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Journal of Medical Microbiology (2012), 61, 743–745 Case Report DOI 10.1099/jmm.0.038547-0 Bacillus cereus, an unusual cause of fulminant liver failure: diagnosis may prevent liver transplantation Mohamed Saleh,1,23 Malik Al Nakib,2,33 Alexandra Doloy,3 Sébastien Jacqmin,1 Sébastien Ghiglione,1 Nicolas Verroust,1 Claire Poyart2,3 and Yves Ozier1,2 1 Correspondence Service d’Anesthésie-Réanimation Chirurgicale, Groupe Hospitalier Cochin Hôtel Dieu Broca, Assistance Publique – Hôpitaux de Paris, Paris, France Claire Poyart [email protected] 2 Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France 3 Service de Bactériologie, Groupe Hospitalier Cochin Hôtel Dieu Broca, Assistance Publique – Hôpitaux de Paris, Paris, France Received 23 September 2011 Accepted 9 January 2012 Bacillus cereus is a well-known cause of foodborne disease usually of benign course. Here, we present the case of a 15-year-old boy who developed reversible fulminant liver failure associated with rhabdomyolysis after pasta consumption. Suspecting B. cereus as the aetiological agent may prevent unnecessary liver transplantation. Introduction Bacillus cereus is a soil-dwelling, spore-forming, Grampositive bacterium surviving in a wide variety of environments. It is a known food-poisoning pathogen but is also responsible for extraintestinal infections. Some strains can produce exotoxins responsible for two different types of disease: diarrhoeal syndrome due to enterotoxins, and emetic syndrome due to cereulide toxin (Stenfors Arnesen et al., 2008). The illness is generally considered mild and short-lasting. Rare fatal cases have been reported involving healthy young persons (Dierick et al., 2005; Mahler et al., 1997). Up to now, very few cases of fulminant liver failure (FLF) have been reported. Two of these were lethal, and one was observed in a child who recovered fully, avoiding liver transplantation (Dierick et al., 2005; Mahler et al., 1997; Pósfay-Barbe et al., 2008). Recently, a case of acute encephalopathy with liver failure mimicking Reye syndrome was reported, with hepatic transplantation not considered for the patient (Ichikawa et al., 2010). Here we report a new case of FLF associated with a cereulideproducing B. cereus strain. Case report In September 2008, a 15-year-old boy was referred to our Centre for FLF. He had no past medical history, and did not take drugs or medications. The first symptoms began 30 h before admission, with acute onset of abdominal pain and emesis without evidence of a triggering factor. The following day, blood was noticed in his vomit, and he was 3These authors contributed equally to this work. Abbreviation: FLF, fulminant liver failure. 038547 G 2012 SGM brought to the emergency department of the nearest hospital. Blood tests showed elevated liver enzymes (alanine aminotransferase .3000 IU l21) and incipient liver failure (prothrombin ratio 52 %, factor V ratio 35 %). An upper gastrointestinal endoscopy revealed ulceronecrotic oesophagitis and gastritis. Echocardiography and Doppler ultrasonography of the liver were unremarkable. The toxicology screen was negative. The patient was seronegative for hepatitis A, C and hantavirus. He had evidence of prior hepatitis B vaccination. He was treated with intravenous rehydration and acetylcysteine. On the same day, given the rapid deterioration in the prothrombin and factor V ratios (20 % and 18 %, respectively) suggesting fulminant hepatic failure, emergency liver transplantation was considered and he was referred to our intensive care unit. On arrival, he was found to be afebrile, with tachycardia (140 b.p.m.). Laboratory results showed elevated alanine aminotransferase (4823 IU l21), aspartate aminotransferase (3729 IU l21), serum bilirubin (42 mmol l21) and creatine kinase (12 592 IU l21) and lactic acidosis (pH 7.41, bicarbonates 20 mmol l21, lactate 5.4 mmol l21). Haemoglobin was within the normal range, with a white blood cell count of 14 500 mm23. The prothrombin ratio was 21 %, with factor V 23 % and factor II 34 %. Procalcitonin was 14.9 ng l21. Plasma PCR assays for the family Herpesviridae were negative. Viral serological testing was negative for herpes simplex virus, cytomegalovirus, human immunodeficiency virus and human T-cell leukemia virus, and showed past infection for Epstein–Barr virus, varicella-zoster virus and parvovirus B19. A thoracoabdominal CT scan showed non-specific hepatomegaly. A few hours later, the neurological status deteriorated with coma and the patient was immediately scheduled for emergency liver transplantation. A profuse nonbloody Downloaded from www.microbiologyresearch.org by IP: 88.99.165.207 On: Wed, 10 May 2017 15:07:46 Printed in Great Britain 743 M. Saleh and others diarrhoea was also noticed, and stools were analysed. Two days after admission, fever appeared and treatment with intravenous piperacillin–tazobactam (4/0.5 g every 6 h) was given for 7 days for positive blood cultures showing growth of Klebsiella pneumoniae and Enterobacter cloacae, which was attributed to intestinal translocation. A leukopenia and thrombopenia were investigated by bone marrow examination, which detected a maturation blockade of the granulocytic series compatible with toxic injury. Bacterial, parasitological and mycological bone marrow cultures were sterile. After 3 days, the hepatic cytolysis started to decrease, and prothrombin and factor V ratios increased, leading to reconsideration of the liver transplantation indication. Clinical improvement ensued, the neurological condition fully resolved and the liver functions normalized in a few days. A detailed history of the patient and his relatives revealed that he had eaten pasta 4 h before the first symptoms. The pasta had been cooked 4 days before, stored in a refrigerator, and was found to have an abnormal taste and smell. Stools were tested for B. cereus on days 3, 4, 5, 7 and 8 after admission. To isolate B. cereus, a Gram-positive selective blood agar plate containing colistin and nalidixic acid was used (Oxoid). Identification of isolates was performed on the basis of Gram staining, motility, colony appearance and haemolysis, amylase production (starch hydrolysis test), API 50 CH and API 20E strips (bioMérieux), and susceptibility to penicillin. Stool cultures yielded growth of B. cereus with decreasing counts from 105 c.f.u. g21 on day 3 to the absence of detection on day 8. To demonstrate the toxigenic potential of B. cereus isolates, genes encoding emetic-toxin cereulide (ces) and enterotoxins (nhe, hbl and cytK) were analysed by multiplex PCR, as previously described (Ehling-Schulz et al., 2006). Strains isolated from each stool showed the same toxin gene pattern, ces+ nhe+ hbl2 cytK2, characteristic of cereulide-producing strains (Ehling-Schulz et al., 2005, 2006; Pósfay-Barbe et al., 2008). Moreover, these strains were not capable of producing amylase, a feature highly suggestive of cereulide-producing strains (Ehling-Schulz et al., 2004). Discussion Cereulide is plasmid-encoded (Stenfors Arnesen et al., 2008), and B. cereus strains producing cereulide are most frequently reported in starchy foods. Once ingested, it resists acid conditions and proteolytic enzymes of the gastrointestinal tract. Mahler et al. (1997) were the first to demonstrate a link between cereulide-producing B. cereus strains and FLF. They provided experimental evidence that cereulide acts as a mitochondrial toxin via fatty-acid metabolism impairment, in keeping with liver microvesicular steatosis observed in their patient. Furthermore, the occurrence of FLF with microvesicular steatosis after cereulide injection has been described in mice. It was reversible within a few weeks with a rapid decrease of hepatic enzymes and regeneration of hepatocytes (Yokoyama et al., 1999). Interestingly, liver microsteatosis was reported in the 744 first description of lethal B. cereus food poisoning in Japan (Takabe & Oya, 1976). Although the presence of cereulide in the pasta could not be tested in this case, the toxin gene pattern of strains isolated from the patient’s stools was characteristic of cereulide-producing strains (EhlingSchulz et al., 2005, 2006; Pósfay-Barbe et al., 2008). Moreover, our report shares many of the hallmarks of B. cereus-associated FLF: an extremely acute onset and rapid progression of the disease in a young person, rhabdomyolysis which is also in keeping with mitochondrial dysfunction, and severe lactic acidosis (Dierick et al., 2005; Mahler et al., 1997; Pósfay-Barbe et al., 2008). The connection between the reversible bone marrow suppression of white cell precursors observed in our case and cereulide is uncertain, as b-lactam antibiotics were used and are a possible cause of leukopenia, especially for a patient with hepatic failure (Singh et al., 1993). Pósfay-Barbe et al. (2008) recently highlighted that, given the incidence of B. cereus food-poisoning outbreaks, it is surprising that so few cases of B. cereus toxin-mediated FLF have been reported so far. They suggested that a dosedependent effect and/or a host genetic susceptibility might explain this rarity, but it could also be an under-recognized aetiology. However, early diagnosis may not lead to efficient specific therapeutic measures that could improve outcome as disease is mainly due to preformed toxin ingestion. On the other hand, we detected B. cereus in the patient’s stools, and in previously described cases B. cereus was found in vomit and intestinal contents (Dierick et al., 2005; Mahler et al., 1997) so antibiotic treatment could help to eradicate the bacteria and stop further toxin production. Charcoal has been suggested for detoxification (Mahler et al., 1997). The hepatoprotective effect of acetylcysteine is based on its ability to replenish glutathione stores, and it could also improve mitochondrial energy metabolism (Zwingmann & Bilodeau, 2006). However, one of the reported fatal cases occurred despite high-dose acetylcysteine administration (Dierick et al., 2005). Close monitoring of hepatic function allowed our patient to avoid liver transplantation with a rapid full recovery, as described in another patient (Pósfay-Barbe et al., 2008) and in agreement with the reversible pathological effect observed in mice (Yokoyama et al., 1999). In conclusion, this case stresses the role of toxigenic B. cereus as a food pathogen and the importance of suspecting this bacterial agent as a cause of FLF of unknown pathogenesis in order to defer hepatic transplantation. References Dierick, K., Van Coillie, E., Swiecicka, I., Meyfroidt, G., Devlieger, H., Meulemans, A., Hoedemaekers, G., Fourie, L., Heyndrickx, M. & Mahillon, J. (2005). Fatal family outbreak of Bacillus cereus-associated food poisoning. J Clin Microbiol 43, 4277–4279. Ehling-Schulz, M., Fricker, M. & Scherer, S. (2004). Bacillus cereus, the causative agent of an emetic type of food-borne illness. Mol Nutr Food Res 48, 479–487. 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(1999). Pathological effect of synthetic cereulide, an emetic toxin of Bacillus cereus, is reversible in mice. FEMS Immunol Med Microbiol 24, 115–120. Zwingmann, C. & Bilodeau, M. (2006). Metabolic insights into the hepatoprotective role of N-acetylcysteine in mouse liver. Hepatology 43, 454–463. Downloaded from www.microbiologyresearch.org by IP: 88.99.165.207 On: Wed, 10 May 2017 15:07:46 745