Urinary tract infections in infants: comparison between those with conjugated vs unconjugated hyperbilirubinaemia

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1 Annals of Tropical Paediatrics (2005) 25, Urinary tract infections in infants: comparison between those with conjugated vs unconjugated hyperbilirubinaemia HUNG-CHANG LEE* {, SHIUH-BIN FANG* {1, CHUN-YAN YEUNG* & JENG-DAW TSAI* { Departments of Paediatrics, *Mackay Memorial Hospital, { Taipei Medical University and { Taiwan Adventist Hospital, Taipei, and 1 Department of Paediatrics, Chung Shan Medical University, Taichung, Taiwan (Accepted September 2005) Annals of Tropical Paediatrics ATP5406.3d 28/9/05 16:30:06 Abstract Aims: The aim was to investigate conjugated and unconjugated hyperbilirubinaemia in association with urinary tract infection (UTI) in young infants. Methods: Fifty infants aged,3 mths who developed prolonged jaundice among 2128 infants with UTI from 1984 to 2004 were enrolled retrospectively. They were divided into conjugated (n522) and unconjugated (n528) hyperbilirubinaemia groups and the clinical variables between the two were compared. Results: Compared with the unconjugated group, the conjugated hyperbilirubinaemia group had statistically significantly lower haemoglobin (1.57 vs 1.80 mmol/l), higher aspartate aminotransferase (96 vs 32.5 U/L) and alanine aminotransferase (81.5 vs 16 U/L), were older on admission (48.0 vs 32.5 days), had a longer duration of jaundice before treatment (43.5 vs 30 days) and a higher incidence of E. coli infections (19/22 vs 15/28). The direct/ total bilirubin ratio was linearly correlated with duration of jaundice before treatment (p50.004). The most significant cut-off value for the duration of jaundice vis-à-visthe type of jaundice was 38 days (p50.007). Patients who on presentation had had jaundice for.44 days (p50.007) were unlikely to have unconjugated hyperbilirubinaemia. Conclusions: Infants with UTI may present with unconjugated hyperbilirubinaemia in the early stage. After 6 weeks, it is always conjugated hyperbilirubinaemia and is frequently associated with anaemia, elevated hepatic aminotransferases and E. coli infections. Introduction Urinary tract infection (UTI) can present with jaundice in early infancy, but when and how the types of hyperbilirubinaemia change is unclear. We analysed the clinical features of UTI associated with jaundice in early infancy. The goals of this study were (i) to compare conjugated and unconjugated hyperbilirubinaemia in association with UTI, (ii) to look for a correlation between the degree of conjugated hyperbilirubinaemia and the duration of jaundice before treatment, (iii) to determine when conjugated hyperbilirubinaemia becomes more likely than unconjugated hyperbilirubinaemia, and (iv) to seek a reasonable explanation for the characteristic features of prolonged jaundice in young infants with UTI. Subjects and methods Reprint requests to: Dr Shiuh-Bin Fang, Department of Paediatrics, Taiwan Adventist Hospital 424, Section 2, Pateh Road, Taipei 105, Taiwan. Fax: z ; drsbfang@ms3.hinet.net We retrospectively reviewed the records of infants in the 1st 3 months of life admitted to Mackay Memorial Hospital, Taipei, Taiwan # 2005 The Liverpool School of Tropical Medicine DOI: / X72421

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4 280 Hung-Chang Lee et al. Annals of Tropical Paediatrics ATP5406.3d 28/9/05 16:30:23 FIG. 1. The cut-off value for duration of jaundice before treatment and the number (%) of patients with jaundice longer than the cut-off value in conjugated and unconjugated hyperbilirubinaemia [ N p-value, * p,0.01, { smallest p-value; & (duration of jaundice) patient no./total no. (%) of patients in group A; m (duration of jaundice) patient no./total no. (%) of patients in group B]. week of life had evidence of pyelonephritis. 2 The jaundice was regarded by these authors as a feature of septicaemia associated with pyelitis. In 1967, three infants aged from 3 to 7 weeks who presented with jaundice were reported to have UTI without sepsis, with or without hepatic dysfunction. 3 This demonstrates the diverse manifestations of jaundice in young infants with UTI. In our retrospective study, the type of jaundice associated with UTI was conjugated hyperbilirubinaemia in 22 and unconjugated hyperbilirubinaemia in 28. Patients with conjugated hyperbilirubinaemia were older than those with unconjugated hyperbilirubinaemia and had a longer duration of jaundice before treatment, even though the total bilirubin levels were not significantly different. Previous studies of sepsis and jaundice in infancy indicate that during the 1st week of life idiopathic hyperbilirubinaemia with elevation of the indirect-reacting fraction might be exacerbated or prolonged by the sepsis. Beyond the 1st week, the characteristic pattern of UTI in infants is that of obstructive jaundice. 2,4 In this study, we found that a number of jaundiced infants presented with unconjugated hyperbilirubinaemia until days of age. The duration of jaundice correlated positively with the direct/total bilirubin ratio but not with the direct bilirubin level. This suggests that the temporal transformation from a preponderance of unconjugated to conjugated hyperbilirubinaemia might result from a gradual decrease in indirect bilirubin rather than an increase in direct bilirubin. However, the levels of hepatic aminotransferases were higher in infants presenting with conjugated hyperbilirubinaemia, suggesting there may also have been some element of hepatic inflammation associated with cholestasis in an untreated UTI. A number of possible mechanisms for UTI-related jaundice or hepatic injury have been documented, including (i) haemolysis, 5 8 (ii) direct invasion of the liver parenchyma by blood-borne or lymphborne micro-organisms, 1,2,4 (iii) hepatocellular injury by circulating endotoxins, 9 13 (iv) serum bactericidal activity 14,15 and (v)

5 Annals of Tropical Paediatrics ATP5406.3d 28/9/05 16:30:24 non-specific injury to the liver related to hyperpyrexia, malnutrition and anoxaemia. Some cases of haemolysis (a diagnosis based on the presence of anaemia and elevated reticulocyte counts) have been reported to contribute to jaundice in patients with infections caused by E. coli, Paracolobacterium, Enterobacter aerogeens and Enterococcus. 5 8 Certain strains of E. coli produce a haemolysin demonstrated by a high titre of anti-a-haemolytic antibodies in a patient s serum 5 and by haemolytic zones on a blood agar plate. 6 Increased red cell fragility in E. coli sepsis is also reported to be a common factor of haemolysis. 16 However, haemolysis is not thought to be the major cause of UTI-related jaundice, although even mild haemolysis can overload the immature liver conjugating mechanism, leading to an increase in serum bilirubin levels. 17 Direct bacterial invasion of the liver parenchyma leading to toxic hepatitis and jaundice might explain some cases of UTIrelated prolonged jaundice. In our series, however, only two of 34 infants who had blood cultures drawn had E. coli bacteraemia. Therefore, direct invasion and haemolysis resulting from bacteraemia would not explain the jaundice in most of our cases. In cases without bacteraemia, other mechanisms have been implicated. Bacterial endotoxin may impair the hepatocyte excretory mechanism, 11,13 cause cholestasis 12 and damage hepatocytes indirectly. 18 Conversely, unconjugated bilirubin, present as prolonged physiological jaundice, might be toxic to cells of the immune system, altering cell-mediated immunity or causing a functional defect of the complement system. 14 Therefore, the hyperbilirubinaemia seen in young infants might not be the consequence of a UTI but rather contribute to infection by partially suppressing the normal bactericidal properties of the immune system. This latter mechanism might explain why we found unconjugated hyperbilirubinaemia to be more common in young infants with UTI. Overloading of an immature conjugating mechanism with Hyperbilirubinaemia in UTI 281 products of even mild haemolysis in the 1st week of life might cause a rise in the indirect bilirubin level. When the conjugating capacity is more mature, liver cell damage affecting bilirubin excretion from the cell might then cause elevation of direct bilirubin, as we saw in the older babies. 18 Regardless of the type of bilirubin elevation, our study found a male predominance, similar to previous reports. 7,8,17,19 Seeler & Hahn cited eight reported series totalling 88 cases with a male predominance of 3:1. This contrasts with the usual pattern of female preponderance in the incidence of UTI in older children who have demonstrable anomalies of their urinary tracts. 8 With regard to the type of pathogen, an infant infected with E. coli is more likely to develop jaundice associated with sepsis than are those infected with other agents. Our study showed that E. coli was more likely to be associated with conjugated hyperbilirubinaemia than was Klebsiella pneumoniae. A reversal of the expected frequencies of A and B blood groups has been observed in jaundiced infants with urosepsis owing to haemolytic E. coli but in our study and another there was no discernible clinical difference in the degree of haemolysis related to blood groups. 6 A shift to the left in the differential white cell count, a common sign of sepsis or severe bacterial infection, occurred in only six of 22 infants with direct hyperbilirubinaemia. Early administration of antibiotics seemingly prevented the development of sepsis. Our study clearly demonstrates that young infants with mild UTI may develop conjugated hyperbilirubinaemia. The question remains as to whether less virulent strains of urinary tract pathogens predispose to afebrile jaundice and whether a prolonged occult UTI is more likely to cause hepatic injury. Mixed urinary infections with more than one organism are reported sporadically 3,7 and account for more than 10% of UTI in infants under 2 mths of age. 20 However, polymicrobial infections were not significantly correlated with conjugated hyperbilirubinaemia in our study.

6 Annals of Tropical Paediatrics ATP5406.3d 28/9/05 16:30: Hung-Chang Lee et al. On the basis of the findings in this study and others, we propose a dynamic model of jaundice in young infants with UTI. Urinary pathogens, mainly E. coli but possibly some others, might simultaneously induce increased levels of both indirect bilirubin and direct bilirubin by way of haemolysis, endotoxins, immune-mediated responses or direct hepatocyte damage in the early stages. With time, the indirect bilirubin level progressively decreases, but the direct bilirubin level does not fall proportionately. Ongoing hepatocyte damage might impair the excretion of conjugated bilirubin, leading to cholestasis mimicking hepatitis. Acknowledgments We are grateful to Dr Mary Jeanne Buttrey for revising the English in this paper and to Dr Shyh-Jye Chen for assistance with data collection. References 1 Görter E, Lignac GOE. On pyelitis complicated by jaundice. Br Med J 1928; 3: Berstein J, Brown AK. Sepsis and jaundice in early infancy. Pediatrics 1962; 29: Arthur AB, Wilson BD. Urinary infection presenting with jaundice. Br Med J 1967; 1: Linder N, Yatsiv I, Tsur M, et al. Unexplained neonatal jaundice as an early diagnostic sign of septicemia in the newborn. J Perinatol 1988; 8: Emody L, Molnar L, Kellermayer M, Paal M, Wadstrom T. Urinary Escherichia coli infection presenting with jaundice. Scand J Infect Dis 1989; 21: Seeler RA. Urosepsis with jaundice due to hemolytic Escherichia coli (letter). Am J Dis Child 1973; 126: Seeler RA. Hemolysis due to gram-negative urinary tract infection. Birth Defects Orig Artic Ser 1977; 13: Seeler RA, Hahn K. Jaundice in urinary tract infection in infancy. Am J Dis Child 1969; 118: Ferluga J, Allison AC. Role of mononuclear infiltrating cells in pathogenesis of hepatitis. Lancet 1978; 2: Naveh Y, Friedman A. Urinary tract infection presenting with jaundice. Pediatrics 1978; 62: Utili R, Abernathy CO, Zimmerman HJ. Cholestatic effects of Escherichia coli endotoxin on the isolated perfused rat liver. Gastroenterology 1976; 70: Utili R, Abernathy CO, Zimmerman HJ. Inhibition of Naz, Kz-adenosinetriphosphatase by endotoxin: a possible mechanism for endotoxin-induced cholestasis. J Infect Dis 1977; 136: Utili R, Abernathy CO, Zimmerman HJ. Studies on the effects of E. coli endotoxin on canalicular bile formation in the isolated perfused rat liver. J Lab Clin Med 1977; 89: Miler I, Vondracek J, Hromadkova L. The bactericidal activity of sera of healthy neonates and of newborns with hyperbilirubinaemia owing to Escherichia coli. Folia Microbiologica 1979; 24: Pal SR, Ayyagari A, Ramanna BC. O-agglutinin antibodies against Alcaligenes faecalis and Escherichia coli in hepatitis cases and normal subjects a preliminary communication. Indian J Med Res 1978; 67: Thurman WG. Changes in red cell fragility with infection. Am J Dis Child 1960; 100: Garcia FJ, Nager AL. Jaundice as an early diagnostic sign of urinary tract infection in infancy. Pediatrics 2002; 109: Rooney JC, Hill DJ, Danks DM. Jaundice associated with bacterial infection in the newborn. Am J Dis Child 1971; 122: Littlewood JM. 66 infants with urinary tract infection in first month of life. Arch Dis Child 1972; 47: Wang SF, Huang FY, Chiu NC, et al. Urinary tract infection in infants less than 2 months of age. Acta Paediatr Sin 1994; 35: