The recent outbreak of enterohaemorrhagic Escherichia coli
associated haemolytic uraemic syndrome in northern Germany, 2011, the largest to date, underscored the threat to public health of such pathogens.1
Diarrhoea associated haemolytic uraemic syndrome is characterised by the triad of microangiopathic haemolytic anaemia, thrombocytopenia, and acute kidney injury. In the outbreak in Germany, 855 of 3842 people infected with enterohaemorrhagic E coli
developed haemolytic uraemic syndrome.2
Adults, especially healthy middle aged women, were predominantly affected (90%), probably because of the source of the infection (fenugreek sprouts). The second largest outbreak was considerably smaller and occurred in Scotland, when 34 of 512 (279 confirmed) people infected with enterohaemorrhagic E coli
O157:H7 developed haemolytic uraemic syndrome; 28 were adults.3
The 22% incidence rate of haemolytic uraemic syndrome was higher than the 1-15% typically reported in other outbreaks of enterohaemorrhagic E coli
This is probably because the outbreak in Germany was caused by an unusual strain: enterohaemorrhagic E coli
O104:H4. Further analysis by several teams, including use of third generation sequencing methods, revealed that the strain carried properties of a shiga 2 toxin producing E coli
and an enteroaggregative E coli
as well as multidrug resistant plasmids.7
This new combination of genes seemed to enhance the occurrence of haemolytic uraemic syndrome in comparison with the O157:H7 strain encountered in most previous outbreaks.8
Importantly, data gathered by German paediatricians suggested that the clinical course and outcome of the O104:H4 induced disease was similar to that of infections with O157:H7.12
Data generated from the 2011 outbreak could therefore add valuable information to the treatment of patients with haemolytic uraemic syndrome.
Over the years different treatments comprising plasmapheresis, glucocorticoids, antibiotics, and eculizumab have been developed to treat enterohaemorrhagic E coli
associated haemolytic uraemic syndrome.5
Owing to the sporadic nature of the disease, most of the published studies examining the efficacy of treatments only analysed small groups and lacked a comparison group. Currently used active interventions are therefore not based on formal evidence. The large number of patients affected and differences in treatment strategies between the hospitals enabled us to compare and analyse treatment options in an exploratory fashion. We were mainly interested in the outcomes after treatment with plasmapheresis, glucocorticoids, antibiotics, and eculizumab (for terminal complement blockade). In some hospitals patients received no more than 3-5 sessions of plasmapheresis (limited plasmapheresis) followed by alternative treatments if required. In contrast, in most hospitals plasmapheresis was continued until platelet counts increased to at least 100/nL. Furthermore, several hospitals did not use glucocorticoids, whereas the others administered at least 50 mg with plasmapheresis. Twenty two hospitals followed the recommendation not to use antibiotics and administered them only if medically required. One hospital, however, used double or triple antibiotic treatment with meropenem, ciprofloxacin, and rifaximin with the aim of speedy eradication. Eculizumab is a monoclonal antibody directed against the complement protein C5. It has been successfully used to treat patients with paroxysmal nocturnal haemoglobinuria15
and atypical haemolytic uraemic syndrome.16
In May 2011, just at the beginning of the Germany outbreak, it was reported that eculizumab seemed to be beneficial in three infants with severe shiga toxin associated haemolytic uraemic syndrome.14
In these cases eculizumab was given to block dysregulated complement activation, which is thought to play a part in the development of haemolytic uraemic syndrome.17
In light of this report, eculizumab was extensively used (>300 patients) as a therapeutic option during the Germany outbreak. The recommended treatment schedule was 900 mg at days 0, 7, 14, and 21, and 1200 mg at days 28, 42, and 56. Additionally, azithromycin was prescribed for 14 days to prevent meningococcal infections.
We evaluated the effectiveness of these various therapeutic strategies in 298 patients with enterohaemorrhagic E coli
associated haemolytic uraemic syndrome (35% of the population affected). These patients were similar for age, sex distribution, and mortality as the 855 patients with the disease reported to the Robert Koch Institute2
and in line with data collected by the relevant German registry (JT Kielstein, personal communication, 2012).