A Tularemia Outbreak in an Extended Family in Tokat Province, Turkey: Observing the Attack Rate of Tularemia

Home , Amasya Province, Suluova, Tokat, Tokat Province

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provided by Elsevier - Publisher Connector International Journal of Infectious Diseases (2009) 13, 745—748

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A tularemia outbreak in an extended family in Tokat Province, Turkey: observing the attack rate of tularemia

Sener Barut a,*, Ilhan Cetin b

a Department of Infectious Diseases and Clinical Microbiology, School of Medicine, Gaziosmanpasa University, Tokat 60100, Turkey b Department of Public Health, School of Medicine, Gaziosmanpasa University, Tokat, Turkey

Received 20 November 2007; received in revised form 28 November 2008; accepted 1 December 2008 Corresponding Editor: William Cameron, Ottawa, Canada

KEYWORDS Summary Turkey; Objective: We report the ﬁrst tularemia epidemic occurring in Tokat Province, located in the Attack rate; Middle Black Sea Region of Turkey, and some features of the cases. This epidemic has allowed the Tularemia epidemic calculation of the attack rate of this disease because of its appearance in a single large family. Methods: The clinical and laboratory features of patients were examined. For serological diagnosis, microagglutination assays were done on serum samples from patients and other members of the family. Results: Seven members of the family developed overt clinical disease (one ulceroglandular, six oropharyngeal). Three patients had conjunctivitis in addition to oropharyngeal involvement. All patients had a microagglutination titer above 1/160. As eight out of 16 members of the extended family were found to be positive for tularemia serology, the attack rate was calculated to be 50%. Conclusions: Tularemia is highly infectious and different clinical forms can occur in a single epidemic. # 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Introduction important role in transmission of the bacteria to humans.1,2 While epidemics related to tick bites are frequently seen in Tularemia, a disease caused by the bacterium Francisella the summer season, epidemics seen in the winter season are tularensis, is characterized by fever and lymphadenopathy. generally related to contact with animals or the use of Tularemia is a zoonosis in which the sources of infection are contaminated water. F.tularensis comprises four subspecies, primarily small animals such as mice, squirrels, voles, hares, two of which are clinically and epidemiologically important. and beavers. Ticks and ﬂies are vectors that may play an F. tularensis subsp. tularensis is generally seen in North America, is the more virulent, and is related to tick bites. Strains of F. tularensis subsp. holarctica cause a milder * Corresponding author. Tel.: +90 356 2129500; disease; epidemics are related to contact with infected fax: +90 356 2143788. animals or contaminated water and are primarily seen in 2—4 E-mail address: [email protected] (S. Barut). Euroasia.

Tularemia comprises six different clinical forms. Although tularemia was suspected and she was referred to our hospi- the ulceroglandular form is most frequently reported in the tal. The patient had no history of tick, rat, or mosquito bite. international literature, the form most frequently seen in On admission she had a tender epitrochlear lymphadenopa- Turkey is the oropharyngeal type.2,4 The first tularemia epi- thy (LAP) on her right arm and had no fever. During repeated demic in Turkey was reported in 1936, and since then other physical examinations a healing ulcerative lesion was noted epidemics have been seen, especially in the northwestern on a finger of the right hand. A diagnosis of the ulcerogland- part of the country.5—8 Here we present the first tularemia ular form of tularemic disease was made and she was treated epidemic occurring in Tokat Province, located in the middle with 14 days of streptomycin 1 Â 1g. Black Sea region of Turkey, and some features of the cases. All the other patients had experienced a severe sore This epidemic has allowed the calculation of the attack rate throat together with chills and fever within the same time of the disease because of its appearance in a single large period, suggesting the oropharyngeal form. Five patients family. developed cervical swelling or preauricular LAP, but one patient had no lymphadenopathy (Table 1). All patients Patients and methods had been previously misdiagnosed with bacterial pharyngitis by specialists in otorhinolaryngology or general practitioners and had been treated with beta-lactams or macrolides with- Seven cases, all members of the same extended family, were out any benefit. Fever lasted for 1—2 weeks in these patients. admitted to our infectious diseases outpatient clinic in Three patients had symptoms of conjunctivitis during the December 2005. All cases had experienced a febrile illness illness and one of them was given topical antimicrobial 20—25 days before admission to our clinic. None of the treatment. Conjunctivitis improved in all patients without patients had fever on admission. Complete blood counts, any complications. All patients were found to be positive for erythrocyte sedimentation rates (ESR), and C-reactive pro- tularemia serology by microagglutination assay (Table 1). tein (CRP) levels were measured. A diagnosis of tularemia During the visit made to the patients’ house in the village, was suspected due to clinical findings; for specific diagnosis, we observed that the family had two water sources, one from sera of the patients were sent to Uludag University Micro- the village water supply and the other from a natural spring. biology Laboratory for microagglutination assay. The antigen The exit site of the spring was closed and water was carried to used in the serological tests was prepared from an F. tular- the house via pipes. It appeared that there was no contam- ensis strain.4 Antibody titers of 1/160 and above were ination risk with dirty water or wild animals. However, they accepted to be significant for diagnosis. Two weeks after reported that there were a lot of mice around or in the house the definite diagnosis of tularemia, a visit was made to the and that food may have become contaminated with their patients’ house in the village. Serum samples were obtained secretions, as they stocked grains and some other foods in the from nine healthy members of the family and were sent to the house. They had had no contact with dead animals. There same laboratory for tularemia microagglutination assay. We were no other tularemia patients in the village. Examination received an informed consent from all study participants. of health records also revealed that there had been no other In addition, a proxy consent was taken for the mentally cases of tularemia in this region up until this time, and that retarded case. these patients were the first cases reported from Tokat Province. Results Among nine healthy members of the family, only one had a titer greater than 1/160 by microagglutination assay. The Of seven patients admitted to our clinic, five had cervical others were found to be seronegative. The person with adenopathy and one patient had adenopathy with location positive serology was a 30-year-old mentally retarded man other than cervical. The first case, a 33-year-old woman, was (case 8, Table 1). He had no symptoms at the time of visit, but the only one who did not have cervical adenopathy (case 1, we learned that he had experienced flu-like symptoms during Table 1). One month before admission to our clinic she the same period. experienced fever and chills lasting 5 or 6 days, followed Aminoglycoside monotherapy (streptomycin 1 Â 1 g for by axillar adenopathy. An axillary adenectomy was done. As adults and gentamicin 5 mg/kg/day for children) was given pathologic examination showed necrotizing lymphadenitis, to four patients. Streptomycin plus doxycycline was given to

Table 1 Characteristics and microagglutination test results of the patients

Case No. Age Gender Lymphadenopathy Clinical form Conjunctivitis Microagglutination titer 1 33 F Axillar, epitrochlear Ulceroglandular No 1/640 2 42 M Cervical Oropharyngeal No 1/640 3 33 F Cervical Oropharyngeal No 1/2560 4 4 M Submandibular, preauricular Oropharyngeal Yes 1/1280 5 14 F Cervical Oropharyngeal Yes 1/1280 6 75 M Cervical Oropharyngeal No 1/1280 7 37 M No Oropharyngeal Yes 1/320 8 a 30 M No Oropharyngeal No 1/320 a This case had a history of fever and sore throat, but was not admitted to our clinic; a microagglutination test was carried out on a serum sample obtained from this patient during a house visit. Tularemia outbreak in an extended family, Turkey 747

Table 2 Laboratory ﬁndings at presentation and treatments applied

Case No. ESR (mm/h) Leukocyte count (Â109/l) CRP (mg/l) Treatment Surgery Treatment failure 1 a 37 8.470 10.2 Strep + No 2 64 9.690 16 Dox + Strep À No 3 88 9.210 27.6 Strep + No 4 52 13.540 7.96 Genta + No 5 55 12.890 <5 Genta À No 6 72 8.470 41.5 Dox b À Yes 7 63 12.060 8.91 Dox À No ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; Genta, gentamicin; Strep, streptomycin; Dox, doxycycline. a This patient underwent a diagnostic adenectomy. b After treatment failure with doxycycline, ciprofloxacin was given to this patient. one patient because of a large cervical lymphadenopathy. and that the possible source of infection was contaminated Two patients started treatment with doxycycline because water or food. Helvacı et al.4 investigated 205 cases of one of them was old and one had a previous history of illness tularemia from small epidemics or occurring sporadically without lymphadenopathy at admission, but had a high ESR between 1988 and 1998 in Turkey. They reported that the and high CRP level. Some of the laboratory findings and the oropharyngeal disease was the most frequent clinical form treatments given to the patients are shown in Table 2. (83%) and that epidemics were related to contaminated A surgical approach was required for two patients. These water. Four of 205 patients had the ulceroglandular or patients developed fluctuation of the adenopathy after they glandular disease. In recent years, reports of tularemia epi- had completed the 14 days of medical treatment (Table 2). demics from the northwestern part of Turkey have shown that The preauricular adenopathy in the 4-year-old patient was almost all cases developed the oropharyngeal type.6—8,13 In a aspirated with a needle and the cervical adenopathy in the recent report from Suluova, Turkey, unlike in the other 33-year-old women was drained through an incision. epidemics, the glandular form was found to be the most Although a slight regression of adenopathies was observed common (60.4%), followed by the ulceroglandular form; only at the end of treatment, a significant regression was observed 4.7% of cases had the oropharyngeal form.14 at two weeks after completion of treatment and it was shown It seems most likely that the source of the present epi- that adenopathies almost fully regressed one month later demic was contaminated food or water, because all patients (after the completion of treatment). A failure of doxycycline except one developed the oropharyngeal disease. The treatment was considered in one patient, as he had persis- patient with ulceroglandular disease (case 1) may have got tent constitutional syndrome with elevated markers of the bacteria through the skin via handling or touching the inflammation.9 A further course of antibiotic treatment with contaminated food or water. Because all cases occurred ciprofloxacin 500 mg bid for 14 days was given to the patient, within a few days, human-to-human transmission was con- which was successful (Table 2). sidered not to have taken place. Also, they had no history of Eight of 16 members of the family were found to be risk factors such as tick bite or contact with dead animals. positive for tularemia by microagglutination assay. Hence Another interesting feature of the present epidemic was the attack rate of tularemia was calculated to be 50%. that three out of seven patients who had the oropharyngeal disease developed conjunctivitis in addition to fever, sore Discussion throat, and cervical lymphadenopathy. In the oculoglandular form of tularemia, infection occurs as a result of the Tularemia is transmitted in several different ways to humans. transfer of bacteria on the fingertips or from contaminated Tick or fly bites are the most frequent means of transmission. splashes and aerosols to the conjunctiva.2,3,11 The finding of The bacteria can survive for long periods in water sources or conjunctivitis occurring in the course of oropharyngeal dis- in animal carcasses. The oropharyngeal form of the disease ease in the present epidemic may have been as a result of characterized by pharyngitis and lymphadenopathy can occur autoinfection, through transfer of the bacteria in oral secre- as a result of ingestion of contaminated water or food. When tionsbymeansofthepatients’ownhands.Thompsonetal.15 bacteria are inoculated into conjunctiva, the oculoglandular reported a case of oculoglandular tularemia in which the form of the disease occurs.2,3 Bacteria may also enter into bacteria were transmitted via contact with a wild animal. the respiratory system and lead to pneumonic tularemia.10,11 Celebi et al.7 reported that four patients had findings of Oropharyngeal tularemia in particular has increasingly oculoglandular tularemia in the oropharyngeal tularemia been reported from different parts of Europe.2,12 Although epidemic that affected 61 individuals in the northwest of in these reports almost all cases have had one form of the Turkey. Two other waterborne tularemia outbreaks have disease, there have been a few reports in which the orophar- occurred in Duzce, Turkey in the years 2000 and 2005.8 yngeal and ulceroglandular forms have been seen in the same The oropharyngeal form was the most commonly seen type epidemic.4 In our epidemic one patient had the ulcerogland- in both outbreaks, whereas three of the total of 11 patients ular form, but the others had the oropharyngeal form. Rein- affected in the 2005 outbreak had the oculoglandular form. tjes et al.12 investigated a tularemia outbreak that occurred In 2004, Leblebicioglu et al.14 investigated a tularemia in Kosovo in the early postwar period, 1999—2000. They epidemic seen in Suluova, Amasya Province, which neigh- reported that all cases were in the oropharyngeal form bors Tokat Province. They observed the concomitance of 748 S. Barut, I. Cetin conjunctivitis with the glandular form in five cases and 5. Karadenizli A, Gurcan S, Kolayli F, Vahaboglu H. Outbreak of suggested that the infectious agent spreads to the eye by tularemia in Golcuk, Turkey in 2005: report of 5 cases and rubbing or scratching following contact with infected ani- overview of the literature from Turkey. Scand J Infect Dis mals or water. 2005;37:712—6. 6. Gurcan S, Otkun MT, Otkun M, Arıkan OK, Ozer B. An outbreak of Sixteen people were living in the same house, so all were tularemia in Western Black Sea region of Turkey. Yonsei Med J exposed to the same risk factors. When serologic tests were 2004;45:17—22. applied to the sera from persons who did not show any 7. Celebi G, Baruonu F, Ayoglu F, Cinar F, Karadenizli A, Ugur MB, symptoms but who had been exposed to the same risk et al. Tularemia, a reemerging disease in northwest Turkey: factors, it was found that only one person had high titers epidemiological investigation and evaluation of treatment of tularemia (titer of 1/320). Thus, eight patients were responses. Jpn J Infect Dis 2006;59:229—34. affected by this epidemic and the attack rate was calculated 8. Ozdemir D, Sencan I, Annakkaya AN, Karadenizli A, Guclu E, Sert to be 50% (8/16). E, et al. Comparison of the 2000 and 2005 outbreaks of The infective dose of the tularemia agent in humans is tularemia in the Duzce region of Turkey. Jpn J Infect Dis extremely low — 10 bacteria when injected subcutaneously 2007;60:51—2. 9. Perez-Castrillon JL, Bachiller-Luque P, Martin-Luquero M, Mena- and 25 when given in an aerosol form.10 Although it is known Martin FJ, Herreros V.Tularemiaepidemic in northwestern Spain: to be an extremely contagious pathogen, we found no report clinical description and therapeutic response. Clin Infect Dis on the attack rate of tularemia in the English language 2001;33:573—6. medical literature. In the present epidemic the source of 10. Feldman KA, Enscore RE, Lathrop SL, Matyas BT, McGuill M, infection was thought to be contaminated food or water and Schriefer ME, et al. An outbreak of primary pneumonic tularemia the attack rate was 50%. Because brucellae and Yersinia on Martha’s Vineyard. N Engl J Med 2001;345:1601—6. pestis are similar pathogens to the tularemia agent, we 11. Tarnvik A, Berglund L. Tularaemia. Eur Respir J 2003;21:361—73. can compare the attack rate of tularemia with the attack 12. Reintjes R, Dedushaj I, Gjini A, Jorgensen TR, Cotter B, Lieftucht rates of brucellosis and plague. Attack rates in Brucella A, et al. Tularemia outbreak investigation in Kosovo: case control epidemics, which have occurred mostly as a result of acci- and environmental studies. Emerg Infect Dis 2002;8:69—73. 13. Gurcan S, Eskiocak M, Varol G, Uzun C, Tatman-Otkun M, Sakru N, dental laboratory exposure, range from 30% to 100%.16—19 et al. 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