A rare cause of granulomatous hepatitis: Tularemia

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A rare cause of granulomatous hepatitis: Tularemia Emine Kocabas¸ a,∗ , Özlem Özgür Gündes¸lio˘glu a , Merve Kılıc¸ C¸il a , Ümmühan C¸ay a , Figen Doran b , Süreyya Soyupak c a b c

C¸ukurova University Faculty of Medicine, Departman of Pediatric Infection Disease. Adana, Turkey C¸ukurova University Faculty of Medicine, Departman of Pathology. Adana, Turkey C¸ukurova University Faculty of Medicine, Departman of Radiology. Adana, Turkey

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Article history: Received 18 July 2019 Received in revised form 16 October 2019 Accepted 17 December 2019 Keywords: Tularemia Granulomatous hepatitis Child

a b s t r a c t Tularemia is a zoonotic infection caused by Francisella tularensis. Tularemia has several clinical form in humans, including ulceroglandular, pneumonic, oropharyngeal, oculoglandular, and systemic (typhoidal). Tularemia may develop granulomatous and suppurative lesions, especially in the affected regional lymph nodes and various organs. Patients with hepatic involvement typically have elevated transaminase levels, hepatomegaly and rarely jaundice. Histologically, there are typically suppurative microabscesses with occasional surrounding macrophages. Rarely, hepatic granuloma can develop due to tularemia. We present a case of an 8 year-old male residing in a rural village in Turkey, who came to our hospital after having intermittent fever for four months and right upper abdominal pain for two months. Liver had a nodular appearance in liver imaging and liver biopsy were consistent with granulomatous hepatitis. The microagglutination test was positive for tularemia in the patient who was investigated for granulomatous hepatitis etiology. Symptoms and signs improved with tularemia treatment. We present a rare case of hepatic involvement of tularemia in a child. Clinicians should be suspicious of and evaluate for typhoidal tularemia in patients who present with prolonged fever and non-specific systemic symptoms, potentially with associated abdominal pain. © 2019 Published by Elsevier Ltd on behalf of King Saud Bin Abdulaziz University for Health Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).

Background Tularemia is a potentially fatal, multisystemic, zoonotic infectious disease that is especially seen in northern hemisphere [1]. Francisella tularensis is transmitted by direct contact from infected animals, ticks, biting flies, and inhaled infected aerosols. Tularemia can also be transmitted through contaminated food or water. Depending on the path and location of the bacteria in the body, ulceroglandular, glandular, oropharyngeal, typhoidal and pneumonic tularemia may develop [1]. Hepatic involvement in tularemia is characterized by elevated transaminase levels, hepatomegaly and suppurative microabscesses with occasional surrounding macrophages histologically [1,2]. Granulomatous hepatitis is a multifactorial liver disease that shows a specific inflammatory response to reticuloendothelial sys-

∗ Corresponding author. E-mail addresses: [email protected] (E. Kocabas¸), [email protected] (Ö. Özgür Gündes¸lio˘glu), [email protected] (M. Kılıc¸ C¸il), [email protected] (Ü. C¸ay), fi[email protected] (F. Doran), [email protected] (S. Soyupak).

tem in liver. Although F. tularensis has been shown in previous experimental studies leading to necrotizing hepatic granulomas, we could not find any case report of granulomatous hepatitis associated with tularemia published in the literature [3]. We present a rare case of hepatic involvement of tularemia in a child.

Case An 8 years-old male patient had fever and malaise complaints intermittently for 4 months. The patient presented with a stomachache 2 months ago. Family was using water supply network of their village and the patient had a habit of eating snow. The patient had no contact with tick or rodents. There were many rodents in the village where the patient lives. In physical examination; he showed normal growth, vital findings were stable, hepatomegaly with the liver edge 3 cm below, splenomegaly 1 cm below the costal margin were found. On physical examination, lymphadenopathy was absent and oropharyngeal examination was normal. In laboratory tests; white blood cell, hemoglobin and plateletcounts were within normal limits. C-reactive protein was 2.29 mg/L (normal value <5 mg/L). Liver function enzymes and bilirubin levels were

https://doi.org/10.1016/j.jiph.2019.12.007 1876-0341/© 2019 Published by Elsevier Ltd on behalf of King Saud Bin Abdulaziz University for Health Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: Kocabas¸ E, et al. A rare cause of granulomatous hepatitis: Tularemia. J Infect Public Health (2020), https://doi.org/10.1016/j.jiph.2019.12.007

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completely resolved. After these treatment, tularemia microagglutination test was 1/20 in the second month of treatment.

Discussion

Fig. 1. Abdominal MRI imaging (numerous microabscesses). The arrows shows the microabcesses. Written and verbal consent was obtained from the parents of the patient.

Fig. 2. Granuloma structure with rich in giant cells and micro-abscesses. The arrows shows granuloma structure in the liver. Written and verbal consent was obtained from the parents of the patient.

normal. In abdominal ultrasonography; partly patchy and nodular, non-sharply circumscribed hyper-echogenic lesions in right lobe of the liver were detected. Many hyperdense lesions with milimetric diameter were reported in abdominal MRI (Fig. 1). Granulomatous hepatitis was identified in liver biopsy (Fig. 2).Tuberculosis PCR from liver biopsy material was negative, chest X-ray and thorax CT were normal and the patient’s PPD value was 0 × 0 mm, so tuberculosis was excluded. Immunologic examinations were normal. IFA and PCR assays for Q fever and cat scratch disease were negative. There was a myelocyte predominance on bone marrow evaluation. Hepatitis B, C, Toxoplasma and CMV serology were negative. While infectious and non-infectious causes of granulomatous hepatitis were under investigation; Tularemia Micro-Agglutination Test was reported 1/320 positive in blood sample. We started treatment of patient with streptomycin and ciprofloxacin for tiphoidal tularemia. Streptomycin was discontinued on the 14th day and oral ciprofloxacin therapy was continued. After 14th day of treatment, the patient’s fever improved. Gentamicin was added to the treatment because there was no improvement in the abdominal ultrasound examination on day 21 st of ciprofloxacin therapy and abdominal pain, fatigue and anorexia were continued. Ciprofloxacin was given for 1 month, gentamicin for 10 days. The patient who had no complaints during the follow-up was found to have a decline in findings in the first three months after the abdominal ultrasonography, and after 6 months, the findings were

In this article, we present an 8-year-old patient with prolonged intermitent fever, abdominal pain and hepatosplenomegaly on physical examination and radiological and histopathological granulomatous involvement of the liver. Autoimmune diseases (Sarcoidosis, Primary biliary cirrhosis), malignant diseases (lymphoma), drugs, idiopathic diseases such as granulomatous hepatitis may develop due to non-infectious reasons. Tuberculosis, other mycobacterial infections, brucellosis, Q fever, Tularemia, whipple disease, fungal infections, Listeriosis, Schistozomiasis, Hepatitis B, Hepatitis C, HIV, CMV, EBV infection, Cat stratch disease are infectious diseases causing granulomas in liver [3,4,5]. In the case of non-infectious causes excluded, we thought that granulomatous lesions of the liver developed due to tularemia because microagglutination test positive for tularemia and clinical and radiological improvement of the patient was seen with the appropriate treatment. Turkey is one of the countries where tularemia is seen as endemic. In Turkey, increasing number of cases of tularemia has been reported as epidemics and case reports [6]. The main routes of transmission to humans are contact with body fluids or infected tissues of animals with reservoirs, contact with vectors, consumption of infected water and food. It is usually difficult to determine the source of the infection and the transmission route in children. There was no tick or animal contact in our patient. However, there were a large number of rodents in the area were they were residing. A water-borne pathway was thought in our patient because of the possibility of contact with rodents and drinking water and snow eating habits in the village [1,6]. The clinical spectrum may range from asymptomatic illness to infection and death. Tularemia usually has an abrupt or rapid onset of nonspecific systemic symptoms, including fever, chills, anorexia, and malaise. Typhoidal tularemia is a febrile illness without prominent regional adenopathy or other localizing signs that does not fit another major form of disease. Major symptoms include fever, chills, anorexia, headache, myalgia, sore throat, cough, abdominal pain, and diarrhea [1]. We considered a typhoidal form in our patient because chronic fever and fatigue symptoms were present but there was no regionel adenopathy and local findings as seen in other tularemia forms. Fever seen in tularemia may be intermittent. Our patient’s fever was also intermittent for 2 months. Hepatic involvement in tularemia is often a component of disseminated infection. Hepatic involvement may be subclinical, but patients with hepatic involvement typically have elevated transaminase levels, hepatomegaly and rarely jaundice. Histologically, there are typically suppurative microabscesses with occasional surrounding macrophages as the lesions evolve they may become more granulomatous [2,7]. Tularemia is one of the rare infectious causes of granulomatous hepatitis [2,8]. Experimental studies have also shown that tularemia produces granulomatous hepatitis [3,9]. There was a limited number of case reports of tularemic hepatic involvement, and we could not find any case report of granulomatous hepatitis associated with tularemia published in the literature [7,10]. Our patient had numerous nodular lesions in the liver during imaging examinations. Liver biopsy was consistent with granulomatous hepatitis. The diagnosis of tularemia mainly relies on clinical suspicion. The isolation of F.tularensis in sterile body samples is the gold standart in diagnosis. Because this method is very difficult and risky for laboratory staff, diagnosis of tularemia depends on clinical signs and serological findings [1,11]. In our case, tularemia was suspected

Please cite this article in press as: Kocabas¸ E, et al. A rare cause of granulomatous hepatitis: Tularemia. J Infect Public Health (2020), https://doi.org/10.1016/j.jiph.2019.12.007

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because of granulomatous hepatitis in liver biopsy and the diagnosis was serologically confirmed by microagglutination test for tularemia. Antimicrobial therapy should be administered to all patients in whom diagnosis of tularemia is suspected or confirmed. Early effective treatment is associated with less morbidity [1,11]. Gentamicin is the recommended treatment for children. However, oral antimicrobial therapy may be appropriate for select children with mild illness who are not given gentamicin and who would be expected to complete the prescribed course of treatment. Fluoroquinolones may be preferred in the treatment of tularemia because they also allow oral treatment in children [12]. In our case, clinical, radiological and laboratory improvements were observed after treatment. Consequently; clinicians should be suspicious of and evaluate for typhoidal tularemia in patients who present with prolonged fever and non-specific systemic symptoms, potentially with associated abdominal pain. Funding No funding Sources. Ethical approval Not required.

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Competing interests None declared.

Please cite this article in press as: Kocabas¸ E, et al. A rare cause of granulomatous hepatitis: Tularemia. J Infect Public Health (2020), https://doi.org/10.1016/j.jiph.2019.12.007