GIT

Treating Shiga toxin induced haemolytic uraemicsyndrome

BMJ 19 July 2012
د. حسين محمد جمعه
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2012

Shiga toxin induced haemolytic uraemic syndrome occurs in aminority of patients after infection with enterohaemorrhagic Escherichia coli or Shigella spp. It is characterised by thrombotic microangiopathy and renal failure, which are
attributed to toxic effects of Shiga toxin on systemic and renal microcirculation. The pathogen is commonly part of the intestinal flora of cattle and is transmitted by contaminated food.

Worldwide, the most common strain is E coli O157:H7, which

causes the syndrome mainly in young children.1 Prognosis is
good and treatment is mainly supportive, because no treatment has been proved to be effective and the use of antibiotics or plasmapheresis is controversial.
In a linked research paper (doi:10.1136/bmj.e4565), Menne and colleagues present data on the effects of various treatments on the course of Shiga toxin induced haemolytic uraemic syndrome in a cohort of 298 patients treated at 23 German hospitals.


In 2011, Germany experienced the largest reported outbreak of Shiga toxin induced haemolytic uraemic syndrome, which affected 855 of the 3842 people who had been infected with enterohaemorrhagic E coli from contaminated fenugreek sprouts. Analyses of isolates from stool samples showed that enterohaemorrhagic E coli O104:H4 was the causative strain.

This unusual and aggressive strain carried virulence factors typical of Shiga toxin-producing enterohaemorrhagic E coli as well as extended spectrum β-lactamase, and it led to severe haemolytic uraemic syndrome in a large proportion of mainly
adult patients. The clinical features of the syndrome commonly included dialysis dependent acute kidney injury or involvement of the central nervous system, which needed treatment in intensive care with mechanical ventilation.
In their retrospective in depth analysis, Menne and colleagues analysed various treatment strategies.

These included supportive treatment, plasmapheresis, and treatment with antibiotics or eculizumab, an antibody that blocks the terminal complement
cascade and was reported to be effective in children with refractory Shiga toxin induced haemolytic uraemic syndrome during the outbreak. Patient outcomes were compared in different subgroups.

These included patients treated with or without the following: plasmapheresis (251 v 47 patients),antibiotics (52 v 246), eculizumab on top of plasmapheresis (67v 65), and glucocorticoids given at the beginning of plasmapheresis (174 v 77).
Overall, 53.7% of patients required dialysis, 12.4% had seizures, and 18.1% were mechanically ventilated. Despite the high morbidity, mortality was low at 4%, and all but three patients recovered kidney function at six months. The authors found no clear benefit of plasmapheresis or eculizumab, whereas
glucocorticoids were associated with a delayed recovery of
platelet count and creatinine concentration.

However, the syndrome was more severe in patients who received plasmapheresis or eculizumab, which introduced substantial indication bias to the data analysis. Surprisingly, antibiotics were the most effective treatment. Antibiotics were associated
with significantly reduced neurological morbidity, no overall mortality, no need for abdominal surgery, and a shorter duration of enterohaemorrhagic E coli excretion.

This is surprising because an earlier study found that antibiotics were associated with an increased risk of developing the syndrome, and this was explained by increased release of Shiga toxin.
In the current outbreak, patients received a combination of meropenem, ciprofloxacin, and rifaximin, with the addition of azithromycin when eculizumab was started.

An in vitro study found that, among other antibiotics, meropenem, rifaximin, and azithromycin downregulated the release and expression of Shiga toxin, whereas ciprofloxacin had a stimulatory effect.
Although the current study comprises the largest cohort yet, analysis of the data cannot draw a line under the controversy about the efficacy of plasmapheresis in Shiga toxin induced haemolytic uraemic syndrome.


Patients with severe disease were treated with plasma exchange and they were compared with patients with milder self limiting disease. In a small case series of patients from the same outbreak, positive effects of plasmapheresis were reported.
Plasmapheresis might interfere with complement dysregulation and reduce the excessive activation of the alternative pathway of complement that is induced by Shiga toxin, as reflected by low concentrations of C3 in patients treated with plasmapheresis.

The current study suggests that many patients with mild to moderate haemolytic uraemic syndrome can be
managed without plasmapheresis, but the possibility that asubgroup with severe disease still benefits from this treatment cannot be excluded. The effects of eculizumab are difficult to evaluate because patients were treated with the antibody on top of plasmapheresis, through which large amounts may have been eliminated, and they also received azithromycin.

Furthermore, the analysis excluded data on another 97 patients who were treated with eculizumab in an industry sponsored trial. Overall, the data show that eculizumab seems to have no clear benefit
when used on top of plasmapheresis or in refractory states.
As with many retrospective studies, Menne and colleagues’ results can be used only to generate new hypotheses that should be investigated in
arandomised trial.

However, their data show that an appropriate antibiotic and a short course of plasmapheresis in a selected subset of patients might be an effective strategy for the treatment of severe Shiga toxin induced haemolytic uraemic syndrome. Controversies about specific treatments aside, the mainstay of treatment that ensures low mortality is optimal care in an intensive care unit, with dialysis and mechanical ventilation tailored to the patient’s needs.