http://informahealthcare.com/rnf ISSN: 0886-022X (print), 1525-6049 (electronic) Ren Fail, 2014; 36(7): 1122–1124 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/0886022X.2014.917575

CASE REPORT

Hemolytic uremic syndrome associated with Acinetobacter hemolyticus Paulo Se´rgio Lucas da Silva1 and Rubens Wolfe Lipinski2 1

Pediatric Intensive Care Unit, Department of Pediatrics, Hospital do Servidor Pu´blico Municipal (HSPM), Sa˜o Paulo, Brazil and 2Division of Pediatric Nephrology, Department of Pediatrics, Hospital do Servidor Pu´blico Municipal (HSPM), Sa˜o Paulo, Brazil Abstract

Keywords

Shiga toxin-producing Escherichia coli and Shigella dysenteriae have been associated with bloody diarrhea and hemolytic uremic syndrome (HUS) in humans. However, there have been only a couple of reports describing bloody diarrhea associated with Acinetobacter spp. and there are no reports of these bacteria causing HUS in children. Here, we report the case of a nine-month-old boy with bloody diarrhea who developed non-oliguric renal failure. The clinical and laboratory findings supported the diagnosis of Acinetobacter hemolyticus infection associated with HUS. The patient responded favorably to antibiotic therapy plus conservative treatment. In conclusion, Acinetobacter infection should be considered as a plausible cause of HUS in cases where E. coli infection is not involved. The rapid transformation ability of Acinetobacter is a matter of concern.

Acinetobacter, acute renal failure, children, diarrhea, hemolytic uremic syndrome

Introduction Acinetobacter spp. are mostly free living saprophytes found ubiquitously in nature.1 These pathogens have received an increased interest because of their potential to cause severe nosocomial infections and develop multidrug (MDR) and extreme drug resistance (XDR), and the ability of some strains to produce verotoxins (Shiga toxin (Stx)).2 Although these organisms are often associated with nosocomial infections,1 they have also been associated with community-acquired diarrhea outbreaks with some frequency in tropical regions of the world, especially during warm (summer) and humid1 months. Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (STEC HUS) is the most common cause of pediatric HUS, accounting for 90% of cases among all cases. It usually occurs after a prodromal episode of diarrhea that is frequently bloody. In the majority of cases, HUS is associated with Shiga toxinproducing enterohemorrhagic Escherichia coli (EHEC) or Shigella.3 While Acinetobacter spp. has rarely been isolated from stools,4–8 an association between HUS and Acinetobacterassociated diarrhea has not yet been reported in the literature.

Case report A previously healthy 9-month-old boy was admitted to the pediatric ward with a 3-day history of bloody diarrhea

Address correspondence to Paulo Se´rgio Lucas da Silva, MD, Department of Pediatrics, Pediatric Intensive Care Unit, Hospital do Servidor Pu´blico Municipal (HSPM), Rua Castro Alves, 60, Aclimac¸a˜o, Sa˜o Paulo 01050-904, Brazil. Tel: +55 11 32082211; E-mail: psls. [email protected]

History Received 27 December 2013 Revised 25 February 2014 Accepted 11 April 2014 Published online 14 May 2014

(410 episodes/day) and fever (38.5  C). On admission, he received adequate intravenous fluid and electrolyte replacement and maintenance. The initial laboratory evaluation showed a hemoglobin level of 10.8 g/dL, white blood cell count of 23,500/mm3, platelet count of 186,000/mm3, and C-reactive protein level of 73.8 mg/dL. Glucose, electrolytes, urea nitrogen (BUN), and creatinine values were normal. A course of ceftriaxone was started empirically (100 mg/kg/ day). After 72-h of hospitalization, the patient was transferred to the pediatric intensive care unit because he developed generalized edema. The laboratory investigation revealed a hemoglobin level of 5.2 g/dL, white blood cell count of 19,600/mm3, platelet count of 68,000/mm3, schistocytes 3+, BUN level of 112 mg/dL (maximum value: 158 mg/dL), and creatinine level of 3.2 mg/dL (maximum value: 3.9 mg/dL). Liver function tests, electrolytes, and C3 and C4 levels were normal. The lactate dehydrogenase (LDH) was 2459 IU/L (normal range: 125–220 IU/L). The evolution of hematological and renal data is summarized in Table 1. The patient received a conservative treatment with packed red blood cells (total of 20 mL/kg), furosemide (ranged from 2 to 4 mg/kg/day), and bicarbonate therapy. The blood culture drawn on the day of admission was positive for Acinetobacter spp. using an automated method (Vitek 2 system, bioMe´rieux, Marcyl’Etoile, France). On the basis of this finding, we conducted a search in order to determine the presence of this pathogen in the stool sample. Thus, Acinetobacter hemolyticus was identified in the stool by both phenotypic and biochemical characteristics.9,10 The organism was non-fermentative and a non-motile, gramnegative, coccobacillus with good growth on MacConkey lactose agar. It was cytochrome oxidase-negative, catalase and gelatin hydrolysis positive, and strictly aerobic and oxidized

Hemolytic uremic syndrome associated with A. hemolyticus

DOI: 10.3109/0886022X.2014.917575

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Table 1. Evolution of hematological and renal data according to hospital day.

Parameters (unit of measurement)

Hospital admission day (Day 1)

PICU admission day (Day 3)

Day 4

Day 5

Day 6

Day 8

Hospital discharge day (Day 10)

10.8 23.5 186 – 135 3.6 17.9 0.4 7.33 16.6

5.2 19.6 68 8.2 135 3.7 112.1 3.2 7.31 13.2

7.4 21.3 72 8.0 132 3.2 158.0 3.9 7.35 17.7

11.3 17.9 91 7.1 133 3.5 147.9 3.2 7.36 14.7

10.4 16.6 121 6.7 131 4.0 132.4 2.2 7.39 16.8

9.7 14.9 165 6.2 133 4.3 115.3 1.0 7.40 17.4

10.6 5.17 237 2.8 139 4.2 28.8 0.5 7.40 19.6

Hemoglobin (g/dL) White blood cell count (103/mm3) Platelets (103/mm3) Reticulocyte count (%) Sodium (mEq/L) Potassium (mEq/L) Urea nitrogen (mg/dL) Creatinine (mg/dL) pH Bicarbonate (mEq/L) Note: PICU ¼ pediatric intensive care unit.

glucose. It failed to grow at 44  C and was surrounded by a wide zone of hemolysis on blood agar. The isolate was susceptible (Kirby–Bauer disk diffusion method) according to the Clinical Laboratory Standards Institute (CLSI) guidelines11 to the following antibiotics: amikacin, ampicillin/ sulbactam, imipenem, meropenem, and gentamicin. A qualitative test was positive for Shiga toxins (RidascreenÕ Verotoxin enzyme immunoassay—R-Biopharm AG, Darmstadt, Germany).12 Stool samples were negative for the following pathogens: Salmonella spp., Shigella spp., Vibrio cholerae, Campylobacter jejuni/coli, Yersinia enterocolitica, diarrheagenic E. coli, Entamoeba histolytica, Giardia lamblia, rotavirus, Cryptosporidium and Campylobacter spp. The patient received a 10-day course of ampicillin/ sulbactam. After a total of 10 days of hospitalization, the child was discharged in good condition. Tests showed normalization of renal function (the serum creatinine level was 0.5 mg/dL and urea level was 28 mg/dL) and hematologic indices (the hemoglobin level was 10.6 g/dL and platelet count was 237,000/mm3).

Discussion Advances in molecular pathology led to the recognition of three different diseases characterized by microvascular thrombosis, with consequent thrombocytopenia, hemolytic anemia, and dysfunction of affected organs: typical HUS caused by Shiga-like toxin-producing Escherichia coli (STEC-HUS); atypical HUS (aHUS), associated with genetic or acquired disorders of regulatory components of the complement system; and thrombotic thrombocytopenic purpura (TTP) that results from a deficiency of ADAMTS13, a plasma metalloproteinase that cleaves von Willebrand Factor.13 Therefore, the current term STEC-HUS, instead of (D+) HUS or typical HUS, is preferred because it is meaningful for description of etiology, pathophysiology, and classification of HUS. The current pathophysiology of STEC-HUS is explained by the binding of Shiga toxins to the globotriaosylceramide (Gb3) receptor expressed by glomerular endothelial cells and causing direct endothelial injury through inhibition of protein synthesis. Increased cytokines and chemokines that cause inflammation also take part in this process.13,14 Another pathophysiological process during STEC-HUS was shown on the alternate complement system.13 Thus, in STEC-HUS,

the toxin triggers endothelial complement deposition through the up-regulation of P-selectin and possibly interferes with the activity of complement regulatory molecules.14 While Shiga toxin-producing E. coli (e.g. O157:H7) and Shigella dysenteriae have been associated with bloody diarrhea and HUS in humans, there have been few reports of bloody diarrhea associated with Acinetobacter spp.7,8 and no reports of Acinetobacter spp. causing HUS in children. Our report suggests that any Shiga toxin-producing microorganism capable of colonizing the human gut may have the potential to cause HUS. Grotiuz et al.8 first reported the production of verotoxins in Acinetobacter. Shiga toxins are associated with bloody diarrhea and produced by many enteric bacteria, including E. coli and S. dysenteriae. Shiga toxins can be classified into two antigenic groups, stx-1 and stx-2, which include (especially for stx-2) an important number of genotypic variants. The pathogenicity, basic structure, and chemical components of the toxins are the same as those of verotoxins from E. coli and other bacteria.8 Therefore, the fact that the isolated A. hemolyticus strain produced Shiga toxins, a relevant virulence factor, and the usual enteric bacterial pathogens associated with bloody diarrhea were not detected in this case suggests that this strain may be the etiological agent. It is noteworthy that some authors8 have speculated that A. hemolyticus may acquire a stx2-producing ability from another Shiga toxin-producing microorganism via horizontal gene transfer in the gut lumen because it can be rapidly transformed. Grotius et al.8 demonstrated that Shiga toxin genes of A. hemolyticus are carried in the context of an infective bacteriophage. Lysogeny has been proven to occur in vivo, and this has important implications for the evolution of new pathogenic strains.8 Given the high transformability of Acinetobacter spp., the emergence of Shiga toxin-producing A. hemolyticus strains is a public health concern.1 Although we used antibiotic therapy in this patient’s treatment, its use is a subject of debate. Previous reports and expert opinions gave rise to an extensive idea that antibiotic usage increases Shiga toxin excretion from the bacteria and the incidence of STEC-HUS increases if the child with STEC infection is treated with antibiotics.15–17 However, recent reports during a German outbreak established new evidence regarding antibiotic usage.18–20 In conclusion, Acinetobacter infection should be considered as a plausible cause of typical HUS in cases with no

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P.S.L. da Silva and R.W. Lipinski

E. coli infection. The high frequency and degree of adaptability and transformability among some strains of Acinetobacter spp. in a scenario of emergence of toxinproducing species highlights a major concern given the increased incidence of infections by this organism and the emergence of multidrug-resistant isolates. These findings call for intensive surveillance of these pathogens, especially in the environment, and the development of proactive control measures.

Declaration of interest

Ren Fail, 2014; 36(7): 1122–1124

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11.

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The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Hemolytic uremic syndrome associated with Acinetobacter hemolyticus.

Shiga toxin-producing Escherichia coli and Shigella dysenteriae have been associated with bloody diarrhea and hemolytic uremic syndrome (HUS) in human...
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