Correspondence: S. Kili ç , Public Health Institution of Turkey (PHIT), Bacterial Zoonoses Reference Laboratory (National Tularemia Reference Laboratory), Refi k Saydam Campus, Saglik Mah. Adnan Saygun str. No:55, 06100 Sihhiye, Ankara, Turkey. Tel: � 90 312 458 2169. Fax: � 90 312 458 2427. E-mail: selcuk.kilic@thsk.gov.tr; mdskilic2003@yahoo.com

(Received 3 August 2012 ; accepted 7 August 2012 )

Scandinavian Journal of Infectious Diseases, 2013; 45: 324–328

ISSN 0036-5548 print/ISSN 1651-1980 online © 2013 Informa HealthcareDOI: 10.3109/00365548.2012.720027

CASE REPORT

Tularemia during pregnancy: Report of four cases

MURAT YE S I · LYURT 1 , SEL Ç UK KILI Ç 2 , BEK I· R Ç ELEBI · 2 & SERDAR G Ü L 3

From the 1 Department of Infectious Diseases, Tekirda g State Hospital, Tekirda g , 2 National Tularemia Reference Laboratory, Public Health Institution of Turkey, Ankara, and 3 Department of Infectious Diseases, Sorgun State Hospital, Yozgat, Turkey

Abstract Tularemia during pregnancy is exceedingly rare and has been reported infrequently in Europe. A review of the literature identifi ed only 3 documented cases. Herein we report 4 tularemia cases occurring early in the second and third trimesters, which were successfully managed without any adverse pregnancy outcomes.

Keywords: Tularemia , pregnancy , treatment , Turkey

Introduction

Although Francisella tularensis, the causative agent of tularemia, has been recognized as a human and zoonotic pathogen for 100 y, infection of pregnant women by F. tularensis is extremely rare, with only 3 cases reported in the literature [1 – 3]. Additionally, in Kavanaugh ’ s review of 123 cases seen before the advent of antibiotics, 3 patients contracted tularemia during pregnancy and adverse pregnancy outcomes were mentioned [4]. Due to the sparse literature on tularemia during pregnancy, it is not entirely known whether there is a difference in the course of tulare-mia during pregnancy or whether tularemia during pregnancy increases the risk of an adverse pregnancy outcome. Herein, we report 4 cases of tularemia dur-ing pregnancy and review the literature on tularemia in pregnancy.

Case reports

Case 1

A 26-y-old woman at 18 weeks of gestation presented with high fever, malaise, myalgia, sore throat, and a swelling on the neck lasting 2 weeks despite treatment with ceftriaxone. She was living in a village in Yozgat Province where index cases of tularemia had been detected. Upon further questioning, she

reported that 1 week prior to her fi rst symptoms, she drank spring water from the environment.

On clinical examination, a painfully enlarged lymph node with a size of 6 � 2 cm, with a hard surface and fi xed to the underlying tissues was palpable in the right submandibular region. Her body temperature was 37.8 ° C and she had a blood pressure of 130/80 mmHg and heart rate of 96/min. The remainder of the physical examination were unremarkable. An obstetric examination revealed a 19-week normal pregnancy, without any indications of preterm delivery. Admission labora-tory fi ndings were a white blood cell count (WBC) of 10.5 � 10 3 / μ l with normal differential, an eryth-rocyte sedimentation rate (ESR) of 72 mm/h, and C-reactive protein (CRP) of 17 mg/l.

An ultrasound (US) examination revealed a single, large (72 � 23 mm) adenomegaly located in the right submandibular region showing poor echo-genicity, with necrotic and cystic components, indicative of an infectious process. A needle aspirate of the submandibular lymph node for bacterial sampling yielded yellowish-green pus. The pus was negative by acid-fast stain, cultures, and fun-gal studies. While culture and polymerase chain reaction (PCR) for F. tularensis in the drained lymph node were negative, F. tularensis serology was positive with a micro-agglutination test (MAT)

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Tularemia during pregnancy 325

titre of 1:2560 and F. tularensis enzyme-linked immunosorbent assay (ELISA) IgM/IgG (Institut Virion\Serion GmbH, Germany). Following this defi nite diagnosis of tularemia, epidemiological and environmental investigations were carried out in the village where the case was resident to identify sources of infection. PCR for F. tularensis was positive in the faecal specimen of a rodent that was obtained from the cellar.

The patient was treated with gentamicin (5 mg/kg/day) for 10 days, during which time her submandibular lymph node continued to enlarge; she developed 2 tender adenomegalies in the right jugulodigastric region while on therapy and ulti-mately required surgical drainage. Antimicrobial therapy was switched to ciprofl oxacin (1 g per day, PO) because of persistent fever, emerging LAPs, and an increase in ESR and CRP levels. A 2-week course of ciprofl oxacin was started and weekly needle drain-age of the lymph nodes was performed. The preg-nancy outcome was not affected by the infection and the patient and the baby were normal during 18 months of follow-up. Blood drawn from the infant after birth contained agglutinins for F. tularensis in low dilutions (MAT titre 1:160) and was non-reactive at 6-months of follow-up. Additionally, ELISA IgG was positive whilst IgM was negative.

Case 2

A 31-y-old woman at 23 weeks of gestation was hos-pitalized with a 10-day history of sudden onset of fever, headache, sore throat, swollen right upper lid, injected and erythematosus right eye, epiphora, pre-auricular and submandibular tender lump on the right, and skin lesions on the legs. She had already been treated with an oral second-generation cepha-losporin and tobramycin eye drops for 7 days with a diagnosis of upper respiratory tract infection and bacterial conjunctivitis at another hospital. Following this, she presented to our hospital since her symp-toms persisted and the swelling had increased despite antibiotic therapy. On admission, she presented symptoms compatible with Parinaud ’ s oculoglandu-lar syndrome, including a fever, purulent conjuncti-vitis of the right eye, and enlarged homolateral pre-auricular and submandibular lymph nodes. Her tonsils were hypertrophic and there was a yellowish-white exudate and ulceration on her right tonsil. Furthermore, she had painful, itchy, erythematous nodules on the tibial surfaces of both legs. Her laboratory studies were remarkable for a WBC of 9.4 � 10 3 / μ l with normal differential, an ESR of 57 mm/h, and CRP level of 81 mg/l.

Lymphadenopathy with central necrosis and cys-tic or hypoechoic appearances was the main fi nding

on US. The pre-auricular and submandibular adenopathies were surgically drained, and standard cultures of the pus sample remained sterile. Patho-logical examination of the aspirates revealed a mixed type of suppurative infl ammation. Specifi c cultures for Francisella from conjunctival and throat swabs and lymph node aspirates were negative, whereas serological testing revealed a high titre (MAT titre 1/1280) and specifi c antibodies, as well as ELISA IgM and IgG positivity. The patient was then treated with gentamicin for 10 days. The signs and symp-toms of conjunctivitis and skin lesions (erythema nodosum) disappeared within 10 days of therapy. Despite a 10-day course of gentamicin, the lymph-adenopathies continued to enlarge and needle aspira-tion yielded 12 ml of purulent fl uid. A 10-day course of oral ciprofl oxacin therapy (1 g per day) was initi-ated due to therapeutic failure and she improved clinically, however her lymph nodes required weekly needle drainage. The patient was delivered of a 38-week term baby and the neonate did not have any evidence of congenital infection. Follow-up samples from the infant were screened for tularemia antibod-ies. Tularemia serology was positive with a MAT titre of 1:80 and ELISA IgG. MAT titres decreased from 1:80 to negative by 4 months of age. The male baby was normal at the 90th percentile during 18 months of follow-up.

Case 3

A 29-y-old woman at 27 weeks of gestation was referred to the hospital because of a 12-day history of fever, chills, myalgias, and throat pain, and a 5-day history of a swelling on the neck. She had been treated empirically with amoxicillin – clavulanate for 7 days with the presumptive diagnosis of tonsil-lopharyngitis. Physical examination disclosed an agi-tated patient with a blood pressure of 140/95 mmHg, a pulse rate of 108 beats/min, respirations of 24/min, and a temperature of 38.6 ° C. There was a 5 � 2 cm tender and hyperemic adenopathy in the right sub-mandibular region. An obstetric examination revealed a 28-week normal pregnancy, without any indica-tions of preterm delivery. On US examination a large (45 � 24 mm) lymphadenopathy located in the right submandibular region showed central necrosis and cystic or hypoechoic appearances, and multiple small upper jugular adenopathies were detected.

Her laboratory studies were remarkable for a WBC of 9.6 � 10 3 / μ l with normal differential, CRP of 4.0 mg/l, and an ESR of 56 mm/h. Routine cultures of the needle aspirate of the lymph node pus were negative for pyogenic bacteria, acid-fast organisms, and fungi. None of the samples obtained from lymph nodes were positive for F. tularensis by

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326 M. Ye s ilyurt et al.

PCR or in culture. The antibody against tularemia was detected as positive at 1/640 dilution on MAT and by ELISA IgM and IgG positivity, and treatment was started with gentamicin. However, since the lymphadenopathies increased in size after gentami-cin therapy, a 2-week course of oral ciprofl oxacin (1 g per day) was started and weekly needle drainage of the lymph nodes was performed. In the follow-up, the adenopathies were distinctly decreased within 2 months. The patient was delivered of a 38-week term baby. The patient and the baby were in good health during 18 months of follow-up. Initial serum samples were positive by MAT and ELISA IgG. The MAT titres of the infant decreased from 1:160 to negative by 5 months of age.

Case 4

A 35-y-old woman at 30 weeks of gestation was hos-pitalized with a high fever, myalgia, throat pain, and a 4-day history of a swelling on the neck. She was treated with amoxicillin – clavulanate 10 days before admission to the hospital; however, she experienced continued fever, general malaise, and pain, and the neck mass appeared. Physical examination was unremarkable except for exudative tonsils and bilat-eral, fl uctuating submandibular lymphadenopathies. Pertinent fi ndings of laboratory studies at admission included the following: WBC of 9.6 � 10 3 / μ l with normal differential, CRP 20 mg/l, and ESR 93 mm/h. On US examination, bilateral lymphadenopathies with central necrosis and abscess formation were detected in the submandibular and upper jugular regions.

Tularemia was diagnosed serologically and the patient was treated with gentamicin. Because of the initial persistence of the lymph node swelling and new emerging lymphadenopathies despite antibiotic treatment, ciprofl oxacin (1 g/day) was added for 2 weeks, and she underwent an incision and drain-age procedure. Her condition improved rapidly on fl uoroquinolone therapy, and in the follow-up, adenopathies were distinctly decreased within 2 months. The patient was delivered of a 38-week term baby. The patient and the baby were in good health during 18 months of follow-up. Serum samples were reactive by ELISA IgG by 3 months of age and MAT titres decreased from 1:160 to negative by 5 months of age.

Discussion

Infections in pregnant women may be grave, lead-ing to foetal and maternal morbidity and mortality. Whilst awareness of tularemia infection as a cause of

intrauterine death in sheep is well known, tularemia as a cause of abortion or intrauterine death in the human is hardly recognized [5]. Evidence of F. tularensis as a cause of abortion or premature birth in humans is very scarce; only 3 cases occurring during pregnancy have been reported [1–3]. A literature search showed only 3 case reports on tularemia in pregnancy and its outcome in the foe-tus. These 3 cases and the cases reported herein are outlined in Table I. The majority of the reports in the literature and our 4 cases describe the mid-dle and last trimester of pregnancy. In the second and third trimesters of pregnancy, abortion and preterm delivery have been observed in more than 30% of cases (case 1 and 2), who became infected before the availability of antibiotics. The remaining cases (cases 3 – 7), who were treated with antibiot-ics, delivered a healthy baby without signs of active disease. Therefore, early diagnosis of tularemia is essential to start appropriate treatment in time, in order to reduce the adverse pregnancy outcomes. On the other hand, to evaluate whether there is an increased risk of adverse pregnancy outcomes and congenital infections, there is a need for reports describing the progression during early pregnancy.

Two issues are important in the management of tularemia during pregnancy: the appropriate clinical management of infection and the preven-tion of adverse pregnancy outcomes. With regard to antimicrobial treatment of tularemia, there are almost no clinical data regarding treatment in pregnant women. Our treatment consisted of gen-tamicin and ciprofl oxacin, which is in agreement with guideline recommendations about initiating treatment with gentamicin. Recommendations for the use of antimicrobial therapy come from proto-cols used in non-pregnant patients. Although sec-ond- and third-generation cephalosporins are quite safe during pregnancy (US Food and Drug Admin-istration (FDA) pregnancy risk category B), F. tularensis produces β -lactamase, rendering peni-cillins, cephalosporins, and carbapenems ineffec-tive [6]. Additionally, there is no antimicrobial drug in risk category B to treat tularemia in preg-nancy. Some guidelines recommend gentamicin, streptomycin, ciprofl oxacin, or doxycycline (risk category C) for treatment and post-exposure pro-phylaxis of tularaemia in pregnant women [6 – 9]. The World Health Organization [6] and the UK Health Protection Agency [7] recommend gen-tamicin or ciprofl oxacin as a fi rst-line therapy option. Similarly, the use of gentamicin or strepto-mycin at standard dosing and ciprofl oxacin or doxycycline as suitable alternatives (second-line treatment) has been recommended by a work-ing group on civilian bio-defence, even though

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Tularemia during pregnancy 327

gentamicin and ciprofl oxacin are not approved for administration in pregnancy by the FDA [8]. Doses are the same as for non-pregnant subjects, but the treatment period should be individualized [6].

Our patients did not recover with the fi rst course of antibiotic (gentamicin), and ciprofl oxacin was given as a second course of antimicrobial treatment because of a recurrence of symptoms and signs. All cases were diagnosed as having oropharyngeal tula-remia 13 – 18 days after the onset of symptoms, which could have contributed to the therapeutic failure. A treatment delay of more than 14 days has been found to be the only statistically signifi cant risk factor for therapeutic failure, reducing the success rate and prolonging the recovery period in oropharyngeal tularemia cases [10].

Our recommendations are to restrict antibiotic use to the aminoglycoside gentamicin, which is safe dur-ing pregnancy; we also recommend avoiding strepto-mycin due to its association with irreversible deafness in children exposed in utero, and the administration of oral ciprofl oxacin in the case of therapeutic failure or non-availability of intravenous gentamicin or due to the known toxicities of doxycycline.

All infants underwent follow-up clinical and lab-oratory evaluation up to 18 months of age. Follow-up serum samples from all tularemia-seropositive moth-er – infant pairs were obtained in order to assess the kinetics of maternally acquired antibody to tularemia in infants. In the comparison of mother – infant paired sera, we found that all mothers who were tularemia-seropositive transferred specifi c antibody to their infants, and all of the infant serum MAT titres were lower than those of the mother. In 18 months of follow-up of the 4 infants studied, we observed that antibody to F. tularensis disappeared in 1 infant by 4 months of age, in 2 by 5 months of age, and in 1 infant by 6 months of age.

In conclusion, on the basis of the limited number of cases reported to date, tularemia infection occur-ring in mid-pregnancy appears to be a relatively mild disease that is not a signifi cant cause of morbidity and mortality in either the gravid mother or the foe-tus. Our cases show that tularemia during pregnancy can be successfully managed just as it is in non-preg-nant women. No adverse effects were observed in the term infants or at the 18-month follow-up. The recovery of these 4 cases without any adverse preg-nancy outcomes could have been due to the low virulence of F. tularensis subspecies holarctica which is seen in Turkey.

Acknowledgements

We thank Mesure Ç elik and Fikret Erdo g an for their assistance in performing this study. T

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328 M. Ye s ilyurt et al.

Declaration of interest: No competing interests to declare. No funding.

References

Bricker D . Tularemia infection during pregnancy . Am J Nursing [1] 1931 ; 31 : 979 – 82 . Dudley PB , Don CW . Tularemia and pregnancy: report of a [2] case . J Am Med Assoc 1936 ; 107 : 577 – 8 . Charles P , Stumpf P , Buffet P , Hot A , Lecuit M , Dupont B , [3] et al . Two unusual glandular presentations of tick-borne tularemia . Med Mal Infect 2008 ; 38 : 159 – 61 . Kavanaugh CN . Tularemia: a consideration of one hundred [4] and twenty-three cases, with observations at autopsy in one . Arch Intern Med 1935 ; 55 : 61 – 85 . O ’ Toole D , Williams ES , Woods LW , Mills K , Boerger-Fields A , [5] Montgomery DI et al . Tularemia in range sheep: an over-looked syndrome? J Vet Diagn Invest 2008 ; 20 : 508 – 13 .

World Health Organization . WHO guidelines on tularaemia . [6] Geneva: WHO Press ; 2007 . Health Protection Agency, UK . Tularemia guidelines for [7] action in the event of a deliberate release. Version 2.4.1 31 . London: HPA Centre for Infections ; 2009 . Available at : http://www.hpa.org.uk/web/HPAwebFile/HPAwebC/1194947357555 ( accessed 12 April 2012). Dennis DT , Inglesby TV , Henderson DA , Bartlett JG , [8] Ascher MS , Eitzen E , et al . Tularemia as a biological weapon: medical and public health management . JAMA 2001 ; 285 : 2763 – 73 . Bossi P , Tegnell A , Baka A , Van Loock F , Hendriks J, [9] Werner A , et al . Bichat guidelines for the clinical manage-ment of tularaemia and bioterrorism-related tularaemia . Euro Surveill 2004 ; 9 : E9 – 10 . Meric M , Willke A , Finke EJ , Grunow R , Sayan M , [10] Erdogan S et al . Evaluation of clinical, laboratory, and therapeutic features of 145 tularemia cases: the role of quinolones in oropharyngeal tularemia . APMIS 2008 ; 116 : 66 – 73 .

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