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Experiences with HUS in Canada: what have we learned about childhood HUS in Canada?

2009; Elsevier BV; Volume: 75; Linguagem: Inglês

10.1038/ki.2008.614

1523-1755

Peter N. McLaine, Peter C. Rowe, Elaine Orrbine,

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Experiences with childhood hemolytic uremic syndrome (HUS) in Canada will focus on the development of the Canadian Pediatric Kidney Disease Research Centre (CPKDRC) and the results of our collaborative research over a 13-year period (1985–1998). Experiences with childhood hemolytic uremic syndrome (HUS) in Canada will focus on the development of the Canadian Pediatric Kidney Disease Research Centre (CPKDRC) and the results of our collaborative research over a 13-year period (1985–1998). The pathogen Escherichia coli O157:H7 was first identified from a patient with diarrhea in 1978 and was first associated with the development of hemolytic uremic syndrome (HUS) in 1983.1McLaine P.N. Orrbine E. Can Ped Kid Disease Research Centre.Ann RCPSC. 1989; 22: 531-532Google Scholar, 2McLaine P.N. Hemolytic uremic syndrome: events of the past decade.Paediatr Child Health. 2002; 7: 533-537PubMed Google Scholar, 3Karmali M.A. Petric M. Steele B.T. et al.Sporadic cases of haemolytic-uremic syndrome associated with faecal cytotoxin-producing Escherichia coli in stools.Lancet. 1983; 1: 619-620Abstract PubMed Scopus (814) Google Scholar Cattle are the primary reservoir for verotoxin-producing E. coli (VTEC), of which E. coli O157:H7 is the most frequently identified serotype.4Borczyk A.A. Karmali M.A. Lior H. et al.Bovine reservoir for verotoxin-producing Escherichia coli 0157:H7.Lancet. 1987; 1: 98Abstract PubMed Scopus (240) Google Scholar Risk factors for contracting VTEC are numerous, ranging from ingestion of undercooked ground beef5Riley L.W. Remis R.S. Helgerson S.D. et al.Hemorrhagic colitis associated with a rare Escherichia coli serotype.N Engl J Med. 1983; 308: 681-685Crossref PubMed Scopus (2209) Google Scholar, 6Griffin P.M. Ostroff S.M. Tauxe R.V. et al.Illnesses associated with Escherichia coli 0157:H7 infections: a broad clinical spectrum.Ann Intern Med. 1988; 109: 705-712Crossref PubMed Google Scholar or unpasteurized apple juice7Steele B.T. Murphy N. Arbus G.S. et al.An outbreak of hemolytic uremic syndrome associated with ingestion of fresh apple juice.J Pediatr. 1982; 101: 963-965Abstract Full Text PDF PubMed Scopus (118) Google Scholar to person-to-person spread.8Spika J.S. Parsons J.E. Nordenberg D. et al.Hemolytic-uremic syndrome and diarrhea associated with Escherichia coli 0157:H7 in a day care centre.J Pediatr. 1986; 109: 287-291Abstract Full Text PDF PubMed Scopus (173) Google Scholar, 9Rowe P.C. Orrbine E. Lior H. et al.Diarrhoea in close contacts as a risk factor for childhood haemolytic uraemic syndrome.Epidemiol Infect. 1993; 110: 9-16Crossref PubMed Scopus (41) Google Scholar Also implicated are contaminated water10Swerdlow D.L. Woodruff B.A. Brady R.C. et al.A waterborne outbreak in Missouri of Escherichia coli 0157:H7 associated with bloody diarrhea and death.Ann Intern Med. 1992; 117: 812-819Crossref PubMed Scopus (405) Google Scholar and vegetables from manured gardens.11Ackers M. Mahon B.E. Leahy E. et al.An outbreak of Escherichia coli 0157:H7 infections associated with leaf lettuce consumption.J Infect Dis. 1998; 177: 1588-1593Crossref PubMed Scopus (373) Google Scholar Risk factors for developing HUS after contracting VTEC are numerous and include:young age, old age12Rowe P.C. Orrbine E. Wells G.A. et al.Canadian Pediatric Kidney Disease Research Centre. Epidemiology of hemolytic uremic syndrome in Canadian children from 1986 to 1988.J Pediatr. 1991; 119: 218-224Abstract Full Text PDF PubMed Scopus (159) Google Scholarantimotility agents13Cimolai N. Carter J.E. Morrison B.J. et al.Risk factors for the progression of Escherichia coli 0157:H7 enteritis to hemolytic uremic syndrome.J Pediatr. 1990; 116: 589-592Abstract Full Text PDF PubMed Scopus (153) Google Scholarantibiotics14Walterspiel J.N. Ashkenazi S. Morrow A.L. et al.Effect of subinhibitory concentrations of antibiotics on extracellular Shiga-like toxin I.Infection. 1992; 20: 25-29Crossref PubMed Scopus (168) Google Scholar, 15Wong C.S. The risk of hemolytic uremic syndrome after antibiotic treatment of Escherichia coli 0157:H7 infections.N Engl J Med. 2000; 324: 1930Crossref Scopus (862) Google ScholarVT2 production16Scotland S.M. Willishaw G.A. Smith H.R. et al.Properties of strains of Escherichia coli belonging to serogroup 0157 with special reference to production of Vero cytotoxins VT1 and VT2.Epidemiol Infect. 1987; 99: 613-624Crossref PubMed Scopus (118) Google Scholar, 17Ostroff S.M. Tarr P.I. Neill M.A. et al.Toxin genotypes and plasmid profiles as determinants of systemic sequelae in Escherichia coli 0157:H7 infections.J Infect Dis. 1989; 160: 994-998Crossref PubMed Scopus (351) Google Scholarsevere gastroenteritis18Pavia A.T. Nicols C.R. Green D.P. et al.Hemolytic uremic syndrome during an outbreak of Escherichia coli 0157:H7 infections in institutions for mentally retarded persons: clinical and epidemiologic observations.J Pediatr. 1990; 116: 544-551Abstract Full Text PDF PubMed Scopus (237) Google Scholarhigh white blood cell count12Rowe P.C. Orrbine E. Wells G.A. et al.Canadian Pediatric Kidney Disease Research Centre. Epidemiology of hemolytic uremic syndrome in Canadian children from 1986 to 1988.J Pediatr. 1991; 119: 218-224Abstract Full Text PDF PubMed Scopus (159) Google Scholarfemale gender12Rowe P.C. Orrbine E. Wells G.A. et al.Canadian Pediatric Kidney Disease Research Centre. Epidemiology of hemolytic uremic syndrome in Canadian children from 1986 to 1988.J Pediatr. 1991; 119: 218-224Abstract Full Text PDF PubMed Scopus (159) Google Scholarlow expression of RBC P1 Ag.19Taylor C.M. Milford D.V. Rose P.E. et al.The expression of blood group P1 in post-enteropathic haemolytic uraemic syndrome.Pediatr Nephrol. 1990; 4: 59-61Crossref PubMed Scopus (51) Google Scholar In 1985, the Canadian Pediatric Kidney Disease Research Centre (CPKDRC) was launched, with headquarters in Ottawa, Canada.1McLaine P.N. Orrbine E. Can Ped Kid Disease Research Centre.Ann RCPSC. 1989; 22: 531-532Google Scholar This inaugurated a 13-year effort of unprecedented collaboration leading to numerous studies and projects being completed, and increasing our understanding of the epidemiology of HUS. The first project, completed in 1989, was a retrospective analysis of 226 children with HUS in 14 Canadian sites between 1986 and 1988.12Rowe P.C. Orrbine E. Wells G.A. et al.Canadian Pediatric Kidney Disease Research Centre. Epidemiology of hemolytic uremic syndrome in Canadian children from 1986 to 1988.J Pediatr. 1991; 119: 218-224Abstract Full Text PDF PubMed Scopus (159) Google Scholar This represented the largest series of patients ever studied and reported at that time. The study revealed an annual incidence of HUS of 1.44 per 100,000 children <15 years of age. Eighty-two per cent of children were diagnosed with HUS between April and September, 72% were <5 years, and the median age was 2.7 years. Diarrhea was present in 95% of patients and was bloody in 74%. E. coli O157:H7 was isolated in 51% of the children in whom stools were screened for this organism. Forty-eight per cent required dialysis and the median length of stay was 11 days. The mortality rate of this cohort was 2.7%. In the summer of 1990, the CPKDRC undertook a case–control study of 34 children with HUS and 102 matched controls in eight pediatric centers.20Rowe P.C. Orrbine E. Lior H. CPKDRC Co-investigators et al.Diarrhoea in close contacts as a risk factor for childhood haemolytic uraemic syndrome.Epidemiol Infect. 1993; 110: 9-16Crossref PubMed Google Scholar, 21Rowe P.C. Orrbine E. Lior H. CPKDRC Co-investigators et al.A prospective study of exposure to verotoxin-producing Escherichia coli among children with haemolytic uraemic syndrome.Epidemiol Infect. 1993; 110: 1-7Crossref PubMed Scopus (53) Google Scholar The key findings were threefold:Antibody response to VT2 (22/22) was greater than that to VT1 (12/22), P=0.002.Risk of contact with an individual with diarrhea was seven times higher in HUS patients (P<0.00001). This confirmed the importance of person-to-person spread,which earlier had been merely suspected.22Carter A.O. Borczyk A.A. Carlson J.A.K. et al.A severe outbreak of E. coli 0157:H7-associated hemorrhagic colitis in a nursing home.N Engl J Med. 1987; 317: 1496-1500Crossref PubMed Scopus (426) Google Scholar, 23Karmali M.A. Arbus G.S. Petric M. et al.Hospital-acquired Escherichia coli 0157:H7 associated haemolytic uraemic syndrome in a nurse.Lancet. 1988; 1: 576PubMed Google Scholar, 24Spika J.S. Parsons J.E. Nordenberg D. et al.Hemolytic uremic syndrome and diarrhea associated with Escherichia coli 0157:H7 in a day care center.J Pediatr. 1986; 109: 287-291Abstract Full Text PDF PubMed Scopus (0) Google Scholar, 25Karmali M.A. Arbus G.S. Ish-Shalom N. et al.A family outbreak of hemolytic uremic syndrome associated with verotoxin-producing Escherichia coli serotype 0157:H7.Pediatr Nephrol. 1988; 1: 409-414Crossref Scopus (30) Google ScholarThe rate of exposure to undercooked ground beef did not differ significantly. In 1991, the CPKDRC undertook a 3-year prospective study to determine the risk of developing HUS after sporadic O157:H7 infection. Nineteen pediatric sites participated between June 1991 and March 1994.26Rowe P.C. Orrbine E. Lior H. The Investigators of the Canadian Pediatric Disease Kidney Research Centre et al.Risk of hemolytic uremic syndrome after sporadic Escherichia coli 0157:H7 infection: results of a Canadian collaborative study.J Pediatr. 1988; 132: 777-782Abstract Full Text Full Text PDF Scopus (86) Google Scholar HUS was diagnosed in 205 children (77% with VTEC) and 582 children had uncomplicated VTEC gastroenteritis, of which 18 had hemolytic anemia (HA). The province of Alberta provided us with a provincial cohort, as all patients with VTEC have their isolates sent to one of their two provincial laboratories on a mandatory basis. The risk of HUS after VTEC in the Alberta cohort was 8.1 versus 31.4% in the other tertiary centers, reflecting a referral bias. However, no difference was detected with regard to age, gender, or severity of HUS. An elevated white blood cell count was a significant risk factor, as was age <5 years. HA without renal injury or thrombocytopenia occurred in 1%. Dialysis was required in 34% of the Alberta cohort versus 40% nationally. An increased incidence of HUS in female patients was not confirmed in this study. In 1992–93, the CPKDRC conducted a large, multicenter study to investigate the hypothesis that children who survive an acute episode of HUS, without obvious neurological injury, will nonetheless have greater impairment of cognitive, academic, and behavioral function when compared with controls.27Schlieper A. Orrbine E. Wells G.A. Investigators of the HUS Cognitive Study et al.Neuropsychological sequelae of haemolytic uraemic syndrome.Arch Dis Child. 1999; 80: 214-220Crossref PubMed Scopus (26) Google Scholar A sample of 184 children was identified from earlier CPKDRC studies, of which 91 were enrolled. These 91 enrolled patients did not differ either clinically or neuropsychologically from the identified, eligible non-participants. The positive conclusion was that children discharged from hospital without apparent neurological injury after an episode of acute HUS do not have an increased risk of subclinical problems with learning, behavior, or attention. Identification of the risk of chronic sequelae of HUS, including chronic renal failure, is confounded by the diverse etiologies of HUS. A number of investigators have traced a prior history of HUS up to 25 years,28Trompeter R. Schwartz R. Chantler C. et al.Haemolytic-uraemic syndrome: an analysis of prognostic features.Arch Dis Child. 1983; 58: 101-105Crossref PubMed Scopus (105) Google Scholar, 29Loirat C. Sonsino E. Varga Moreno A. et al.Hemolytic-uremic syndrome: an analysis of the natural history and prognostic features.Acta Paediatr Scand. 1984; 73: 505-514Crossref PubMed Scopus (80) Google Scholar, 30O'Regan S. Blais N. Rousseau P. et al.Hemolytic uremic syndrome: glomerular filtration rate, 6 to 11 years later measured by 99mTc DTPA plasma slope clearance.Clin Nephrol. 1989; 32: 217-220PubMed Google Scholar, 31Fitzpatrick M.M. Shah V. Trompeter R.S. et al.Long term renal outcome of childhood haemolytic uraemic syndrome.BMJ. 1991; 303: 489-492Crossref PubMed Scopus (94) Google Scholar, 32Gagnadoux M.F. Habib R. Gubler M.C. et al.Long-term (15–20 years) outcome of childhood hemolytic-uremic syndrome.Clin Nephrol. 1996; 46: 39-41PubMed Google Scholar, 33Siegler R.L. Milligan M.K. Burningham T.H. et al.Long-term outcome and prognostic indicators in the hemolytic-uremic syndrome.J Pediatr. 1991; 118: 195-200Abstract Full Text PDF PubMed Scopus (109) Google Scholar, 34Siegler R.L. Pavia A.T. Christofferson R.D. et al.A 20-year population-based study of postdiarrheal hemolytic-syndrome in Utah.Pediatrics. 1994; 94: 35-42PubMed Google Scholar but such studies, which rest on retrospective classification of HUS, must be interpreted with some caution. Although all studies agree that children with the post-diarrheal form of HUS will have a small risk of hypertension and the late development of chronic renal failure, there is considerable variation in the estimate of that risk. In 1995, the CPKDRC undertook a case–control study to evaluate the renal health of survivors of HUS from the 1991 Arctic epidemic of E. coli O157:H7 gastroenteritis.35Ogborn M.R. Hamiwka L. Orrbine E. et al.Renal function in Inuit survivors of epidemic hemolytic-uremic syndrome.Pediatr Nephrol. 1998; 12: 485-488Crossref PubMed Scopus (11) Google Scholar Eighteen children who developed HUS during the epidemic, and 18 age- and sex-matched controls from the same community who had uncomplicated gastroenteritis were compared for height, weight, blood pressure, urinalysis, and glomerular filtration rate, measured using continuous subcutaneous infusion of non-radioactive iothalamate. There were no differences in height, weight, blood pressure, or glomerular filtration rate between the two groups, or between those who underwent initial dialysis (75% of cases). Hematuria was detected more frequently in HUS survivors (11/18 versus 4/18, P<0.05), but no child had proteinuria. Survivors of post-enteric HUS had excellent renal function 4 years after the epidemic. In 1991, Glen Armstrong et al.36Armstrong G.D. Fodor E. Vanmaele R. Investigation of Shiga-like toxin binding to chemically synthesized oligosaccharide sequences.J Infect Dis. 1991; 164: 1160-1167Crossref PubMed Scopus (108) Google Scholar reported that VT1 and VT2 bound with high-affinity trisaccharides (Pk trisaccharide) attached to physically inert Chromosorb (silicon dioxide) Synsorb Pk. A hypothesis was developed to determine whether Synsorb Pk was capable of reducing the entry of verotoxin into interstitial mucosa and thereby limiting injury to extraintestinal sites. To test this hypothesis, the CPKDRC embarked on pre-clinical studies, followed by a phase I randomized controlled trial that determined the safety of administering Synsorb Pk to adults.37Armstrong G.D. Rowe P.C. Goodyear P. et al.A phase I study of chemically synthesized Verotoxin (Shiga-like toxin) Pk-trisaccharide receptors attached to Chromosorb for preventing hemolytic-uremic syndrome.J Infect Dis. 1995; 171: 1042-1045Crossref PubMed Scopus (132) Google Scholar A phase II randomized controlled trial was commenced on 1 June 1994, the objectives of which were to estimate the efficacy and safety of Synsorb Pk in the prevention of HUS and HA in children with probable or proven VTEC gastroenteritis. By 31 December 1995, 364 children were enrolled, of whom 17 had HUS or HA at entry. The study was stopped after two HUS seasons on the basis of preliminary data suggesting a 54% relative risk reduction attributable to Synsorb Pk. We concluded that Synsorb Pk was safe and was tolerated by more than 90% of children with acute diarrhea.38Armstrong G.D. McLaine P.N. Rowe P.C. Clinical trials of Synsorb-Pk in preventing hemolytic-uremic syndrome.in: Kaper J.B. O'Brien A.D. Escherichia coli Strains. American Society for Microbiology, Washington, DC1998: 374-384Google Scholar A phase III randomized controlled trial began in June 1996, which included centers from Canada, Argentina, and the United States. This study would enroll only those children free of HUS and HA at entry, those with ≤4 days of diarrhea, and those in whom VTEC was confirmed by either a rapid diagnostic test or a positive stool culture for VTEC. Although 155 patients were enrolled, the trial was inconclusive because the study was terminated prematurely. In summary, much has been accomplished during the 13 years the CPKDRC was active as a direct result of the extraordinary degree of national and, laterally, international collaboration. Initially, data were collected retrospectively with our 3-year analysis of HUS in Canadian children, which contributed to some of our epidemiological and demographic knowledge of this condition. Attention was then focused on prospective multicenter studies, determining our further understanding of the risk factors for developing VTEC infection and the risks for developing HUS after exposure to VTEC. Positive evidence was established regarding the neuropsychological outcome of children surviving an acute episode of HUS in whom there was no recognizable neurological injury. Our 4-year follow-up case–control study of renal function in Inuit survivors of epidemic HUS was reassuring, especially as 75% of the children with HUS underwent dialysis. However, the long-term renal prognosis of VTEC-associated HUS is controversial. Hüseman et al.39Hüsemann M. Gellermann J. Volloner I. et al.Long-term prognosis of hemolytic-uremic syndrome and effective renal plasma flow.Pediatr Nephrol. 1999; 13: 672-677Crossref PubMed Scopus (43) Google Scholar reported on a cohort of 127 of 149 children who had survived the acute phase of HUS. Effective renal plasma flow and filtration fractions were abnormal in 47 and 54%, respectively, whereas glomerular filtration rates were normal in 84%. The decreased effective renal plasma flow in the second year reflects the decrease in functional nephron mass, and it was postulated that the resulting hyperfiltration may lead to progressive renal disease, which they observed in 23% of their patients (median follow-up of 5 years). In 2003, Garg et al.40Garg A.X. Suri R.S. Barrowman N. et al.Long-term prognosis of diarrhea-associated hemolytic-uremic syndrome: a systematic review, meta-analysis and meta-regression.JAMA. 2003; 290: 1379-1381Crossref PubMed Scopus (403) Google Scholar reported on the long-term renal prognosis of patients (age 1 month to 18 years) with diarrhea-positive HUS using a meta-analysis of 3476 patients in 49 studies. Follow-up was for a mean of 4.4 years (1–22 years) with 12% dead or in chronic renal failure, and 25% had long-term renal sequelae. Further long-term studies are required to clarify the renal outcome of childhood HUS. As proved to be the case for the CPKDRC studies on the epidemiology of HUS, studies of renal outcomes will need to be large and representative of the entire spectrum of HUS severity in order to provide accurate estimates of the risk of long-term renal injury. National collaborative studies in countries with a high incidence of HUS may prove to be informative. The authors have declared no financial interests.