performing a thorough examination of skin for ticks after potential exposure (10–12). Untreated water and undercooked meat should not be consumed (11). Finally, if possible, aerosol-generating activities in potentially risky situations, such as mowing the lawn nearby dead animals, is recommended (10,11).

Treatment options include gentamicin, streptomycin, ciprofloxacin, doxycycline, and chloramphenicol (13,14). No modern systematic, randomized trials exist to guide the therapy of tularemia. Patients presenting with F. tularensis have traditionally been treated successfully with aminoglycosides, fluoroquinolones, and tetracycylines (13). F. tularensis is intrinsically resistant to penicillin. Treatment failures have also occurred with cephalosporins, macrolides, and clindamycin (8,9,15). Carbapenems were also shown to be poorly active against F. tularensis, displaying very high minimum inhibitory concentration in vitro (15,16). Single treatment with doxycycline or ciprofloxacin is reserved for mild cases, while gentamicin alone is recommended for most cases of severe tularemia. Combination therapy with gentamicin and either ciprofloxacin or doxycycline is recommended for severe tularemia complicated with meningitis or endocarditis (10,14). We elected to treat our patient with this combination antibiotic therapy given the severity of his initial presentation and potential concern for airway patency in the event of deterioration.

Conclusion

Tularemia is easily preventable and treatable if diagnosed on time, but potentially fatal if unrecognized. We hope that increased awareness will help lead to early diagnosis and proper management, including safer referral practices to the laboratory.

Funding Statement

No funding was obtained for the preparation of the case report.

Contributors:

Conceptualization, Y Keynan, JM Embil; Writing – Original Draft, É Gemme; Writing – Review & Editing, É Gemme, P Lagacé-Wiens, Y Keynan, T Wuerz, J McEachern, JM Embil.

Ethics Approval:

N/A

Informed Consent:

Written informed consent has been obtained from the patient, including approval for the information and pictures to be published in this case report.

Registry and the Registration No. of the Study/Trial:

N/A

Data Accessibility:

N/A

Funding:

No funding was obtained for the preparation of the case report.

Disclosures:

The authors have nothing to disclose.

Peer Review:

This article has been peer reviewed

Animal Studies:

N/A