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Tularemia: Epidemiology, Diagnosis, and Treatment Nada S. Harik, MD

ularemia is a rare zoonosis caused ETIOLOGY AND EPIDEMIOLOGY by . Al- is a zoonotic Tthough many animals may be caused by F. tularensis, a small, fastidi- infected with tularemia, human infection ous, aerobic gram-negative coccobacillus. most commonly occurs via an insect vec- There are four distinct subspecies of F. tu- tor such as a tick or deer fly. In the US, larensis; however, disease is mainly caused most cases of tularemia occur in the sum- by F. tularensis subspecies tularensis (type mer in the south-central states, specifically A) and F. tularensis subspecies holarctica Missouri, Arkansas, and Oklahoma. There (type B).1 Type A is more virulent and is are six major tularemia clinical syndromes primarily found in North America.1 Type each with different clinical presentations: B is found throughout the Northern Hemi- ulceroglandular tularemia (42%-75% of sphere, mainly in Europe and Asia, and all tularemia cases), glandular tularemia causes milder infection than type A.1 F. tu- (15%-44% of all tularemia cases), oro- larensis is highly contagious; only a small pharyngeal tularemia, oculoglandular inoculum is needed to produce disease.1 tularemia, typhodial tularemia, and pneu- More than 100 species of mammals monic tularemia. The diagnosis of tula- have been noted to be infected with tulare- remia is typically made clinically, taking mia. This includes rabbits, hares, muskrats, into account exposure history and clinical prairie dogs, skunks, raccoons, rats, voles, manifestations and confirmed by serologic squirrels, sheep, cattle, and cats.1 Disease © Shutterstock testing. Aminoglycosides are the drugs of transmission can occur via handling the in laboratories where F. tularensis is pres- choice for the treatment of tularemia. Tu- carcass of an infected animal, via the bite ent. The disease can also be transmitted by laremia prevention is best accomplished by of a infected animal, or via ingestion of contaminated with F. tula- keeping away from dead or infected ani- meat from a diseased animal. rensis; this organism can survive in water mals and avoiding ticks. The bite of an insect such as a and animal carcasses for long periods. tick, deer fly, or can also transmit tula- Frozen rabbit meat has remained infective Nada S. Harik, MD, is Assistant Professor, De- remia to humans. Insects become infected for greater than 3 years.3 Person-to-person partment of Pediatrics, Division of Pediatric when they feed on an infected animal; ticks transmission of tularemia does not occur. Infectious Diseases, University of Arkansas for can also become infected by transovarian In the US, 90 to 154 cases of tularemia Medical Sciences. passage.2 In the , ticks are the have been reported yearly to the Centers Address correspondence to: Nada S. Harik, most common and important insect vector for Disease Control and Prevention (CDC) MD, Department of Pediatrics, Division of Pediat- of tularemia.2 Tick species that transmit from 2001 to 2010.4 Tularemia has been ric Infectious Diseases, University of Arkansas for tularemia to humans include Amblyomma reported by every state except Hawaii.4 Ar- Medical Sciences, 1 Children’s Way, Slot 512-11, americanum (lonestar tick), Dermacentor kansas, Oklahoma, and Missouri account Little Rock, AR 72202-36591; email: hariknada@ andersoni (wood tick), and Dermacentor for approximately 50% of the cases of tula- uams.edu. variabilis (dog tick). remia reported in the US each year.5 Figure Disclosure: The author has no relevant finan- Tularemia can also be caused by con- 1 (see page 289) is a CDC map detailing cial relationships to disclose. tact with aerosolized from mow- the locations of reported cases of tularemia doi: 10.3928/00904481-20130619-13 ing lawns, working on farms, or working from 2001 to 2010.4

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Tularemia presents most commonly TABLE 1. in the summer, due to high tick activity, in the south-central US and peaks in the Common Characteristics of the Six Tularemia winter, the primary hunting season, in the Clinical Syndromes northeastern US.1 Individuals at risk for Tularemia Syndrome Characteristics Portal of Entry developing infection include hunters, trap- Ulceroglandular Skin papule followed by ulcer, tender lymph- Skin pers, taxidermists, grounds maintenance adenopathy, workers, sheep herders/shearers, labora- Glandular Tender lymphadenopathy, fever Unknown (likely skin) tory workers, those with tick exposure, and Oropharyngeal Severe pharyngitis, cervical lymphadenitis, fever Oropharyngeal mucosa those living in or traveling to areas where Oculoglandular Conjunctivitis, Parinaud’s oculoglandular Conjunctiva tularemia is endemic. The highest inci- syndrome dence of tularemia occurs in children (and Typhodial Fever of unknown cause, , myalgia, Oropharyngeal mucosa in adults older than age 75 years); boys or respiratory tract have a higher incidence of infection than Pneumonic , fever Respiratory tract girls.5 The higher incidence in boys is most likely due to their greater participation in activities such as hunting that increase exposure to tularemia. Figure 2 (see page 290) shows the age and gender of reported tularemia cases from 2001 to 2010.4

CLINICAL SYNDROMES AND MANIFESTATIONS The of tularemia is 1 to 21 days, with an average of 2 to 5 days. There are six major tularemia clinical syn- dromes, which are classified by the portal of entry of the infection (see Table 1).

Ulceroglandular Tularemia The most common syndrome, account- Figure 1. Reported cases of tularemia, United States, 2001 to 2010. One dot placed randomly within ing for between 42% and 75% of all cases county of residence for each confirmed case. (From US Centers for Disease Control and Prevention4) of tularemia, is ulceroglandular tulare- mia.6-8 This syndrome is characterized by . The most common sites of lymph younger than 6 years and had ulceroglan- a painful swollen papule at the portal of en- node involvement in a recent review of dular or glandular disease.8 try of the infection (skin) that becomes an pediatric tularemia in Arkansas were head ulcer. Tender lymphadenopathy is present and neck (33%), followed by inguinal ad- Oropharyngeal Tularemia proximal to the papule/ulcer (see Figure 3, enitis (30%).8 Traditionally representing less than page 291). Fever and malaise are common- In 50% of untreated cases of ulcero- 5% of cases of tularemia, infection with ly seen with ulceroglandular tularemia. glandular or glandular tularemia, lymph oropharyngeal tularemia is established nodes suppurate and drain.1 Lymph node through the oropharyngeal mucosa, most Glandular Tularemia suppuration can occur even in the setting of commonly by eating undercooked meat Glandular tularemia, representing 15% appropriate antibacterial therapy. Glandu- from an infected animal.6,7 The hallmarks to 44% of all cases of tularemia,6-8 presents lar tularemia is more common in children of oropharyngeal tularemia are severe with tender lymphadenopathy. Involved than adults; 44% of children compared pharyngitis (out of proportion to pharyn- lymph nodes are most commonly axillary, with 16% of adults had primary glandular geal appearance), cervical lymphadenitis, inguinal, or cervical. The portal of entry tularemia in a Missouri study of tularemia.7 and fever. Oral ulcers and/or an oropha- with glandular tularemia is unknown but Likewise, in a review of 30 cases of pediat- ryngeal pseudomembrane may be pres- most likely is through the skin. Common ric tularemia from 1996 through 2006 from ent. Cervical lymph nodes may suppurate additional symptoms include fever and Arkansas, the majority of children were and drain.

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TABLE 2. Differential Diagnoses for the Various Clinical Syndromes of Tularemia Ulceroglandular and Oropharyngeal Tularemia Oculoglandular Typhodial Tularemia Pneumonic Tularemia Glandular Tularemia Tularemia Staphylococcus aureus Streptococcal pharyngitis Bacterial sepsis Typical and atypical bacterial pneumonia lymphadenitis Staphylococcus pyogenes Diphtheria Sporotrichosis Tuberculosis lymphadenitis Tuberculosis Viral pharyngitis Tuberculosis Legionnaire’s disease Non-tuberculous mycobacterium Syphilis Q fever Bartonella Coccidioidomycosis Rickettsial diseases Fungal pneumonia HSV Viral pneumonia HIV Typhoid fever Infectious mononucleosis Disseminated tuberculosis Sporotrichosis Disseminated Lymphoma histoplasmosis Lymphogranuloma venereum Lymphoma

Oculoglandular Tularemia Oculoglandular tularemia was noted 80 to cause 4% of all cases of tularemia in 70 Missouri from 2000 to 2007.7 Nodular conjunctivitis, conjunctival inflammation, 60 and edema are typically seen and corneal Male ulcers may occur. Regional lymphadeni- 50 Female tis is also seen. Oculoglandular tularemia 40 can manifest as Parinaud’s oculoglandular Cases syndrome (conjunctivitis and painful ip- 30 silateral preauricular lymphadenopathy). The conjunctiva is the portal of entry for 20 oculoglandular tularemia and infection is 10 usually caused by direct inoculation from infected fingers. 0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 5 year age group Typhodial Tularemia Figure 2. Reported tularemia cases in the United States by age and gender, 2001 to 2010. (From US The portal of entry for typhodial tula- Centers for Disease Control and Prevention4) remia is either the oropharyngeal mucosa by ingestion (more common in children) symptoms, a history of tularemia exposure ic tularemia.7 Type A Francisella pneu- or the respiratory tract by inhalation (more is often needed before this diagnosis is monic tularemia has a high mortality rate common in adults).1 Typhoidal tularemia considered. and is the most severe form of tularemia. is a serious illness that often presents with Symptoms include fever, cough, and chest septic shock. Fever is present without lo- Pneumonic Tularemia pain. Pulmonary infiltrates, hilar adenopa- calizing signs. , myalgias, pha- Pneumonic tularemia is uncommon in thy, and/or pleural effusions may be pres- ryngeal pain, and are common children. In a Missouri study of 107 cases ent. Via inhalation of aerosolized bacteria, symptoms. Hepatomegaly and splenomeg- of tularemia, 4% of children compared the respiratory tract is the portal of entry for aly are usually seen. Given the nonspecific with 39% of adults had primary pneumon- pneumonic tularemia.

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MORTALITY AND PROGNOSIS Mortality is less than 1% for all types of tularemia except typhoidal and pneumon- ic.1 Lymph node suppuration is the most common complication of tularemia. The risk of lymph node suppuration increases if there is a delay in beginning appropriate antibacterial therapy.8 Treatment failure is also more common if appropriate antibac- terial therapy is delayed.9 Other possible complications include A B Figure courtesy of Nada S. Harik, MD. sepsis, disseminated intravascular coagu- Figure 3. Photographs documenting an ulcerative lesion (A) and posterior cervical lymphadenitis (B) in lation, renal failure, acute respiratory dis- a child with ulceroglandular tularemia. tress syndrome (ARDS), rhabdomyolysis, jaundice, hepatitis, meningitis, encepha- between acute and convalescent serology TREATMENT litis, , pericarditis, , with one specimen having a minimum titer therapy should be initiated as osteomyelitis, splenic rupture, and throm- of 1:160 by TA or 1:128 by MA.11 Of note, soon as tularemia is suspected, rather than bophlebitis.1 Subcutaneous nodules and cross-reactivity may occur because of anti- awaiting results of serologic testing. The various rashes (maculopapular, erythema, bodies to Brucella, Legionella, , illness may be prolonged, complications erythema multiforme, pustular lesions) Yersinia, or other gram-negative bacteria. are more likely to occur, and treatment fail- have also been described in individuals Diagnosis is also confirmed by isola- ure is more frequent if antibiotic therapy is with tularemia. tion of F. tularensis in , body fluids, delayed.1,8,9,12 Relapse is possible even af- Common differential diagnoses for the or tissue. F. tularensis is a fastidious bac- ter appropriate antibiotic therapy. Jarisch- various clinical syndromes of tularemia are teria that rarely is seen on Gram’s staining. Herxheimer reactions can occur with anti- listed in Table 2 (see page 290). The bacteria grows best on culture media bacterial therapy. supplemented by cysteine.10 Health care DIAGNOSIS providers should alert microbiology labo- and Gentamicin The diagnosis of tularemia is usually ratory personnel if tularemia is suspected, The aminoglycosides streptomycin made clinically, taking into account expo- as it is highly infectious, and laboratory and gentamicin are the drugs of choice for sure history and clinical manifestations and workers have a high risk of acquiring in- the treatment of tularemia. However, only confirmed by serologic testing. Serologic fection. Cultures of F. tularensis should be streptomycin is approved by the US Food testing was diagnostic in 77% of children done only in a 3 (BSL-3) and Drug Administration for the treatment with tularemia in Arkansas from 1996 to laboratory. of tularemia. A literature review of in vitro 2006.8 Polymerase chain reaction (PCR) as- susceptibilities, cure rates, and relapse rates Standard agglutination tests, tube ag- says for the diagnosis of tularemia are of used to treat adult and pedi- glutination (TA), and microagglutination very sensitive but are not commercially atric cases of tularemia showed that cure (MA), for tularemia are commercially available.10 rates were highest and relapse rates lowest available. Agglutinating usually The count may be for streptomycin.13 However, gentamicin are not detectable until the second week normal or elevated, with a predominance was noted to have similar efficacy to strep- of illness.10 Therefore, effective antibi- of neutrophils, in children with tularemia. tomycin.13 otic therapy should not be withheld while C-reactive protein and erythrocyte sedi- Given the limited availability of strep- awaiting results of serologic testing. mentation rate are typically elevated; tomycin in the US, gentamicin, considered Acute and convalescent serum testing function tests may also be elevated. Chest the best alternative, is typically used for should be obtained at least 2 weeks apart. X-ray findings in pneumonic tularemia treatment of tularemia. Twenty-eight of A presumptive diagnosis of tularemia can may include hilar lymphadenopathy, pul- 30 children with tularemia seen at Arkan- be made if a single serum titer is monary infiltrates, pleural effusions, and/ sas Children’s hospital between 1996 and at least 1:160 by TA or at least 1:128 by or empyema. 2006 were treated with gentamicin; only MA;11 however, this can also represent In the US, tularemia is a nationally no- one child had treatment failure with persis- past infection. Diagnosis is confirmed if tifiable disease; cases should be reported to tent lymphadenitis. Of note, that child had there is a fourfold or higher increase in titer the local department of health. symptoms of tularemia for 30 days prior to

PEDIATRIC ANNALS 42:7 | JULY 2013 Healio.com/Pediatrics | 291 FEATURE initiation of therapy with gentamicin, mak- Beta-lactams, clindamycin, and trime- traveled to endemic areas, especially dur- ing treatment failure more likely. thoprim-sulfamethoxazole are not effective ing summer months. The recommended pediatric dose of for the treatment of tularemia. gentamicin for treatment of tularemia is 5 REFERENCES mg/kg divided every 8 or 12 hours and the PREVENTION 1. Feigin RD, Nag PK. Tularemia. In: Feigin RD, typical treatment course with aminogly- Tularemia prevention is best accom- Cherry JD, Demmler-Harrison GJ, Kaplan SL cosides is 10 days. However, extension of plished by steering clear of infected ani- (eds). Textbook of Pediatric Infectious Dis- therapy may be indicated for severe disease mals and insect vectors. Common sense eases. 6th ed. Philadelphia, PA: WB Saunders; 2009:1725-1734. or for those children with prolonged symp- strategies include avoiding dead or sick 2. Hopla CE. The ecology of tularemia. Adv Vet Sci toms prior to diagnosis. Aminoglycoside animals and areas that are tick-infested. Comp Med. 1974;18:25-53. levels should be monitored closely during For hunters or abbatoir workers, ani- 3. Chin JE (ed). Control of Communicable Diseas- es Manual. 17th ed. Washington DC: American therapy due to potential ototoxicity and mals should not be skinned with bare Public Health Association; 2000. nephrotoxicity. Once-daily gentamicin has hands; gloves and eye protection are indi- 4. Centers for Disease Control and Prevention. Re- been reported to be successful for the treat- cated when removing animal skin. All wild ported tularemia cases by state, United States, ment of adults with glandular tularemia,14 game should be cooked thoroughly before 2001 – 2010 and reported tularemia cases by age and sex, United States, 2001 – 2010. Available but no data are available on the efficacy of eating. Patients should be counseled to not at: www.cdc.gov/tularemia/statistics/. Accessed once-daily gentamicin for the treatment of drink untreated water. When mowing the June 10, 2013. tularemia in children. lawn, care should be taken to avoid mow- 5. Centers for Disease Control and Prevention. Tu- laremia—United States, 1990-2000. Morb Mor- ing over any sick or dead animals. tal Wkly Rep. 2002;51:181-184. Alternative Antibiotic Therapies When engaging in outdoor activities, to 6. Levy PD, Chiang WK. Update on emerging Alternative antibiotic therapies for tula- prevent bites from tick and deer flies, pro- : news from the Centers for Dis- ease Control and Prevention. Ann Emerg Med. remia include doxycycline and ciprofloxa- tective clothing such as long pants tucked 2002;40:356-360. cin. Relapse is more common in patients into long socks and long sleeves should 7. Centers for Disease Control and Prevention. treated with tetracyclines (12%) than gen- be worn. Insect repellents that contain Tularemia-Missouri, 2000-2007. Morb Mortal tamicin (6%).13 Therefore, doxycycline is DEET (diethyltoluamide) provide protec- Wkly Rep. 2009;58:744-748. 8. Snowden J, Stovall S. Tularemia: retrospective not recommended as a first-line therapy for tion against ticks but need to be reapplied review of 10 years’ experience in Arkansas. Clin tularemia. In addition, a longer treatment frequently. Formulations that contain 10% Pediatr. 2011;50:64-68. course (14 days) is recommended due to to 30% DEET can be used in children 2 9. Kaya A, Deveci K, Uysal IO, et al. Tularemia in children: evaluation of clinical, laboratory and 11 11 the increased relapse rate. months and older. Children should be therapeutic features of 27 tularemia cases. Turk Unless the benefits outweigh the risks, checked for ticks frequently, especially in J Pediatr. 2012;54:105-112. doxycycline should not be given to chil- the warmer months, in tularemia-endemic 10. Tärnvik A, Chu MC. New approaches to diagno- sis and therapy of tularemia. Ann NY Acad Sci. dren younger than 8 years for the treatment areas. Ticks should be removed as soon 2007;1105:378-404. of tularemia because of the potential for as possible using tweezers, not fingers, by 11. Committee on Infectious Diseases. Tularemia. teeth staining. grabbing the tick as close to the skin sur- In: Pickering LK, Baker CJ, Kimberlin DW, has been shown to have face as possible, then pulling straight up. Long SS (eds). Red Book: 2012 Report of the Committee on Infectious Disease. 29th ed. Elk efficacy in the treatment of tularemia. For Hands should be washed immediately after Grove Village, IL: American Academy of Pedi- example, a Swedish study documented removing a tick. atrics; 2012:768-769. the successful treatment of 12 children As there is no evidence for person-to- 12. Penn RL, Kinasewitz GT. Factors associated with a poor outcome in tularemia. Arch Intern with ulceroglandular tularemia with oral person transmission of tularemia, isolation Med. 1987;147:265-268. ciprofloxacin.15 However, most studies on of infected individuals is not indicated. 13. Enderlin G, Morales L, Jacobs RF, et al. Strep- fluoroquinolone efficacy have been done in Although tularemia is a rare zoonosis, tomycin and alternative agents for the treatment of tularemia: review of the literature. Clin Infect Europe where F. tularensis subspecies hol- pediatricians need to be aware of this in- Dis. 1994;19:42-47. arctica (type B) predominates. F. tularensis fection as the diagnosis is typically made 14. Hassoun A, Spera R, Dunkel J. Tularemia and holarctica causes far less severe disease clinically based on the appropriate expo- once-daily gentamicin. Antimicrob. Agents Che- than F. tularensis tularensis, the major caus- sure history and the classic clinical mani- mother. 2006;50:824. 15. Johansson A, Berglund L, Gothefors L, et al. 16 ative agent of tularemia in North America. festations of the various tularemia syn- Ciprofloxacin for treatment of tularemia in chil- Ciprofloxacin is not recommended dromes. Pediatricians in the south-central dren. Pediatr Infect Dis J. 2000;19:449-453. for the treatment of tularemia in children US are ever vigilant for this infection. Pe- 16. Pechous RD, McCarthy TR, Zahrt TC. Working toward the future: insights into Francisella tula- younger than 18 years because of the po- diatricians across the US should be on the rensis pathogenesis and development. tential for joint and/or cartilage injury. lookout for tularemia in children who have Microbiol Mol Biol Rev. 2009;73:684-711.

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