Ulceroglandular tularemia in a nonendemic area.

Abstract: Two patients present with the abrupt onset of fever, malaise, anorexia, fatigue, progressive skin lesions and lymphadenitis. These patients represent two of the six cases of tularemia reported in Alabama over the last decade. The cases illustrate how mode of acquisition (direct versus vector-mediated) influences the clinical manifestations of ulceroglandular tularemia. In addition, a brief review of the epidemiology, differential diagnosis, clinical manifestations, and treatment of tularemia is provided.

Key Words: ulceroglandular syndrome, Francisella tularensis, tularemia, zoonosis, pediatrics

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Tularemia is a zoonotic infection caused by the small, aerobic, pleomorphic Gram negative coccobacillus Francisella tularensis to which humans are a highly susceptible host. F tularensis is found in approximately 100 different species of wild animals and 9 species of domestic mammals (including dogs and cats). (1-3) In the US, rabbits, hares, and ticks are among the most important natural reservoirs for the organism, and infection is most commonly transmitted by tick, deerfly, flea or by direct contact with infected animal products. (1,4,5) In addition, inhalation of aerosolized droplets of organisms can be acquired through recreational or occupational exposure or from a biologic weapon. (6)

We report two cases of ulceroglandular tularemia in children. The disease is rare in Alabama, and the children were referred to an infectious disease (ID) clinic after failing antibiotic therapy for lymphadenitis.

Case Reports

Patient 1

A 10-year-old male developed painless pustules on his right thumb and fifth finger and fever (100.4-102[degrees]) lasting 2 weeks despite treatment with ceftriaxone. In the infectious disease clinic, he was afebrile with a normal examination except for two painless, fluctuant violaceous lesions on his right thumb and 5th digit (Fig. 1A) and a mildly tender 2 X 2 cm axillary node. He lived on a working farm with a pond. His animal exposure included dogs, cats, horses, goats, and cows, and he reported seeing rabbits and a dead squirrel in the woods by their farm. Before the illness, he scratched himself while tending rosebushes and had recently been deer hunting. His laboratory studies were remarkable for a WBC of 9,000 with normal differential, platelet count of 508,000, and an ESR of 57. The ulcer was lanced and pus was negative by Gram stain, acid-fast stain, cultures and fungal studies. F tularensis serology was > 1:1280 (normal < 1:20) and Bartonella henselae titers were 1:256 for IgG with negative IgM. He was hospitalized and treated with intravenous (IV) gentamicin for 10 days, during which time his hand lesions healed. His axillary lymph node continued to enlarge while on therapy and ultimately required surgical drainage. During hospitalization, it was revealed that he had actually snared, skinned and buried bare-handed a rabbit which he claimed to have "seen."

Patient 2

A 3-year-old female presented with fever (102-104[degrees]F), malaise, congestion, sore throat, and a 7-day history of an enlarging, erythematous nodule on her left chest after returning from a camping/boating vacation in Kansas. Her fever resolved by day 12 of her illness, but the chest nodule ulcerated and she developed tender left axillary adenopathy (Fig. 1B) by day 21 of her illness despite a 10-day treatment of amoxicillin-clavulanate. There was no history of tick or animal exposure, but she did receive mosquito bites, including one on the chest. Her laboratory studies were remarkable for a WBC of 19,000 with normal differential, platelet count of 462,000, and an ESR of 85. Her initial B henselae and F tularensis serologies were negative. A biopsy of the ulcer showed chronic inflammation, necrosis, and early granulomatous changes (Fig. 2 A-D) and was negative for fungal, mycobacterial, and bacterial stains and cultures. She was treated with IV gentamicin, ampicillin/sulbactam and seroconverted (F tularensis IgG titer--1:512) during therapy. Clinically she improved, but her suppurated axillary nodes (Fig. 3) required surgical drainage.

Discussion

Tularemia has been called "rabbit fever," "deer-fly fever," and "market man disease" in the United States, "wild hare disease" and "Ohara disease" in Japan, and "water-rat trapper's disease" in Russia. (1,7-9) The causative agent was discovered in 1911 during a plague-like illness in ground squirrels in Tulare County, California, and was originally named Bacterium tularense. (7) A decade later, while investigating an outbreak of deerfly fever in Utah, Dr. Edward Francis proved the transmission of B tularense to humans by deerfly vector and named the human disease tularemia to reflect the frequent accompanying bacteremia. (7) He later identified the tick and other reservoirs for its transmission, improved culture methods, and clarified the clinical syndromes associated with it. In honor of his achievements, the organism was renamed Francisella tularensis.

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Tularemia has been reported in the entire continental United States but remains an uncommon infection, especially in nonendemic areas. (1) The described cases represent one third of the reported cases in Alabama over the last decade (Brian Whitley, AL State Public Health Department, personal communication). Two main biovars of F tularensis cause human disease. (1) F tularensis biogroup tularensis (biovar A) is the more virulent species and causes 70 to 90% of reported cases in North America. Overall death rates in the antibiotic era have been 4% or less but are as high as 33 to 60% without the utilization of effective antibiotics. (4,7) F tularensis biogroup palearctica (biovar B) accounts for a minority of cases in North America but is the predominant biovar in Europe and Asia and causes milder disease. (10)

The clinical consequences of F tularensis infection (summarized in Table 1) depends on the virulence of the particular organism, the portal of entry, the extent of systemic involvement, and the immune status of the host. (7) The most common forms, ulceroglandular and glandular, occur after direct inoculation in the skin with subsequent spread to local lymph nodes. (2,7) The bacteria can be directly inoculated by insect bite (Patient 2) or can pass directly through the dermis (Patient 1); prior abrasions or loss of skin integrity are not required for bacterial entry. (11) Animal contacts tend to yield ulcers on the hands and forearms (Patient 1), while vector transmission commonly produces an ulcer on the trunk (Patient 2), perineum, lower extremities, head or neck. (12) Our cases also reflect the bimodal seasonal presentation of tularemia. The patient in case one contracted tularemia by direct transmission during the hunting season (late fall/winter), while the patient in case two experienced vector-borne transmission during summer vacation. (2) Other forms of tularemia (oculoglandular, oropharyngeal, typhoidal, and pneumonic) are less common. Their mode of acquisition and frequency are summarized in Table 1. (2,13) Both patients required surgery because of abscessed nodes. In a study of 3333 patients with tularemia from the Czech Republic, almost 50% of the patients developed lymph node suppuration with negative tissue bacterial cultures, as was the case in both of our patients. (14)

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Tularemia is most often confirmed by serologic studies. (1) Culture of the fastidious organism is possible but should only be attempted in a biosafety level 3 facility, as it is a potential biohazard to laboratory personnel. (13) Tularemia, while rare, is the second most frequent cause of laboratory-associated infection in the US and is the third most frequent laboratory-associated infection worldwide. (15) Diagnostic methods are summarized in Table 2. (2,13,16-18)

F tularensis must be differentiated from other etiologies of ulceroglandular disease including B henselae (cat scratch disease), Yersinia pestis (plague), Bacillus anthracis (anthrax), and Spirillum minus (spirillary rat bite fever). Neither patient developed the pain or edema expected with bubonic plague or cutaneous anthrax. Both scrub typhus and spirillary rat-bite fever produce eschars at the site of inoculation with lymph node enlargement, but are uncommon in the United States. An expanded list of diseases that mimic ulceroglandular tularemia is provided (Table 3).

Therapy for tularemia is based upon case reports and meta-analysis. Our patients were treated with gentamicin and improved clinically, with resolution of ulcers and erythema within 72 hours. Fluoroquinolones and aminoglycosides are the mainstay of therapy and are effective in 86% of cases. (2) Other treatments, their success rates, and special indications are summarized in Table 4. (2,19-23)

Tularemia was removed from the lists of nationally notifiable diseases in 1994, but concerns about its potential use as a biologic weapon led to its reinstatement in 2000. (1) Although tularemia has been reported from every US state except Hawaii, 56% of all cases were reported from four states: Arkansas 23%, Missouri 19%, South Dakota 7%, and Oklahoma 7%. (1) During 1990 to 2000, the average annual incidence of tularemia was highest in persons aged 5 to 9 years and in persons over 75 years, although tularemia can occur in any age group. In the adult population, males are disproportionately infected. In the pediatric age group, males and females are equally affected. Most infections (70%) occur during the summer months of May to August, although the disease is reported throughout the year. (1) Incidence of tularemia was highest among American Indians and Alaska Natives (0.5 per 100,000) and is seen in 0.04 per 100,000 in whites and less than 0.01 per 100,000 among blacks and Asians/Pacific Islanders. (1)

While ulceroglandular and glandular tularemia remain the more common presentation, a number of outbreaks of typhoidal and pulmonary tularemia have been reported and reflect a diverse range of environmental exposures resulting in infection. (24) Obscure and circuitous routes of infection are well reported and are easily missed without careful questioning. (6) For example, outbreaks of pneumonic tularemia have occurred after dogs have shaken themselves dry, aerosolizing F tularensis present on their fur and infecting the household. (5,24,25)

The Working Group on Civilian Biodefense classified F tularensis as a class A biologic weapon because of its extreme infectivity, ease of dissemination, and substantial capacity to cause illness and death (with as few as 10 organisms). (22,26,27) Exposure to aerosolized F tularensis principally manifests as typhoidal or pneumonic disease and produces greater mortality (30-60%) if untreated. While ocular and pharyngeal findings may be present after biowarfare exposure, ulceroglandular disease is infrequent. (28) The Centers for Disease Control and Prevention predicted that biowarfare delivery of the bacterium as a "tularemic cloud" in the US would produce disease in 82.5% and kill 6.2% of exposed people. (29,30) Detection of tularemia as the etiologic agent would require knowledge about the natural history of F tularensis, an understanding of its clinical presentations, and a high index of suspicion for its proper diagnosis and treatment.

Conclusion

Tularemia is an acute febrile zoonosis that should be considered in the differential diagnosis of lymphadenitis, conjunctivitis, any typhoid-like illness, and pneumonia. Tularemia causes substantial morbidity with high spiking fevers and a prolonged illness. Because the pneumonic and typhoidal forms carry a risk of fatal outcome, a clinical suspicion, thorough history, and compatible clinical manifestations are indicators for initiating therapy. Confirmation is often by serologic conversion and frequently occurs after completion of therapy. (31)

These two cases of ulceroglandular tularemia demonstrate that while rare in a nonendemic area, the disease must be considered in children with lymphadenitis who fail to improve with antibiotic therapy. A history of insect bite or rabbit exposure should guide the use of aminoglycoside (children) or fluoroquinolone (adults) therapy and treatment is often initiated before diagnostic confirmation of the disease. Public health department notification of tularemia is an important component of disease management, especially because it is a potential biologic agent. While ulceroglandular disease would be an atypical presentation for a biologic agent, notification of public health authorities is still warranted.

Acknowledgments

The authors wish to thank the patients involved and Dr. Masako Shimamura for their help with this manuscript.

References

1. Centers for Disease Control and Prevention. Tularemia: United States, 1990-2000. MMWR Morb Mortal Wkly Rep 2002;51:181-184.

2. Amsden JR, Warmack S, Gubbins PO. Tick-borne bacterial, rickettsial, spirochetal, and protozoal infectious diseases in the United States: a comprehensive review. Pharmacotherapy 2005;25:191-210.

3. Baldwin CJ, Panciera RJ, Morton RJ, et al. Acute tularemia in three domestic cats. J Am Vet Med Assoc 1991;199:1602-1605.

4. Centers for Disease Control and Prevention. Tularemia transmitted by insect bites: Wyoming, 2001-2003. MMWR Morb Mortal Wkly Rep 2005;54:170-173.

5. Hornick R. Tularemia revisited. N Engl J Med 2001;345:1637-1639.

6. Dembek ZF, Buckman RL, Fowler SK, et al. Missed sentinel case of naturally occurring pneumonic tularemia outbreak: lessons for detection of bioterrorism. J Am Board Fam Pract 2003;16:339-342.

7. Weinberg AN. Commentary: Wherry WB, Lamb BH: Infection of man with Bacterium tularense. J Infect Dis 1914;15:331-40. J Infect Dis 2004;189:1317-1320.

8. Ohara Y, Sato T, Homma M. Arthropod-borne tularemia in Japan: clinical analysis of 1,374 cases observed between 1924 and 1996. J Med Entomol 1998;35:471-473.

9. Ohara S. Studies on yato-byo (Ohara's disease, tularemia in Japan): I. Jpn J Exp Med 1954;24:69-79.

10. Uhari M, Syrjala H, Salminen A. Tularemia in children caused by Francisella tularensis biovar palaearctica. Pediatr Infect Dis J 1990;9:80-83.

11. Quan SF, McManus AG, Von Fintel H. Infectivity of tularemia applied to intact skin and ingested in drinking water. Science 1956;123:942-943.

12. Evans ME, Gregory DW, Schaffner W, et al. Tularemia: a 30-year experience with 88 cases. Medicine (Baltimore) 1985;64:251-269.

13. Shapiro DS, Schwartz DR. Exposure of laboratory workers to Francisella tularensis despite a bioterrorism procedure. J Clin Microbiol 2002;40:2278-2281.

14. Cerny Z. Changes of the epidemiology and the clinical picture of tularemia in Southern Moravia (the Czech Republic) during the period 1936-1999. Eur J Epidemiol 2001;17:637-642.

15. Pike RM. Laboratory-associated infections: summary and analysis of 3921 cases. Health Lab Sci 1976;13:105-114.

16. Centers for Disease Control and Prevention. Case definitions for infectious conditions under public health surveillance. MMWR Recomm Rep 1997;46:1-55.

17. Koskela P, Salminen A. Humoral immunity against Francisella tularensis after natural infection. J Clin Microbiol 1985;22:973-979.

18. Johansson A, Berglund L, Eriksson U, et al. Comparative analysis of PCR versus culture for diagnosis of ulceroglandular tularemia. J Clin Microbiol 2000;38:22-26.

19. 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;19:42-47.

20. Cross JT, Jacobs RF. Tularemia: treatment failures with outpatient use of ceftriaxone. Clin Infect Dis 1993;17:976-980.

21. Cross JT Jr, Schutze GE, Jacobs RF. Treatment of tularemia with gentamicin in pediatric patients. Pediatr Infect Dis J 1995;14:151-152.

22. Dennis DT, Inglesby TV, Henderson DA, et al. Tularemia as a biological weapon: medical and public health management. JAMA 2001;285:2763-2773.

23. Russell P, Eley SM, Fulop MJ, et al. The efficacy of ciprofloxacin and doxycycline against experimental tularaemia. J Antimicrob Chemother 1998;41:461-465.

24. Feldman KA, Enscore RE, Lathrop SL, et al. An outbreak of primary pneumonic tularemia on Martha's Vineyard. N Engl J Med 2001;345:1601-1606.

25. Siret V, Barataud D, Prat M, et al. An outbreak of airborne tularaemia in France, August 2004. Euro Surveill 2006;11:50-60.

26. Jensen WA, Kirsch CM Tularemia. Semin Respir Infect 2003;18:146-158.

27. Christopher GW, Cieslak TJ, Pavlin JA, et al. Biological warfare: a historical perspective. JAMA 1997;278:412-417.

28. Jacobs RF. Tularemia. Adv Pediatr Infect Dis 1996;12:55-69.

29. Franz DR, Jahrling PB, Friedlander AM, et al. Clinical recognition and management of patients exposed to biological warfare agents. JAMA 1997;278:399-411.

30. Kaufmann AF, Meltzer MI, Schmid GP. The economic impact of a bioterrorist attack: are prevention and postattack intervention programs justifiable? Emerg Infect Dis 1997;3:83-94.

31. Jacobs RF, Condrey YM, Yamauchi T. Tularemia in adults and children: a changing presentation. Pediatrics 1985;76:818-822.

M. Brad Guffey, MD, Alex Dalzell, MD, David R. Kelly, MD, and Kevin A. Cassady, MD

From the Department of Pediatrics, Division of Pediatric Infectious Diseases, and Department of Pathology, the University of Alabama at Birmingham, Birmingham, AL.

Reprint requests to Dr. Kevin A. Cassady. UAB Department of Pediatrics, 1600 6th Avenue South, CHB-118C, Birmingham, AL 35233. Email: [e-mail]

Accepted July 6, 2006.

RELATED ARTICLE: Key Points

* We report two pediatric patients diagnosed with ulceroglandular tularemia who had been treated unsuccessfully for acute lymphadenitis.

* The cases illustrate some of the differences seen following arthropod-mediated vs. direct inoculation of Francisella tularensis.

* Tularemia, while not endemic in many areas of the southeastern US, nonetheless must be included in the differential diagnosis for ulceroglandular disease.

* The manuscript provides a brief review of the microbiology, diagnosis, clinical manifestations and treatment of tularemia.

* A diagnosis of tularemia, especially in a nonendemic area, should alert the clinician to possible bioterrorism exposure.

Table 1. Tularemia -- clinical manifestations

Disease          Frequency  Mode of acquisition

Ulceroglandular  80%        Arthropod inoculation or direct inoculation
Glandular        15%          across the dermis
Oculoglandular    1%        Inoculation of tularemia in the eye
                              (infectious fluids, auto-inoculation or
                              dander)
Oropharyngeal    <5%        Ingestion of raw/undercooked meat or
Typhoidal        Rare         contaminated water
Pneumonic        Rare       Inhalation or hematogenous spread following
                              local (glandular or typhoidal) infection

Table 2. Diagnosis of tularemia

Method              Sensitivity  Notes

Serology            >85%         Single titers >1:160 historically were
                                   diagnostic. CDC now recommends
                                   documented seroconversion with acute
                                   and convalescent titers.
                                   Seroconversion occurs 2-7 weeks (peak
                                   antibody levels 4-7 weeks) after
                                   exposure
Culture             10-25%       Potential biohazard to lab personnel.
                                   Notification of lab is mandatory.
                                   Culture should only be performed in a
                                   biosafety level 3 facility
Polymerase chain    50-73%       Available at research institutions and
  reaction (PCR)                   primer sets may differ between labs
Direct fluorescent               Frequently negative with less than
  antibody (DFA)                   10 (6) cells per ml tissue

Table 3. Differential diagnosis for ulceroglandular syndrome

Bacterial
  Bacterial Adenitis (Staphylococcus aureus, Streptococcus pyogenes,
    Anaerobes)
  Bartonella infection
  Plague (Yersinia pestis)
  Anthrax (Bacillus anthracis)
  Mycobacteria infection (Atypical or Tuberculosis)
  Water born infection (Aeromonas hydrophila, Erysipelothrix
    rhusiopathiae, Mycobacterium marinum, Edwardsiella tarda, Linuche
    unguilculata)
  Syphilis (Treponema pallidum)
  Lymphogranulum venereum
  Chancroid (Haemophilus ducreyi)
  Scrub Typhus (Orientia tsutsugamushi)
  Spirillary Rat Bite fever (Spirillum minus)
Fungal
  Sporotrichosis (Sporothrix schenckii)
  Blastomycosis (Blastomyces dermatitidis)
Other infections
  Toxoplasma gondii
  Herpetic whitlow (Herpes simplex virus type 1 and type 2)
Non-infectious
  Histiocytosis X
  Thyroglossal duct or branchial cleft cysts
  Dermoid cyst
  Sarcoidosis
  Brown Recluse spider bite

Table 4. Therapy for tularemia

Therapy           Regimen             Success  Notes

Aminoglycoside,   3-5 mg/kg/d IV      86%      Treatment of choice for
  Gentamicin,       10-14 days                   children or life-
  Amikacin                                       threatening illness.
                                                 Effective following
                                                 treatment failures with
                                                 other antimicrobial
                                                 classes. Bacteriocidal
Fluoroquinolone,  400 mg IV/500 mg    86%      Alternative therapy,
  Ciprofloxacin,    p.o. b.i.d. 7-14             adults. Bacteriocidal.
  Levofloxacin      days 500 mg IV               Has been used to
                    or p.o. b.i.d.               successfully treat
                    7-14 days                    pneumonic tularemia in
                                                 adults
Doxycycline/      100 mg p.o. b.i.d.  77%      Alternative therapy if
  Tetracycline      14-21 days                   gentamicin or
                                                 ciprofloxacin
                                                 unavailable or
                                                 contraindicated.
                                                 Bacteriostatic, high
                                                 relapse rates.
Streptomycin      30 mg/kg/d divided  97%      Historical interest,
                    q. 12 hours Not              painful IM injections
                    to exceed 2 g
                    daily
Chloramphenicol   50-100 mg/kg/d      77%      High rates of relapse,
                    divided q.6                  bacteriostatic, good
                    hours Monitor                CSF and CNS
                    for bone marrow              penetration, possible
                    suppression                  therapeutic option for
                                                 meningeal tularemia