occurs though presentation as acute fulminant hepatitis is uncommon. Quinolones have been the mainstay of therapy for typhoid but there are increasing reports ...
Case Report
Quinolone-Resistant Salmonella enterica Serovar typhi presenting as Acute Fulminant Hepatitis S Mitra*, R Karthik*, V Balaji**, Ige Abraham George*, Arti Kapil***, OC Abraham*
T
Introduction
17.5 cms; spleen (along the long axis), 15.1 cms and ascites. Serology for HIV, Hepatitis A, B and C were negative. Serology for Hepatitis-E was not done. Since there was no past medical or family history suggestive of liver disease so work up for other causes of liver disease, such as Wilson’s disease was not done. Chest X-ray was normal.
yphoid remains a major public health problem in India and must be considered in the differential diagnosis of any acute febrile illness. Hepatic involvement in typhoid occurs though presentation as acute fulminant hepatitis is uncommon. Quinolones have been the mainstay of therapy for typhoid but there are increasing reports of quinolone resistance in S. typhi. We report a case of typhoid fever due to Ciprofloxacin resistant S. typhi presenting with acute fulminant hepatitis.
Blood culture by semi automated BacT/Alert ® system grew Salmonella enterica serovar typhi (S. typhi). Antimicrobial susceptibility testing by Kirby Bauer disk diffusion method showed that the isolate was resistant to nalidixic acid and ciprofloxacin (zone of inhibition < 15 mm) but susceptible to ceftriaxone, ampicillin, trimethoprim–sulphamethoxazole and chloram-phenicol. Minimal Inhibitory Concentration (MIC) determined by agar dilution method as per CLSI guidelines (2007) showed ciprofloxacin MIC of 4 µg/ml.
Case Report A thirty two year old male from Tamil Nadu in India presented with 20 days history of high grade fever with chills and progressive jaundice. At the time of the onset of his symptoms he had generalised malaise and constipation. There was no history of vomiting or diarrhoea. He did not consume alcohol and there was no history suggestive of underlying liver disease. Prior to hospitalisation he received empirical antibiotics elsewhere but there was no improvement.
The quinolone-resistance-determining region (QRDR) of the GyrA gene of this isolate was amplified and sequenced. Molecular analysis and comparison with the standard strain showed that this isolate strain had two mutations, namely substitution of phenylalanine for serine at position 83 (Ser83 →Phe) and asparagine for aspartate at position 87 (Asp87 →Asn) (Fig. 1).
At the time of admission he was confused and disoriented to time. There was no pallor, skin rash or lymphadenopathy. He was febrile with a temperature of 102 degree Fahrenheit; blood pressure was 100/40 mm of Hg and pulse rate was 112 /min. General physical examination revealed deep icterus and bilateral pitting pedal oedema. There was no Kayser-Fleischer ring or peripheral signs of chronic liver cell failure. On per abdominal examination liver was palpable 2 cm below right subcostal margin and spleen was palpable 1 cm below the left subcostal margin with minimal ascites. Fundus was normal. The patient had grade 2 hepatic encephalopathy. Rest of the systemic examination was unremarkable.
The final diagnosis made was ciprofloxacin resistant S. typhi infection complicated by acute fulminant hepatitis. He was treated with ceftriaxone for 14 days with which he became afebrile and there was complete resolution of the hepatitis.
Discussion Typhoid fever is an acute multi system febrile illness caused by S. typhi. Typhoid hepatitis occurs during the second and third week of the illness and varies from mild hepatic dysfunction (23-60%) to a severe hepatic involvement (0.5-7.6%). Patients with anemia, malnutrition, and poor health are more prone for typhoid hepatitis.
Initial laboratory investigation showed: Haemoglobin, 10.2 gm/dL; total WBC count, 9,300 cells/µl with shift to the left; platelet count, 86,000 cells/µl; liver function test showed total bilirubin,16.4mg/dL; direct bilirubin, 9.2 mg/dL; total protein, 5.9 gm/dL; albumin, 2.3gm/dL; aspartate aminotransferase (AST ), 360 U/L; amino alanine transferase (ALT ), 372 U/L; alkaline phosphatase, 444 U/L; prothrombin time of the patient was 16.5 sec (control = 9.7-13.3 sec; INR = 1.364). His renal function tests showed creatinine, 2.3 mg/dL and urea, 64 mg/ dL. Sonological examination of the abdomen showed liver span,
Clinically, the hepatic manifestations of typhoid fall into three groups: a) no hepatic enlargement or abnormalities in hepatic
*Department of Medicine Unit 1 and Infectious Diseases, **Department of Microbiology, Christian Medical College and Hospital, Vellore - 632 004; ***Department of Microbiology, All India Institute of Medical Sciences, New Delhi. Received : 11.7.2008; Revised : 20.10.2008; Re-Revised : 1.1.2009; Accepted : 7.1.2009 338
Fig. 1 : Molecular analysis showing 2 mutations namely (Ser83 Phe) and (Asp87 Asn).
© JAPI • APRIL 2009 • VOL. 57
(Renuka et al form north India and Joshi et al6 from Bangalore). Similar dual mutation has been reported recently by Chau et al in Vietnam.
function, b) either hepatomegaly or abnormal liver function tests, but of no great clinical importance and occurred incidentally and c) hepatic manifestations as the dominant and presenting feature of the illness.
In this patient one has to consider the possibility of typhoid and acute Hepatitis E co-existing, as Hepatitis E serology was not done. The possibility of co-existing asymptomatic chronic liver disease such as Wilson disease is a possibility, but further tests for the same such as slit lamp examination for KF ring, 24 hour urinary copper and isotope liver spleen scan were not done. Follow up of the patient at 1 year did not reveal any clinical evidence of hepatitis or chronic liver disease.
Kamath et al1 evaluated 47 patients with fever and fulminant hepatic failure and out of these, 11 patients (23%) were diagnosed to have typhoid with hepatitis and encephalopathy. The clinical and lab features favouring a diagnosis of typhoid hepatitis as the cause of hepatic failure include (i) liver span of more than 9 cms (ii) presence of thrombocytopenia (iii) Alkaline phosphatase more than 3 times the upper limit of normal (iv) Aspartate aminotransferase (AST) > Amino alanine transferase (ALT) (v) Lower peak of AST and ALT.
This case is being reported for its unique presentation as acute fulminant hepatitis and also to sensitize clinicians about the growing problem of Quinolone resistant S. typhi – in this case due to dual mutations, which is being increasingly reported from several parts of the country.
The mechanism by which S. typhi causes hepatitis is unclear. Interaction of S. typhi endotoxin with hepatic macrophages may be responsible for the major manifestations of typhoid fever. Liver biopsy done in 5 patients with typhoid hepatitis, reported by Khosla et al showed cloudy swelling, ballooning degeneration with vacuolation, moderate fatty change, mononuclear cell infiltration in few focal areas with minimal portal tract infiltration, areas of focal necrosis, Kuppfer cell hyperplasia and dilated and congested sinusoids.
References
In 2005, Tamilarasu et al2 from New Delhi, India, concluded that infections with NARST isolates were significantly associated with poor clinical outcome, higher frequency of hepatomegaly, higher levels of AST and increased MIC of ciprofloxacin as compared to infections with nalidixic acid-susceptible isolates. By 2004, Rupali et al3 from Vellore documented a case series of typhoid fever with both clinical as well as microbiological failure and reported progressive increase (upto 15-fold) in MIC value of quinolones among the ciprofloxacin sensitive isolates of S. typhi. Stepwise acquisition of dual mutation in the QRDR of Gyrase (GyrA) gene of S. typhi reduces the susceptibility to fluoroquinolone by 4–8-fold 4 by altering the enzyme binding the drug. In India, the first report of the similar dual mutation in S. typhi was reported from Vellore in 1998 by Shanahan et al.5 Following this there have been other reports from different parts of India on the emergence of Ciprofloxacin resistant S. typhi
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