Nationwide study of haemolytic uraemic syndrome: clinical, microbiological, and epidemiological features

AIMS—To establish the incidence and aetiology of haemolytic uraemic syndrome (HUS) in Australia and compare clinical and microbial characteristics of sporadic and outbreak cases.
METHODS—National active surveillance through the Australian Paediatric Surveillance Unit with monthly case notification from paediatricians, July 1994 to June 1998. Children under 15 years presenting with microangiopathic haemolytic anaemia, thrombocytopenia, and acute renal impairment were identified.
RESULTS—Ninety eight cases were identified (incidence 0.64 per 10⁵ children <15 years/annum and 1.35 per 10⁵ children <5 years/annum). Eighty four were associated with diarrhoea (64 sporadic, 20 constituting an outbreak) and 14 were atypical. Shiga toxin producing Escherichia coli (STEC) O111:H− was the most common isolate in sporadic HUS and caused the outbreak. However O111:H− isolates from outbreak and sporadic cases differed in phage type and subtyping by DNA electrophoresis. STEC isolates from sporadic cases included O26:H−, O113:H21, O130:H11, OR:H9, O157:H−, ONT:H7, and ONT:H−. STEC O157:H7 was not isolated from any case. Only O111:H− isolates produced both Shiga toxins 1 and 2 and possessed genes encoding E coli attaching and effacing gene (intimin) and enterohemolysin. Outbreak cases had worse gastrointestinal and renal disease at presentation and more extrarenal complications.
CONCLUSIONS—Linking national surveillance with a specialised laboratory service allowed estimation of HUS incidence and provided information on its aetiology. In contrast to North America, Japan, and the British Isles, STEC O157:H7 is rare in Australia; however, non-O157:H7 STEC cause severe disease including outbreaks. Disease severity in outbreak cases may relate to yet unidentified virulence factors of the O111:H− strain isolated.

     

Childhood haemolytic uraemic syndrome: Long-term outcome and prognostic features

From January 1970 to December 1982, 95 infants and children with the haemolytic uraemic syndrome were admitted to our unit. Six patients died (6.3%) in the acute phase, 4 went into end-stage renal failure (4.2%) within months after the acute episode. The remaining 85 patients (89.5%) survived and recovered. They were followed as outpatients at yearly intervals for 5 years. Arterial hypertension was a major problem in 7. Eighty patients were studied 10 years later: 52 of them (65%) had no sequelae, 21 (26%) had mild defects and 7 (9%) severe sequelae. Clinical and laboratory data at the onset were analysed for prognostic significance. The immediate outcome was significantly worse in patients with either arterial hypertension or central nervous system manifestations on admission. Yet, no single variable studied during the acute phase was predictive of the presence of sequelae after 10 years. Even when all complications i.e. anuria, hypertension and central nervous system involvement, were taken together, there was no difference between patients with and patients without sequelae.     

Recurrent haemolytic uraemic syndrome.

Two children are described with frequent relapsing haemolytic uraemic syndrome. In the first child, the disease reoccurred twice and in the second three times. In both, relapses could be related to a viral infection, as well as to a preceding inoculation for diphtheria--pertussis--tetanus--poliomyelitis in the second patient. Recurrent haemolytic-uraemic syndrome (H.U.S.) may constitute a discrete clinical form of H.U.S.     

Myocarditis and haemolytic uraemic syndrome.

A 13 year old girl is reported who presented with haemolytic uraemic syndrome (HUS) due to Escherichia coli O157:H7 infection. She died during the acute phase of the illness after an episode of unexplained sudden circulatory collapse. Postmortem examination confirmed the diagnosis of HUS and showed histological evidence of myocarditis manifested by the presence of inflammatory cell infiltration in the myocardium and around the conducting system.     

Sequelae of haemolytic uraemic syndrome.

Twenty two patients with previous episodes of haemolytic uraemic syndrome (HUS) were investigated for evidence of deficits in cognitive, behavioural, and academic function. Patients were pair matched with 22 controls for age (+/- 1 year), gender, and socioeconomic status. HUS patients had numerically lower cognitive and achievement scores and higher behavioural problem ratings than their controls on every measure. None of the group differences was significant at the 0.01 level. Significance values between 0.10 and 0.01 were obtained for the Wechsler full scale and verbal intelligence quotient scores and for several of the achievement measures and behaviour ratings. These results were conservatively interpreted as trends and are considered to provide preliminary indications of a post-HUS deficit in behaviour, verbal intelligence, and the verbally based skills of reading comprehension and vocabulary. The findings provide interim guidelines for follow up care but require confirmation and elaboration in a larger study.     

Clostridium difficile after haemolytic uraemic syndrome.

Six children are described who developed diarrhoea associated with Clostridium difficile during the course of haemolytic uraemic syndrome. The significance of this infection is discussed within the context of the pathophysiology of haemolytic uraemic syndrome.     

Childhood brucellosis--a microbiological, epidemiological and clinical study

A total of 5726 blood specimens (from children aged 14 years and younger) were studied for the serological evidence of brucellosis. Ninety-three (1.6 per cent) showed diagnostic agglutinin titres with a geometric mean titre of 403 (SD +/- 547). Forty-three (59.7 per cent) blood specimens yielded the growth of Brucella melitensis. Thirty-nine patients (41.93 per cent) were shepherds, who constituted the major occupational group affected in the present series. More than 60 per cent of the patients had a history of both consumption of fresh goat's milk and close animal contact. The habit of consuming fresh goat's milk to obtain relief from chronic ailments was noted in nine patients. Seventy-three (78.49 per cent) were males and 20 (21.51 per cent) were females, with a male to female ratio of 3:1. The disease occurred mainly in the school age group (mean age 10.3 years). All the patients had an acute history of less than 2 months. Forty-nine (52.68 per cent) patients presented with persistent fever, 19 (20.43 per cent) with joint pain, and the rest with a combination of fever and joint pain with and without low backache, fever being the commonest complaint. One case presented with involuntary movements of limbs alone and the other with burning feet only. Pityriasis alba was the consistent physical finding, with fever in the majority of the patients. The major joint found to be involved was the knee (52.77 per cent). The synovial fluid obtained from the knee joint of five patients demonstrated Brucella agglutinins and also three grew B. melitensis. Eight patients presented with complications that included skin lesions (3), carditis (2), neurobrucellosis such as chorea (1), peripheral neuritis (1), and meningitis (1). Brucella melitensis biotype 1 was successfully isolated from the papular eruption of one out of three cases who presented with skin lesions. To our knowledge this is the fourth confirmed isolation of B. melitensis from skin lesions with brucellosis, reported in the literature. The cerebrospinal fluid obtained from the meningitis patient was positive for B. agglutinins. To our knowledge chorea of brucellar origin appears to be the first case reported in the literature. In 15 cases (16.13 per cent) brucellosis was suspected clinically whereas 78 (83.87 per cent) cases, only serological evidence of brucellosis confirmed the diagnosis. None of the cases relapsed. In our experience an initial combination therapy with a three-drug regimen followed by a two-drug regimen for a minimum of 6 weeks has been found to be effective in the prevention of a relapse.     

Neuropsychological sequelae of haemolytic uraemic syndrome

BACKGROUND—Severe haemolytic uraemic syndrome (HUS) in childhood can cause stroke, hemiplegia, cortical blindness, and psychomotor retardation. These outcomes are evident at the time of discharge immediately after the acute illness. Less is known about the neuropsychological outcomes of less severely affected children who recover from acute HUS.AIMS—This multicentre case control study investigated the hypothesis that children who survive an acute episode of HUS without recognisable neurological injuries have greater impairment of cognitive, academic, and behavioural functions than controls.DESIGN—Children with HUS were eligible if they had no evidence of severe neurological dysfunction when discharged from one of six Canadian hospitals. Controls had been admitted to hospital for a non-HUS illness and were matched by age, sex, first language, and socioeconomic status. All subjects underwent evaluation of behaviour, academic achievement, cognitive function, and verbal abilities using standardised tests administered by a psychometrist blinded to the case or control status.RESULTS—Ninety one case control pairs were enrolled. No important differences between patients with HUS and paired controls were evident on tests of IQ, behaviour, verbal abilities, or academic achievement. There was no increased risk of attention deficit disorder among patients with HUS. There was no correlation between the severity of acute renal failure and neuropsychological measures, although scores on some verbal ability tests were lower in those with the highest serum creatinine concentrations during illness.CONCLUSIONS—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, behaviour, or attention.     

Surgical complications of the haemolytic uraemic syndrome

During the first outbreak of haemolytic uraemic syndrome (HUS) to be reported in Australia, 22 children were admitted to the Women's and Children's Hospital, Adelaide. The outbreak was caused by an entero-haemorrhagic Escherichia coli strain (EHEC) of serotype 011:H-, a strain rarely implicated as a cause for HUS. In all 22 patients, the onset of HUS was preceded by a gastrointestinal (GI) prodrome. All patients had diarrhoea. In 17 (73%), the diarrhoea became bloody; in 20 (86%) there was vomiting; in 15 (65%) there was abdominal pain; and in 12 (50%) all three symptoms were present. Abdominal symptoms continued to complicate the course of 4 patients. Two of these underwent exploratory laparotomy, both had gangrenous colon excised, and both survived. The 2 remaining patients were successfully treated non-operatively. One further patient underwent appendicectomy before the diagnosis of HUS was made. There was 1 death during this epidemic. In patients with HUS and GI involvement, optimal surgical management requires careful consideration of the indications for, and the timing of, surgical intervention.     

Inhibitor of prostacyclin production in sporadic haemolytic uraemic syndrome.

Prostacyclin (PGI2) production was diminished when rat aortic rings were incubated with plasma from 5 of 6 patients with the sporadic form of haemolytic uraemic syndrome but was normal in the presence of plasma from 7 patients with the epidemic form of haemolytic uraemic syndrome or from patients with other renal diseases. The reduced PGI2 production was caused by an unstable inhibitor, extractable into polar lipid solvents, in sporadic haemolytic uraemic plasma. These results suggest that there may be at least 2 different pathogenetic mechanisms in epidemic and sporadic haemolytic uraemic syndrome and that the reduced PGI2 production observed in the sporadic type is due to an inhibitor of PGI2 production rather than a deficiency of stimulating factors.     

The haemolytic uraemic syndrome in childhood: A study of the long-term prognosis

From January 1970 to June 1976, 45 children with the haemolytic uraemic syndrome were admitted to our department. They all received heparin in addition to supportive therapy. For the last ten patients heparin was given with dipyridamole (Persantin^®). Three children died in the acute stage of the illness giving an acute fatality rate of 6.6%. A fourth patient immediately needed chronic haemodialysis. In the other 41 patients, kidney function only partially recovered in two; they subsequently developed terminal renal insufficiency after 18 months and four years, respectively. The remaining 39 children have been regularly followed for three to eight years. None has been lost to follow-up. With only one exception, they all have shown a favourable evolution with negative urinalysis, normal blood pressure, and an endogenous creatinine clearance within the normal range for age.     

Renal functional reserve compared in haemolytic uraemic syndrome and single kidney.

Creatinine clearance and microalbuminuria were measured before and after an oral protein load in 17 children with a history of haemolytic uraemic syndrome, 11 with a single kidney, and 15 controls, all of them normotensive and without evidence of renal damage, to look for indirect evidence of glomerular hyperfiltration. While creatinine clearance increased significantly after the protein load in controls, it did not change in patients with either haemolytic uraemic syndrome or a single kidney. Basal microalbuminuria was significantly higher in those with haemolytic uraemic syndrome when compared with those with a single kidney and controls. It increased significantly in all groups after a water load; this increase was significantly higher in haemolytic uraemic syndrome. After the protein load microalbuminuria returned to baseline. In conclusion, children with a history of haemolytic uraemic syndrome have an abnormal renal functional reserve like children with a single kidney. Only patients with haemolytic uraemic syndrome exhibited an increased microalbuminuria, however, suggesting that it may be the expression of a pathophysiological mechanism involved in haemolytic uraemic syndrome and not in single kidney, that could account for their different prognosis.     

Inhibitor of prostacyclin production in sporadic haemolytic uraemic syndrome

Prostacyclin (PGI2) production was diminished when rat aortic rings were incubated with plasma from 5 of 6 patients with the sporadic form of haemolytic uraemic syndrome but was normal in the presence of plasma from 7 patients with the epidemic form of haemolytic uraemic syndrome or from patients with other renal diseases. The reduced PGI2 production was caused by an unstable inhibitor, extractable into polar lipid solvents, in sporadic haemolytic uraemic plasma. These results suggest that there may be at least 2 different pathogenetic mechanisms in epidemic and sporadic haemolytic uraemic syndrome and that the reduced PGI2 production observed in the sporadic type is due to an inhibitor of PGI2 production rather than a deficiency of stimulating factors.     

Prostacyclin concentrations in haemolytic uraemic syndrome after acute shigellosis in children.

The role of prostacyclin in the pathogenesis of haemolytic uraemic syndrome was evaluated in 11 children with acute shigellosis. Plasma concentrations of 6-keto prostaglandin, F1 alpha, a stable metabolite of prostacyclin, were measured by radioimmunoassay during acute illness, early convalescence, and after clinical recovery. Its concentration was low during acute illness in each patient, returning to normal concentrations or above at the time of the last sample. These results suggest that plasma prostacyclin may be involved in the development of the syndrome.     

Neuropsychological sequelae of haemolytic uraemic syndrome. Investigators of the HUS Cognitive Study.

BACKGROUND: Severe haemolytic uraemic syndrome (HUS) in childhood can cause stroke, hemiplegia, cortical blindness, and psychomotor retardation. These outcomes are evident at the time of discharge immediately after the acute illness. Less is known about the neuropsychological outcomes of less severely affected children who recover from acute HUS. AIMS: This multicentre case control study investigated the hypothesis that children who survive an acute episode of HUS without recognizable neurological injuries have greater impairment of cognitive, academic, and behavioural functions than controls. DESIGN: Children with HUS were eligible if they had no evidence of severe neurological dysfunction when discharged from one of six Canadian hospitals. Controls had been admitted to hospital for a non-HUS illness and were matched by age, sex, first language, and socioeconomic status. All subjects underwent evaluation of behaviour, academic achievement, cognitive function, and verbal abilities using standardised tests administered by a psychometrist blinded to the case or control status. RESULTS: Ninety-one case control pairs were enrolled. No important differences between patients with HUS and paired controls were evident on tests of IQ, behaviour, verbal abilities, or academic achievement. There was no increased risk of attention deficit disorder among patients with HUS. There was no correlation between the severity of acute renal failure and neuropsychological measures, although scores on some verbal ability tests were lower in those with the highest serum creatinine concentrations during illness. CONCLUSIONS: 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, behaviour, or attention.     

Simultaneous occurrence of the haemolytic uraemic syndrome and acute post-infectious glomerulonephritis

We report on two children, a 12-year-old boy and a 6-year-old girl, with simultaneous occurrence of clinical and laboratory features consistent with both diarrhoea-negative haemolytic uraemic syndrome (D-HUS) and acute post-infectious glomerulonephritis (APGN). Both presented with acute renal insufficiency, hypertension and oedema. Laboratory evaluation revealed micro-angiopathic anaemia with burr cells, thrombocytopenia, elevated lactic dehydrogenase and low complement C3. Urinalysis showed marked proteinuria and haematuria. Renal biopsy was characteristic of APGN, but not of HUS. The outcome was good in both children. Conclusion The simultaneous occurrence of diarrhoea-negative haemolytic uraemic syndrome and acute post-infectious glomerulonephritis is rare. The outcome is generally good as is expected in the latter condition in contrast to the former. Received: 10 August 2000 / Accepted: 20 September 2000