Unusual Presentatıon Of Oropharyngeal Tularemıa: A Case Report

Introduction

T ularemia is a zoonotic infection caused by Francisella tularensis, a Gram-negative, strictly aerobic coccobacillus (Rubin 2008). Although there are 4 subspecies, human disease is primarily due to 2 subspecies: F. tularensis subspecies tularensis (type A) and F. tularensis subspecies holarctica (type B) (Gurycova et al. 1998, Ellis et al. 2002). The clinical presentations have been classically divided into ulceroglandular, glandular, oculoglandular, oropharyngeal, pneumonic, and typhoidal tularemia, depending on the route of transmission, patient characteristics, and bacterial subspecies (Nigrovic et al. 2008).

Clinical diagnosis of tularemia in an infant can be challenging because of its rarity and overlapping symptoms with other febrile illnesses (Nigrovic et al. 2008). In this report, we describe a case of an 11-month-old toddler with oropharyngeal tularemia presenting as fever of unknown origin (FUO).

Case Report

An 11-month-old and otherwise healthy boy was admitted to our hospital with a 3-week history of fever. Previously, he had been examined at different medical centers for the complaint of fever, and empiric antibiotic treatment with amoxicillin/clavulanate had been administered orally for 7 days followed by intramuscular ceftriaxone treatment for 3 days. However, his fever had not decreased. There was no history of ingestion of contaminated water or food, animal contact, or travel. He was living in an urban area of Ankara province in the central part of Turkey. Physical examination revealed only pharyngeal hyperemia without exudate, tonsillar hypertropy, and cervical adenitis. The patient was hospitalized with the prediagnosis of “FUO” for further investigation and treatment.

Laboratory examinations were as follows: Hemoglobin 9.4 g/dL; hematocrit 28.4%; white blood cell count 19,960/mm³ with 48% neutrophils, 42% lymphocytes, and 10% monocytes; platelet count 626,000/mm³; C-reactive protein (CRP) level 18 mg/L; and erythrocyte sedimentation rate (ESR) 89 mm/h. For renal and hepatic function tests, urine analysis was normal and throat, blood, and urine cultures were negative. Serological tests for Salmonella, Brucella, toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, Epstein-Barr virus, human immunodeficiency virus (HIV), and hepatitis A,B, and C were all negative. There was no abnormality in the patient's laboratory investigation except for elevation of acute-phase reactants; empiric treatment with ampicillin-sulbactam was initiated considering occult bacteremia. However, his fever persisted.

We repeated the history of the patient during follow-up, and his family stated that dead mice were seen in their water supply, which was noticed incidentally only after the patient was hospitalized. This finding led us to the consideration of tularemia, and on the 4th day of hospitalization, antibody positivity for F. tularensis with a titer of 1:1280 was detected. The patient was diagnosed as having oropharyngeal tularemia, and treatment was changed to intravenous gentamicin (5 mg/kg per day). On the 2nd day of therapy, the patient became afebrile and the treatment was completed to 10 days. During the 6-month follow-up, he was well with no relapse.

Discussion

Tularemia has re-emerged as a water-borne endemic in Turkey in recent years (Akalın et al. 2009). Although tularemia was commonly seen in Marmara and the western Karadeniz region before 2005, new tularemia cases were reported from other regions, especially the central Anatolia region, between 2009 and 2010 (Turkish Ministry of Health 2011). The present case came from the central Anatolian region of Turkey. Re-emergence of tularemia might have been due to ecological changes (Akalın et al. 2009). Especially after the rainy seasons, an increase in the rodent population and the contamination of water supplies with rodents are seen as the most important factors (Turkish Ministry of Health 2011). The oropharyngeal form is the most frequently reported form of the disease in our country (Akalın et al. 2009).

The diagnosis of tularemia is established by a thorough history of possible exposure, clinical manifestations, and serial serologic tests (Feigin and Nag 2009). In an infant with FUO, recognition of tularemia may be challenging at initial assessment when the history of patient is not consistent with tularemia. In our patient, there was no known epidemiological risk factor, exposure history, and typical oropharyngeal involvement with cervical adenitis, which is suggestive for oropharyngeal tularemia at the admission.

Regardless of the portal of entry, the mode of onset of tularemia and the general features of the disease are the same. The onset of symptoms is abrupt and include fever, with a temperature usually higher than 39.4°C. In untreated patients, fever may persist for longer than 3 weeks (Feigin and Nag 2009). Although typhoidal or pneumonic tularemia can manifest predominantly as FUO (Feigin and Nag 2009), presentation of oropharyngeal tularemia as FUO is uncommon. So far, no case of infant with oropharyngeal tularemia that manifests as FUO has been reported in the literature.

The patient's physical examination was normal except for pharyngeal hyperemia and fever. For these reasons, tularemia was not considered at the initial assessment. In previously reported cases, the most common symptoms of oropharyngeal tularemia were fever, sore throat, and swelling on the neck; physical examination frequently reveals tonsillopharyngitis and/or cervical lymphadenopathy (Celebi et al. 2008, Meric et al. 2008, Sencan et al. 2009, Kaya et al. 2012). Unlike previous reports, the present case did not have typical oropharyngeal involvement, except for pharyngeal hyperemia. However, hyperemia of the pharynx, even in the absence of exudate or specific symptoms, can be a clue to the diagnosis of tularemia (Feigin and Nag 2009, Palazzi and Feigin 2009).

When a child presents with an unexplained febrile illness or infectious disease, repeated history should be taken by clinicians about the potential exposures to animals and ingestion of contaminated food or water (Lieberman 2009). In the present case, the diagnosis was established by the repeated history and confirmed by serologically.

Although the gold standard for diagnosis of tularemia is positive culture, the definitive diagnosis is complicated by its poor growth with routine laboratory culture and the potential for aerosol inhalation that causes infection of laboratory personnel. Thus, serologic diagnosis in the presence of a compatible clinical illness is the most common method of diagnosis currently used. The standard agglutination test is used for serological diagnosis, and having a single titer of ≥1:160 or a 4-fold increase in convalescent titer confirms the diagnosis. However, it does not provide an early diagnosis because agglutinating antibodies usually are not detectable until the 2nd week of illness (Feigin and Nag 2009, Rubin 2008). For this reason, convalescent serology is especially recommended in patients that are clinically suspicious for tularemia and remain seronegative in the early course of the illness (Snowden et al. 2011). Titers of 1:1280 or greater often develop in patients with active disease as the initial manifestation of seroconversion (Feigin and Nag 2009).

In our patient, a single high titer of 1:1280 that was obtained 3 weeks after the onset of symptoms was thought to be an initial manifestation of seroconversion in the presence of compatible clinical illness. The consumption of contaminated water with dead mice, pharyngeal hyperemia, and a 3-week history of fever unresponsive to amoxicillin/clavulanate, ampicillin-sulbactam, and ceftriaxone treatment and subsiding of the fever with gentamicin therapy led us to the diagnosis of tularemia.

In patients with prolonged FUO, an empiric treatment with β-lactam antibiotics is often initiated. However, F. tularensis strains are generally resistant to β-lactam antibiotics (Rubin 2008). Although in vitro susceptibility testing indicates that the 3rd-generation cephalosporins may be effective against F. tularensis, 1 report showed treatment failure in 8 children given ceftriaxone (Cross and Jacobs 1993). Tetracyclines, aminoglycosides, and quinolones are effective antibiotics (Scheel et al. 1992, Feigin and Nag 2009). The initial empiric antibiotic treatments with amoxicillin/clavulanate, ceftriaxone, and ampicillin-sulbactam were insufficient in our patient and his fever subsided with gentamicin therapy.

In conclusion, even if the clinical findings are not typical, tularemia should be considered in the differential diagnosis of pediatric patients with FUO, particularly in endemic areas like our country.