Tularemia by tick bite:
Unusual cause of lymphadenitis

By Stan Block, MD

Tularemia is far down in the differential diagnosis of lymphadenitis, but knowing the signs and symptoms of this tick-borne infection will help you keep it in mind.

Last May, a previously healthy, 4 ¹/₂-year-old girl with a 24-hour history of low-grade fever to 37.8° C (100° F, axillary), sore throat, abdominal and neck pain, and a mass behind the right ear presented to our general pediatric office in rural Kentucky. She appeared slightly ill, and her temperature was 38.9° C (102° F) axillary. She had a healing lesion on her frontal scalp where a tick had been removed four days earlier.

Several small, shotty nodes were palpable throughout the entire left posterior cervical chain, along with a mildly erythematous, slightly tender, 1.5-cm moveable lymph node in the retroauricular area. Her pharynx, cardiac status, lung, abdomen, neurologic status, and skin were normal. She had no exposure to cat scratches, farm animals, animal carcasses, or tuberculosis.

Even though we began antibiotic therapy with once-daily cefadroxil, the child returned two days later with persistent fever as high as 39.4° C (103° F), headache, dizziness, and several new punctate hemorrhagic vesicles surrounding the tick bite. The child's persistent symptoms were attributed to the enteroviral epidemic circulating in the community.

During the next five days, our patient continued to complain of malaise, fatigue, and abdominal pains, but had no fever. As we worked to establish the differential diagnosis, tularemia grew prominent in light of additional findings on her physical examination. The initial tick bite totally resolved, but she had developed four new, 0.2- to 0.3-cm ulcerative, herpetic-looking lesions, situated around a larger 1-cm crusted central lesion distally in the vertex of her scalp (Figure 1). The retroauricular node had enlarged to a palpable 3.5 cm, was erythematous, and had become increasingly tender (Figure 2). Several tender smaller 0.5- to 1.5-cm nodes were palpated distally in the posterior cervical chain.

The child's erythrocyte sedimentation rate (ESR) was 5 mm/h; the white blood cell count was 9,000/mm³ with 53% segmented neutrophils, 38% lymphocytes, and 2% eosinophils. Platelet count was 404,000/mm³. The initial acute tularemia agglutination titer was negative.

She underwent complete excisional biopsy of the large sentinel lymph node under general anesthesia in a pediatric tertiary care center. Using special respiratory precautions to avoid inhaling organisms, laboratory personnel cultured the 1.0 cm by 1.2 cm lymph node. The node also was submitted for pathologic examination (Figure 3). Following surgery, antibiotic therapy with doxycycline was initiated after discussing with the parents the risks and benefits of each antibiotic choice for a presumptive diagnosis of tularemia.

Five days after surgery, culture confirmed Francisella tularensis, the causative agent of tularemia. A two-week convalescent tularemia agglutination titer of 1:320 further corroborated the diagnosis.

What is tularemia?

Tularemia is ubiquitous in the northern hemisphere. It is the third most commonly reported tick-borne disease in the United States, behind Lyme disease and Rocky Mountain spotted fever. Children account for one third of the 100 to 200 cases reported annually.¹ Many of these 30 to 60 children may appear to be asymptomatic or have minimal illness.^2,3 Although most cases occur between May and September, when ticks are most active and prevalent, incidence in northern and eastern states peaks in the winter months during the hunting season. Arkansas, Missouri, Oklahoma, Montana, and South Dakota report the largest number of cases.^1,4,5 In Kentucky, only two or three cases of tularemia are reported annually (personal communication, SK Billings, DVM, MSPH, Department of Epidemiology, Kentucky Division, September 2000).

F tularensis is a fastidious, nonmotile, highly pleomorphic, gram-negative coccobacillus. Although the microorganism grows best on enhanced medium, it can be isolated overnight in routine and enriched chocolate agar medium. Animals that carry the organism include more than 100 species of wild mammals and nine species of domestic animals; rabbits and ducks are the major animal vectors.¹ Most often, tularemia is transmitted to humans by a tick, predominantly the wood tick, dog tick, and Lone Star tick. Person-to-person transmission has not been reported.

A variety of presentations

The incubation period for tularemia is usually three to five days but may be as long as 21 days. The routes of inoculation are arthropod bites, direct contact through broken skin, inhalation, and ingestion. Regardless of the route they take, bacteria typically invade regional lymph nodes and are disseminated to other lymph nodes and organs via secondary bacteremia.⁶ Constitutional symptoms such as fever, chills, malaise, fatigue, and gastrointestinal complaints are more common in children than in adults.

Tularemia can present as any of six clinical forms, depending on the route of inoculation. The glandular or ulceroglandular type (80% of cases) is the most common presentation in children and is acquired from the bite of a blood-sucking arthropod.¹ As in the child discussed here, this form manifests as lymphadenitis in the region of the lymphatic drainage for the tick bite, with or without an ulcer distal to the adenitis. Lymphadenitis is commonly accompanied by systemic symptoms, adjacent distal lymphadenopathy, and a painful, swollen, large papule near involved nodes. The papule may rupture, leaving a residual ulcerated lesion with raised edges.

The oropharyngeal form is also common in children. It is acquired by ingesting infected meat or contaminated milk or water. It presents as an intensely painful pharyngitis, often with ulcerations and membranous exudates, along with a suppurative cervical adenitis. Systemic symptoms and fever are usually present. Other less common types of tularemia include typhoidal, intestinal, and pneumonic. Typhoidal/ pneumonic forms of tularemia can be fatal. They usually present like typhoid fever with protracted fever, dry cough, substantial chest pain, and sometimes hemoptysis. This presentation is usually associated with hepatosplenomegaly and roentgenographic findings of pulmonary infiltrates and mediastinal lymphadenopathy.

As the case described here demonstrates, manifestations of the glandular forms of tularemia are often protean and without pathognomonic signs.^1,5 Laboratory tests, including the complete blood count, ESR, and electrolytes, are commonly normal. Diagnosis is most frequently confirmed by a serologic titer of 1:160 or higher but, as in the case described here, this level of titer is rarely observed until seroconversion after the second week of illness.

Other tests that can establish a diagnosis within a few days are an indirect fluorescent antibody test of the ulcer or a polymerase chain reaction-based assay of a node aspirate.¹ Neither is routinely available in most laboratories, however. Cultures, particularly in the glandular form of tularemia, often are obtained inadvertently from fluctuant or refractory lymphadenitis, while searching for other more common bacterial pathogens. Cultures for tularemia should be avoided, however; the plates must be handled with extreme caution so that laboratory personnel do not inhale the microorganisms. This places the clinician in a double bind: We need to aspirate and culture the node in most cases of severe lymphadenitis. Yet we shouldn't perform this procedure in patients infected with tularemia. Prescient, we are not.

Regrettably, these obstacles leave the pediatrician who encounters a child with lymphadenitis in the outpatient clinic to suspect tularemia solely on an empiric basis. Even though tick bites often are seen in children during the warmer months, the most common infectious cause of lymphadenitis in a child is either Staphylococcus aureus or Streptococcus pyogenes. When a patient does not respond to standard antistaphylococcal antibiotics, such as a first-generation cephalosporin, the clinician usually suspects a loculated staphylococcal abscess, Bartonella henselae, atypical mycobacterial pathogens, or Mycobacteria tuberculosis. Additional evaluation for these organisms is then initiated, including tuberculin skin testing. Empiric therapy with azithromycin for cat-scratch disease is also usually started (Figure 4).

Persistent illness and a negative skin tuberculin test often prompt surgical consultation for total excision of the node, in anticipation of atypical tuberculosis or cat-scratch disease. If, at any point, the child becomes very ill, he or she should be hospitalized to be given intravenous antibiotics. Methicillin-resistant S aureus may also need to be considered in light of recent reports of this organism in some previously healthy children.^7­9

You may be able to narrow the differential diagnosis of lymphadenitis further if you know that the child has been bitten by a tick. At most, only 60 cases of tularemia are reported among children each year. Thus, this disease still remains far down the list of possible diagnoses. Ulcers at, or near, the tick bite may be a significant clue to the diagnosis. But the eschar formation or somewhat herpetic appearance may lead the clinician to suspect herpes simplex or cat-scratch fever rather than ulceroglandular tularemia, which he or she has rarely, or never, seen.

Treating tularemia

To treat tularemia, antibiotics usually are administered for seven to 14 days. Although streptomycin has been the drug of choice, parenteral gentamicin (5 mg/kg/d in two divided doses) has become the preferred antibiotic because it is much more widely available and causes fewer adverse reactions.^1,10 Gentamicin is potentially associated with ototoxicity and renal toxicity, however. This possible adverse reaction requires that hearing be assessed before and after therapy. Serum concentrations of the drug and renal function should be measured multiple times during treatment. Also, either a painful intramuscular injection twice a day or prolonged intravenous (often central) access is needed.

Doxycycline (5 mg/kg/d in two divided doses) may be a suitable alternative, but it must be used cautiously in children younger than 8 years because it may cause dental staining reported with other tetracycline antibiotics. A recent study, however, showed that doxycycline staining of dental enamel in young children treated for Rocky Mountain spotted fever was uncommon and clinically insignificant.¹¹ Cure rates for gentamicin (86%) and tetracycline/doxycycline (88%) appear comparable, but relapses are twice as likely with doxycycline as they are with gentamicin (12% compared with 6%).¹ Although ceftriaxone is very active in vitro against F tularensis, it appears to lack clinical efficacy.¹²

We treated our patient empirically with doxycycline for seven days after surgery. Symptoms and signs resolved completely within 24 hours and 96 hours, respectively, after surgery. The family opted for doxycycline because of the potential, but rare, serious adverse effects that have been reported with gentamicin. Interestingly, we had treated the patient's cousin with gentamicin for tularemia five years earlier, and the family had observed the tribulations of parenteral therapy. The safety profile of doxycycline, when used as a single course in rickettsial disease, has been excellent.¹³ Another advantage of doxycycline is that serum monitoring is unnecessary.

The last word

You may never encounter tularemia in your pediatric practice. Nonetheless, it is an important disease entity to keep in mind when you evaluate a child with lymphadenitis who is not responding to standard antibiotic therapy. This is particularly significant when you know that the child has been bitten by a tick or has been exposed to rabbits or skinning of animals. h

1. Lau CC, Feigin RD: Tularemia, in Feigin RD, Cherry J, Fletcher J (eds): Textbook of Pediatric Infectious Diseases, ed 4. Philadelphia, WB Saunders, 1994, pp 1458­1464

2. Engelfried JJ: Antibodies to Pasteurella Tularensis in a selected human population. Milit Med 1968;135:723

3. Casper EA, Phillip RN: A skin test survey of tularemia in a Montana sheep-raising community. Public Health Rep 1969;84(7):611

4. Taylor JP, Istrc GR, McChesney TC, et al: Epidemiologic characteristics of human tularemia in the southwest-central states, 1981­1987. Am J Epidemiol. 1991;133:1032

5. Markwitz LE, Hynes NA, de la Cruz P, et al: Tick-borne tularemia: An outbreak of lymphadenopathy in children. JAMA 1985;254:2922

6. Rubin LG: Francisella tularensis (tularemia), in Long SS, Pickering LK, and Prober CG (eds): Principles and Practice of Pediatric Infectious Disease, ed 1. New York, Churchill Livingston, 1997, p 1016­1020

7. Suggs AH, Maranan MC, Boyle-Vavra S, et al: Methicillin-resistant and borderline methicillin-resistant asymptomatic Staphylococcus aureus colonization in children without identifiable risk factors. Pediatr Infect Dis J 1999;18:410

8. Feder HM Jr: Methicillin-resistant Staphylococcus aureus infections in two pediatric outpatients. Arch Fam Med 2000;9:560

9. Frank AL, Marcinak JF, Mangat PD, et al: Community-acquired and clindamycin-susceptible methicillin-resistant Staphylococcus aureus in children. Pediatr Infect Dis J 1999;18:993

10. Enderlin G, Morales L, Jacobs RF, et al: Streptomycin and alternative agents for the treatment of tularemia: Review of the literature. Clin Infect Dis 1994;19:42

11. Lochary ME, Lockhart PB, Williams WT: Doxycycline and staining of teeth. Pediatr Infect Dis J 1998;17:429

12. Cross JT, Jacobs RF: Tularemia: Treatment failures with outpatient use of ceftriaxone. Clin Infect Dis 1993;17:976

13. American Academy of Pediatrics: Antimicrobial agents and related therapy, in Pickering LK, (ed): 2000 Red Book. Report of the Committee on Infectious Diseases, ed 25. Elk Grove Village, Ill., American Academy of Pediatrics, 2000, p 648

THE AUTHOR is associate clinical professor of pediatrics at the University of Louisville and at the University of Kentucky, Lexington. He practices pediatrics in Bardstown, Ky.

 

Stan Block. Tularemia by tick bite: Unusual cause of lymphadenitis. Contemporary Pediatrics 2001;8:101.