580406
research-article2015
CPJXXX10.1177/0009922815580406Clinical PediatricsAnastaze Stelle et al
Brief Report
Streptococcus pneumoniae–Associated Hemolytic and Uremic Syndrome With Cholestasis: A Case Report and Brief Literature Review
Clinical Pediatrics 1–3 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/0009922815580406 cpj.sagepub.com
Karine Anastaze Stelle, MD1, Francois Cachat, MD1, Marie-Helene Perez, MD1, and Hassib Chehade, MD1
Introduction Streptococcus pneumoniae (Sp)–associated hemolytic and uremic syndrome (HUS) accounts for 5% to 15% of all HUS with an incidence of 0.4% to 0.6%1 following Sp infections. Epidemiology of invasive pneumococcal disease changed since the introduction of antipneumococcal conjugated vaccine and SpHUS appeared to follow the serotype shift.2 Presently, SpHUS seems to be mostly due to the serotype 3, 6B, 7, 8, 9V, 14, 19, and 23F.2,3 Renal complication of SpHUS is well known, and 10% to 16% of cases will develop an end-stage renal failure (ESRF).1 However, hepatic complications are rare and uncommon. Here, we describe a child with SpHUS associated with severe cholestatic jaundice secondary to acute liver injury.
Case Report A 2½-year-old female child with fever and cough was admitted to our institution for bilateral pneumonia. Her medical history revealed 2 pyelonephritis (at 10 and 15 months) and correct vaccination, including complete antipneumococcal vaccination with Prevenar 13 (3 doses). At admission, blood tests revealed anemia (6.9 g/dL) with schistocytes (25‰), thrombocytopenia (68 g/L), renal insufficiency (serum creatinine [SCreat] 2.9 mg/dL), blood urea nitrogen (BUN) 23.5 mmol/L), indicating HUS. A day later, she developed jaundice and anuria and blood tests revealed the presence of elevated liver enzymes (alanine transaminase [ALT] 128 U/L, aspartate transaminase [AST] 292 U/L) associated with conjugated hyperbilirubinemia (21.4 mg/dL, normal value 0-0.6 mg/dL). There was no neurological involvement (Glasgow Coma Scale 15/15). Intravenous antibiotic (cephalosporin third generation) and peritoneal dialysis was initiated and the child was transferred to the pediatric intensive care unit for mechanical ventilation. Thoracic and abdominal computed tomography showed bilateral pneumonia, normal liver appearance except for some periportal edema and
stoneless gallbladder. Blood cultures were positive for serotype 3 Streptococcus pneumoniae and T-Ag activation was positive in the urine. In the pediatric intensive care unit, SCreat peaked at 3 mg/dL together with an important hemolysis (Hb 5.9 g/dL, schistocytes 30 ‰, direct Coomb’s test was negative, haptoglobin less than 10 mg/L and lactate dehydrogenase (LDH) increased to 2537 U/L. The child showed a favorable evolution recovering progressively her diuresis after 2 days, and peritoneal catheter was removed after 6 days. After a peak at 333 and 128 U/L of AST and ALT, respectively, values were quickly normalized. Total serum bilirubin was maximal at 26.3 mg/dL (normal value 0-1.2 mg/dL) and conjugated bilirubin was maximal at 21.5 mg/dL, which prompted us to introduce ursodeoxycholic acid. She also normalized her complete blood count, cholestasis, and renal function tests within 2 weeks, and was discharged home after 3 weeks with oral antibiotic and angiotensinconverting enzyme inhibitor treatment for residual arterial hypertension, which was stopped after 6 months. After follow-up of 12 months, the child showed a normal physical examination without arterial hypertension, no proteinuria, normal renal function, normal complete blood count, and normal liver function tests.
Discussion Hemolytic and uremic syndrome is a rare but increasing complication of Sp infection with higher morbidity than usual shiga-like toxin–producing Escherichia coli (STEC)-HUS. Increased unconjugated bilirubin and serum transaminase levels were described and attributed 1
Lausanne University Hospital, Lausanne, Switzerland
Corresponding Author: Hassib Chehade, Department of Pediatrics; Division of Pediatric Nephrology, Lausanne University Hospital, Rue Bugnon 46, 1011 Lausanne, Switzerland. Email: [email protected]
Downloaded from cpj.sagepub.com at DALHOUSIE UNIV on June 21, 2015
2
Clinical Pediatrics
Table 1. Patient’s Clinical Characteristics and Clinical Course. Patients
1a
Age in months 21 Gender Female Disease Pneumonia Peak SCreat (mg/dL) 1.4 Peak AST/ALT (U/L) 390/125 Peak bilirubin (total/ 11.6/9.9 conjugated) in mg/dL Days until liver 9 function tests normalization Duration of dialysis 12 in days Renal outcome Normal renal function at 6 months
2a
3a
4b
Our patient
10 Male Meningitis 2.4 500/60 19.8/18.4
17 Male Pneumonia 2 1630/280 11.6/10.2
10 Female Pneumonia 2.4 430/120 26.9/18.4
30 Female Pneumonia 3 333/128 26.3/21.5
5
10
8
13
10
28
26
6
Normal renal function at 10 days
Data not shown Mild renal failure at 1 year
Normal renal function at 6 months
Abbreviations: SCreat, serum creatinine; ALT, alanine transaminase; AST, aspartate transaminase. a Pan et al.10 b Chen et al.6
to hemolysis.4-7 Cholestasis has been also described in (STEC)-HUS.8 It is believed to be due to an intrahepatic vasculitis and microangiopathic thrombosis leading to hypoxia, liver damage, and cholestasis.8,9 However, cholestasis with increased conjugated hyperbilirubinemia is uncommon in SpHUS. To our knowledge, a few cases were described in literature.6,10 Lee et al,11 reported in 20 children with HUS, a hepatocellular dysfunction with elevated ALT and conjugated hyperbilirubinemia in 9 and 13 children, respectively. The authors reported that hepatocellular injury in SpHUS patients group was more serious than the non-SpHUS group. Conjugated bilirubinemia levels were mildly elevated in the 2 groups (maximal value, 1.34 mg/dL), however, authors did not find significant difference in conjugated bilirubinemia levels between these 2 groups. In our case report, SpHUS was associated with severe increased conjugated hyperbilirubinemia (maximum value, 21.5 mg/dL). Pathophysiological mechanism of cholestasis in SpHUS has not yet been established. Proposed mechanisms are, as in classic HUS, intrahepatic vasculitis and thrombosis that may contribute to hepatocellular injury and cholestasis. Some authors suggested that the activated T-Ag presented on hepatocytes may explain the occurrence of transient hepatic dysfunction.4,11,12 Chen et al6 suggested the occurrence of a plasma extravasation, secondary to an increased vascular permeability due to the inflammatory syndrome associating endotoxin, cytokine, and leukotriene, leading to a reduced bile flow and thus to increased conjugated hyperbilirubinemia.
When comparing our patient and the 4 published cases of Chen et al6 and Pan et al,10 our patient was older, severity of cholestasis and renal failure were comparable, days until liver function recovery, and duration of renal replacement therapy varied from 5 to 13 days, and from 6 to 28 days, respectively (Table 1). Concerning renal outcome, SpHUS is associated with a poorer renal outcome than (STEC)-HUS.13 The occurrence of cholestasis, after carefully analysing our case and the other reported cases in literature, does not seem to affect the kidney function recovery in SpHUS. In conclusion, pediatricians should be aware that cholestatic jaundice may complicate the course of SpHUS. Here, we report a case of a child with SpHUSassociated severe conjugated hyperbilirubinemia with an excellent clinical outcome. This observation associated with the previous few cases reported in the literature; demonstrate that cholestasis does not seem to affect the clinical outcome of the disease. However, more cases should be reported to confirm this observation. Author Contribution KAS participated to the patient care treatment, drafted the initial manuscript, and approved the final manuscript as submitted. FC participated to the draft of the manuscript, and corrected/approved the final manuscript as submitted. MHP participated to the patient care treatment and approved the final manuscript as submitted. HC participated to the patient care treatment and to the draft of the manuscript, and corrected/approved the final manuscript as submitted.
Downloaded from cpj.sagepub.com at DALHOUSIE UNIV on June 21, 2015
3
Anastaze Stelle et al Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Spinale JM, Ruebner RL, Kaplan BS, Copelovitch L. Update on Streptococcus pneumoniae associated hemolytic uremic syndrome. Curr Opin Pediatr. 2013;25: 203-208. 2. Novak D, Lundgren A, Westphal S, Valdimarsson S, Olsson ML, Trollfors B. Two cases of hemolytic uremic syndrome caused by Streptococcus pneumoniae serotype 3, one being a vaccine failure. Scand J Infect Dis. 2013;45:411-414. 3. Quiviger S, Flechelles O, Cecile W, Hatchuel Y. Streptococcus pneumoniae-induced hemolytic uremic syndrome: a serotype-3-associated case. Arch Pediatr. 2012;19:599-602. 4. Copelovitch L, Kaplan BS. Streptococcus pneumoniaeassociated hemolytic uremic syndrome. Pediatr Nephrol. 2008;23:1951-1956. 5. Jeffrey G, Kibbler CC, Baillod R, Farrington K, Morgan MY. Cholestatic jaundice in the haemolytic-uraemic syndrome: a case report. Gut. 1985;6:315-319.
6. Chen JP, Chen SM, Sheu JN. Unusual manifestation of severe conjugated hyperbilirubinemia in an infant with Streptococcus pneumoniae-associated hemolytic uremic syndrome. J Formos Med Assoc. 2007;106(2 suppl):S17-S22. 7. Grodinsky S, Telmesani A, Robson WL, Fick G, Scott RB. Gastrointestinal manifestations of hemolytic uremic syndrome: recognition of pancreatitis. J Pediatr Gastroenterol Nutr. 1990;11:518-524. 8. Riley MR, Lee KK. Escherichia coli O157:H7-associated hemolytic uremic syndrome and acute hepatocellular cholestasis: a case report. J Pediatr Gastroenterol Nutr. 2004;38:352-354. 9. de Buys Roessingh AS, de Lagausie P, Baudoin V, Loirat C, Aigrain Y. Gastrointestinal complications of post-diarrheal hemolytic uremic syndrome. Eur J Pediatr Surg. 2007;17:328-334. 10. Pan CG, Leichter HE, Werlin SL. Hepatocellular injury in Streptococcus pneumoniae-associated hemolytic uremic syndrome in children. Pediatr Nephrol. 1995;9:690-693. 11. Lee CS, Chen MJ, Chiou YH, Shen CF, Wu CY, Chiou YY. Invasive pneumococcal pneumonia is the major cause of paediatric haemolytic-uraemic syndrome in Taiwan. Nephrology (Carlton). 2012;17:48-52. 12. Vanderkooi OG, Kellner JD, Wade AW, et al. Invasive Streptococcus pneumoniae infection causing hemolytic uremic syndrome in children: two recent cases. Can J Infect Dis. 2003;14:339-343. 13. Brandt J, Wong C, Mihm S, et al. Invasive pneumococcal disease and hemolytic uremic syndrome. Pediatrics. 2002;110:371-376.
Downloaded from cpj.sagepub.com at DALHOUSIE UNIV on June 21, 2015
research-article2015
CPJXXX10.1177/0009922815580406Clinical PediatricsAnastaze Stelle et al
Brief Report
Streptococcus pneumoniae–Associated Hemolytic and Uremic Syndrome With Cholestasis: A Case Report and Brief Literature Review
Clinical Pediatrics 1–3 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/0009922815580406 cpj.sagepub.com
Karine Anastaze Stelle, MD1, Francois Cachat, MD1, Marie-Helene Perez, MD1, and Hassib Chehade, MD1
Introduction Streptococcus pneumoniae (Sp)–associated hemolytic and uremic syndrome (HUS) accounts for 5% to 15% of all HUS with an incidence of 0.4% to 0.6%1 following Sp infections. Epidemiology of invasive pneumococcal disease changed since the introduction of antipneumococcal conjugated vaccine and SpHUS appeared to follow the serotype shift.2 Presently, SpHUS seems to be mostly due to the serotype 3, 6B, 7, 8, 9V, 14, 19, and 23F.2,3 Renal complication of SpHUS is well known, and 10% to 16% of cases will develop an end-stage renal failure (ESRF).1 However, hepatic complications are rare and uncommon. Here, we describe a child with SpHUS associated with severe cholestatic jaundice secondary to acute liver injury.
Case Report A 2½-year-old female child with fever and cough was admitted to our institution for bilateral pneumonia. Her medical history revealed 2 pyelonephritis (at 10 and 15 months) and correct vaccination, including complete antipneumococcal vaccination with Prevenar 13 (3 doses). At admission, blood tests revealed anemia (6.9 g/dL) with schistocytes (25‰), thrombocytopenia (68 g/L), renal insufficiency (serum creatinine [SCreat] 2.9 mg/dL), blood urea nitrogen (BUN) 23.5 mmol/L), indicating HUS. A day later, she developed jaundice and anuria and blood tests revealed the presence of elevated liver enzymes (alanine transaminase [ALT] 128 U/L, aspartate transaminase [AST] 292 U/L) associated with conjugated hyperbilirubinemia (21.4 mg/dL, normal value 0-0.6 mg/dL). There was no neurological involvement (Glasgow Coma Scale 15/15). Intravenous antibiotic (cephalosporin third generation) and peritoneal dialysis was initiated and the child was transferred to the pediatric intensive care unit for mechanical ventilation. Thoracic and abdominal computed tomography showed bilateral pneumonia, normal liver appearance except for some periportal edema and
stoneless gallbladder. Blood cultures were positive for serotype 3 Streptococcus pneumoniae and T-Ag activation was positive in the urine. In the pediatric intensive care unit, SCreat peaked at 3 mg/dL together with an important hemolysis (Hb 5.9 g/dL, schistocytes 30 ‰, direct Coomb’s test was negative, haptoglobin less than 10 mg/L and lactate dehydrogenase (LDH) increased to 2537 U/L. The child showed a favorable evolution recovering progressively her diuresis after 2 days, and peritoneal catheter was removed after 6 days. After a peak at 333 and 128 U/L of AST and ALT, respectively, values were quickly normalized. Total serum bilirubin was maximal at 26.3 mg/dL (normal value 0-1.2 mg/dL) and conjugated bilirubin was maximal at 21.5 mg/dL, which prompted us to introduce ursodeoxycholic acid. She also normalized her complete blood count, cholestasis, and renal function tests within 2 weeks, and was discharged home after 3 weeks with oral antibiotic and angiotensinconverting enzyme inhibitor treatment for residual arterial hypertension, which was stopped after 6 months. After follow-up of 12 months, the child showed a normal physical examination without arterial hypertension, no proteinuria, normal renal function, normal complete blood count, and normal liver function tests.
Discussion Hemolytic and uremic syndrome is a rare but increasing complication of Sp infection with higher morbidity than usual shiga-like toxin–producing Escherichia coli (STEC)-HUS. Increased unconjugated bilirubin and serum transaminase levels were described and attributed 1
Lausanne University Hospital, Lausanne, Switzerland
Corresponding Author: Hassib Chehade, Department of Pediatrics; Division of Pediatric Nephrology, Lausanne University Hospital, Rue Bugnon 46, 1011 Lausanne, Switzerland. Email: [email protected]
Downloaded from cpj.sagepub.com at DALHOUSIE UNIV on June 21, 2015
2
Clinical Pediatrics
Table 1. Patient’s Clinical Characteristics and Clinical Course. Patients
1a
Age in months 21 Gender Female Disease Pneumonia Peak SCreat (mg/dL) 1.4 Peak AST/ALT (U/L) 390/125 Peak bilirubin (total/ 11.6/9.9 conjugated) in mg/dL Days until liver 9 function tests normalization Duration of dialysis 12 in days Renal outcome Normal renal function at 6 months
2a
3a
4b
Our patient
10 Male Meningitis 2.4 500/60 19.8/18.4
17 Male Pneumonia 2 1630/280 11.6/10.2
10 Female Pneumonia 2.4 430/120 26.9/18.4
30 Female Pneumonia 3 333/128 26.3/21.5
5
10
8
13
10
28
26
6
Normal renal function at 10 days
Data not shown Mild renal failure at 1 year
Normal renal function at 6 months
Abbreviations: SCreat, serum creatinine; ALT, alanine transaminase; AST, aspartate transaminase. a Pan et al.10 b Chen et al.6
to hemolysis.4-7 Cholestasis has been also described in (STEC)-HUS.8 It is believed to be due to an intrahepatic vasculitis and microangiopathic thrombosis leading to hypoxia, liver damage, and cholestasis.8,9 However, cholestasis with increased conjugated hyperbilirubinemia is uncommon in SpHUS. To our knowledge, a few cases were described in literature.6,10 Lee et al,11 reported in 20 children with HUS, a hepatocellular dysfunction with elevated ALT and conjugated hyperbilirubinemia in 9 and 13 children, respectively. The authors reported that hepatocellular injury in SpHUS patients group was more serious than the non-SpHUS group. Conjugated bilirubinemia levels were mildly elevated in the 2 groups (maximal value, 1.34 mg/dL), however, authors did not find significant difference in conjugated bilirubinemia levels between these 2 groups. In our case report, SpHUS was associated with severe increased conjugated hyperbilirubinemia (maximum value, 21.5 mg/dL). Pathophysiological mechanism of cholestasis in SpHUS has not yet been established. Proposed mechanisms are, as in classic HUS, intrahepatic vasculitis and thrombosis that may contribute to hepatocellular injury and cholestasis. Some authors suggested that the activated T-Ag presented on hepatocytes may explain the occurrence of transient hepatic dysfunction.4,11,12 Chen et al6 suggested the occurrence of a plasma extravasation, secondary to an increased vascular permeability due to the inflammatory syndrome associating endotoxin, cytokine, and leukotriene, leading to a reduced bile flow and thus to increased conjugated hyperbilirubinemia.
When comparing our patient and the 4 published cases of Chen et al6 and Pan et al,10 our patient was older, severity of cholestasis and renal failure were comparable, days until liver function recovery, and duration of renal replacement therapy varied from 5 to 13 days, and from 6 to 28 days, respectively (Table 1). Concerning renal outcome, SpHUS is associated with a poorer renal outcome than (STEC)-HUS.13 The occurrence of cholestasis, after carefully analysing our case and the other reported cases in literature, does not seem to affect the kidney function recovery in SpHUS. In conclusion, pediatricians should be aware that cholestatic jaundice may complicate the course of SpHUS. Here, we report a case of a child with SpHUSassociated severe conjugated hyperbilirubinemia with an excellent clinical outcome. This observation associated with the previous few cases reported in the literature; demonstrate that cholestasis does not seem to affect the clinical outcome of the disease. However, more cases should be reported to confirm this observation. Author Contribution KAS participated to the patient care treatment, drafted the initial manuscript, and approved the final manuscript as submitted. FC participated to the draft of the manuscript, and corrected/approved the final manuscript as submitted. MHP participated to the patient care treatment and approved the final manuscript as submitted. HC participated to the patient care treatment and to the draft of the manuscript, and corrected/approved the final manuscript as submitted.
Downloaded from cpj.sagepub.com at DALHOUSIE UNIV on June 21, 2015
3
Anastaze Stelle et al Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Spinale JM, Ruebner RL, Kaplan BS, Copelovitch L. Update on Streptococcus pneumoniae associated hemolytic uremic syndrome. Curr Opin Pediatr. 2013;25: 203-208. 2. Novak D, Lundgren A, Westphal S, Valdimarsson S, Olsson ML, Trollfors B. Two cases of hemolytic uremic syndrome caused by Streptococcus pneumoniae serotype 3, one being a vaccine failure. Scand J Infect Dis. 2013;45:411-414. 3. Quiviger S, Flechelles O, Cecile W, Hatchuel Y. Streptococcus pneumoniae-induced hemolytic uremic syndrome: a serotype-3-associated case. Arch Pediatr. 2012;19:599-602. 4. Copelovitch L, Kaplan BS. Streptococcus pneumoniaeassociated hemolytic uremic syndrome. Pediatr Nephrol. 2008;23:1951-1956. 5. Jeffrey G, Kibbler CC, Baillod R, Farrington K, Morgan MY. Cholestatic jaundice in the haemolytic-uraemic syndrome: a case report. Gut. 1985;6:315-319.
6. Chen JP, Chen SM, Sheu JN. Unusual manifestation of severe conjugated hyperbilirubinemia in an infant with Streptococcus pneumoniae-associated hemolytic uremic syndrome. J Formos Med Assoc. 2007;106(2 suppl):S17-S22. 7. Grodinsky S, Telmesani A, Robson WL, Fick G, Scott RB. Gastrointestinal manifestations of hemolytic uremic syndrome: recognition of pancreatitis. J Pediatr Gastroenterol Nutr. 1990;11:518-524. 8. Riley MR, Lee KK. Escherichia coli O157:H7-associated hemolytic uremic syndrome and acute hepatocellular cholestasis: a case report. J Pediatr Gastroenterol Nutr. 2004;38:352-354. 9. de Buys Roessingh AS, de Lagausie P, Baudoin V, Loirat C, Aigrain Y. Gastrointestinal complications of post-diarrheal hemolytic uremic syndrome. Eur J Pediatr Surg. 2007;17:328-334. 10. Pan CG, Leichter HE, Werlin SL. Hepatocellular injury in Streptococcus pneumoniae-associated hemolytic uremic syndrome in children. Pediatr Nephrol. 1995;9:690-693. 11. Lee CS, Chen MJ, Chiou YH, Shen CF, Wu CY, Chiou YY. Invasive pneumococcal pneumonia is the major cause of paediatric haemolytic-uraemic syndrome in Taiwan. Nephrology (Carlton). 2012;17:48-52. 12. Vanderkooi OG, Kellner JD, Wade AW, et al. Invasive Streptococcus pneumoniae infection causing hemolytic uremic syndrome in children: two recent cases. Can J Infect Dis. 2003;14:339-343. 13. Brandt J, Wong C, Mihm S, et al. Invasive pneumococcal disease and hemolytic uremic syndrome. Pediatrics. 2002;110:371-376.
Downloaded from cpj.sagepub.com at DALHOUSIE UNIV on June 21, 2015
