Strategies for E. Coli Induced Hemolytic Uremic Syndrome
Strategies for E. Coli Induced Hemolytic Uremic Syndrome
Current treatment recommendations for adults with haemolytic uraemic syndrome might need to be modified in light of the findings in this large cohort of patients from the outbreak of enterohaemorrhagic Escherichia coli associated haemolytic uraemic syndrome in northern German, 2011. Evidence of the benefits from plasmapheresis was not clear. Contrary to current notions, antibiotic treatment of established haemolytic uraemic syndrome is not harmful and might even improve the outcome.
The major strength of this study was the large number of patients and the extensive data available by database to describe the population. Another advantage was that not all the centres used the same treatment strategy. These differences allowed a retrospective analysis of treatment strategies. This non-randomised group assignment was also the major weakness of our study. Our comparisons involved imperfect controls and thus bias was introduced by indication. Such bias is obvious in the analysis of plasmapheresis, a treatment that was begun in patients with severe haemolytic uraemic syndrome but not in the less severely affected patients who served as controls. Whenever possible we used adjusted analyses to take into account the differences in baseline severity. Nevertheless, these results should be interpreted with caution. Comparisons are easier when baseline characteristics are similar, such as in patients who received limited plasmapheresis versus platelet guided plasmapheresis.
Importantly, differences in participation between the centres owing to the exclusion of patients taking part in the industry sponsored trial gives rise to bias. For example, none of the patients receiving the early antibiotic strategy were excluded, owing to participation in the eculizumab trial, but 28% were excluded in the respective control group when they received eculizumab ( Table 2 ). As patients receiving eculizumab were usually sicker than the rest of the study population this biases the analysis towards a smaller therapeutic effect of antibiotics. Limited plasmapheresis would be biased towards a more favourable outcome as only 49.1% of the patients in these centres were included in the present analysis.
The 298 patients with haemolytic uraemic syndrome in the present study had a similar sex and age distribution to the adults with haemolytic uraemic syndrome reported by the Robert Koch Institute. Our figures for mortality were also in line with the national data (4.0% v 4.1%). Most of the formerly healthy patients were severely ill during the acute phase of the disease: 54% required dialysis, many had neurological problems, and more than 12% had seizures. Over half of the patients (n=156, 52%) were treated on an intensive care ward and more than 18% (n=54) required ventilation for an average of 10 days. Despite the severity of the disease during the acute phase, most of the patients recovered completely and only five were still receiving renal replacement therapy after nine months. A previous study reported that the neurological symptoms resolved completely in most patients.
At the beginning of this outbreak the German Society of Nephrology recommended use of plasmapheresis, especially for cases of enterohaemorrhagic E coli associated haemolytic uraemic syndrome with neurological or severe renal involvement. This recommendation is supported by the American Society for Apheresis, which gives a low II-3 recommendation for the usage of plasmapheresis in patients with typical haemolytic uraemic syndrome. It is believed that plasmapheresis might remove the circulating shiga toxin or factors that damage the endothelium. Data to support such an assumption are, however, scarce. Firstly, shiga toxin has never been identified in the circulation. Secondly, the density of the infecting organism and concentration of toxin in stools diminish in the colon as haemolytic uraemic syndrome develops. Thirdly, there is ample evidence of vascular injury before haemolytic uraemic syndrome ensues, and the microvascular damage is possibly already manifested before the clinical manifestation of the disease. In addition, injected shiga toxin in animal models has shown a short half life in the circulation. Hence the evidence for plasmapheresis is based on empirical observations. In the Scottish outbreak overall mortality seemed better in the small number of patients treated with plasmapheresis, although statistically robust conclusions were not possible owing to lack of power. More recently, findings in five patients in the 2011 outbreak were published and it was suggested that plasmapheresis is beneficial. Furthermore, the authors of an accompanying editorial mentioned that plasmapheresis remains “the cornerstone of treatment.” We observed an improvement in the average platelet count and a drop in the levels of lactate dehydrogenase after initiation of plasmapheresis in 251 patients. However, our data also suggest that this might reflect the natural course of the disease, as plasmapheresis was usually started at the peak of disease activity, around days 6-8, misleading the observers to conclude that the improvement shortly after the start of therapy resulted from plasmapheresis. In our cohort, 47 patients were not treated with plasmapheresis. The time courses of platelet count and levels of lactate dehydrogenase, haemoglobin, and creatinine during recovery from the disease were similar to the group that received plasmapheresis. Secondly, the three centres that treated patients with limited plasmapheresis (3-5 sessions) had similar or better outcomes than centres that continued plasmapheresis until platelet counts had increased to more than 100/nL. These results question the current recommendation to use plasmapheresis as a standard treatment in adults with enterohaemorrhagic E coli associated haemolytic uraemic syndrome and are in agreement with the experience of paediatric nephrologists, who encounter shiga toxin induced haemolytic uraemic syndrome more often than doctors treating adults and use plasmapheresis only rarely. During the current epidemic, 17 of the 90 children were treated with plasmapheresis (data not shown) and the outcome was good.
According to the recommendation of the German Society of Nephrology, fresh frozen plasma should be used for plasmapheresis. No plasmapheresis was carried out with albumin in the adults, whereas albumin was mainly used in the children. We cannot exclude the possibility that fresh plasma enhanced the disease process—for example, through further complement activation. This needs further research.
We believe that a randomised trial analysing supportive treatment plus limited plasmapheresis (3-5 sessions using albumin) compared with no additional treatment is necessary for clarification. However, from our experience during the outbreak in Germany and the experience of the paediatricians in the routine treatment of children with typical haemolytic uraemic syndrome, we believe that no benefit or only a marginal benefit will be found.
Despite our finding that glucocorticoids had an effect on recovery of lactate dehydrogenase and creatinine levels and platelet counts, it was not significant and led to a higher number of patients requiring dialysis. As enterohaemorrhagic E coli associated haemolytic uraemic syndrome is an infectious disease, concomitant treatment with glucocorticoids might be harmful—an observation in keeping with a randomised trial from Italy, in which no benefit was found in children.
The use of antibiotics to treat enterohaemorrhagic E coli infection is controversial. In theory antibiotic treatment may lead to higher toxicity through an intestinal Jarisch-Herxheimer reaction, with a massive release of shiga toxin through bacterial death during the prodromal phase of diarrhoea. This concept is supported by a mouse model with shiga toxin producing E coli, showing that treatment with fluoroquinolone resulted in a higher release of toxin and mortality. A report in 71 children with enterohaemorrhagic E coli O157:H7 induced diarrhoea described that five of nine children receiving antibiotics developed haemolytic uraemic syndrome compared with five of 62 children not receiving antibiotics. In our patient cohort, all but one medical centre did not use antibiotic treatment. In this centre patients were treated with a combination of at least two antibiotics sensitive to enterohaemorrhagic E coli (meropenem and ciprofloxacin and additionally rifaximin in patients on intensive care ward) after a diagnosis of haemolytic uraemic syndrome. None of the patients treated with antibiotics developed signs of toxic shock. Enterohaemorrhagic E coli was eradicated about eight days earlier than in the other centres and the rates of seizures and mortality were improved. None of the patients required intestinal surgery. In this centre the lower incidence of seizures might also be explained by a more aggressive use of prophylactic antiepileptics in patients with neurological symptoms. Nevertheless, the results are encouraging as they suggest that the production and potential drug induced release of shiga toxin might be irrelevant and that pre-emptive antibiotics do not worsen the clinical course of established haemolytic uraemic syndrome. Moreover, in contrast with previous studies the antibiotic strategy was more aggressive. Patients simultaneously received at least two (many even three) antibiotics effective against enterohaemorrhagic E coli, which might have contributed to the beneficial outcome. As antibiotics seem to improve, but definitely do not worsen, the course of the infection we believe that they are beneficial in the later stages of the disease when the prodromal phase with diarrhoea has nearly subsided. Mice infected with different enterohaemorrhagic E coli O157:H7 strains have shown lower mortality and weight loss if treated with rifampicin compared with placebo. Therefore it could be speculated that a suitable antibiotic combination strategy at the onset of bloody diarrhoea in (enteroaggregative) enterohaemorrhagic E coli infections might even prevent the development of haemolytic uraemic syndrome.
We believe that a randomised trial should be carried out to assess whether antibiotic treatment is beneficial in patients with enterohaemorrhagic E coli associated haemolytic uraemic syndrome.
Eculizumab was used widely as a compassionate treatment (that is, outside the currently accepted indication for atypical haemolytic uraemic syndrome and paroxysmal nocturnal haematuria) during the outbreak in Germany. Evaluations of treatment effects were prone to bias by indication, as most of the centres treated the least sick patients with supportive care only, sicker patients with plasmapheresis, and the sickest with eculizumab. The treatment patterns in the different centres were not uniform; one larger hospital did not give eculizumab at all and in other hospitals it was administered only later during the outbreak. This enabled us to identify a control group of similarly sick patients to compare eculizumab treatment with plasmapheresis. This evaluation cannot be a substitute for a randomised controlled trial, but we believe that this is the only way to get an impression of the true effect of eculizumab treatment. Based on the data presented, patients treated with eculizumab did not improve significantly compared with a control group of patients with the same severity of haemolytic uraemic syndrome. Patients treated with eculizumab still developed new complications, such as seizure or requirement for ventilation, and in more than 40% of the patients plasmapheresis was continued after eculizumab had been started. Data on long term (6-12 months) renal and neurological follow-up in all patients treated with eculizumab will be required to assess the effect of this treatment strategy. In addition, the effect of eculizumab might be confounded because more than 98% of patients who received the drug were simultaneously treated with the antibiotic azithromycin for meningococcal prophylaxis. Recently, this antibiotic has been shown to eradicate O104:H4 quickly and does not lead to shiga toxin release in vitro.
A major shortcoming of our analysis was that we did not carry out a randomised study. The large number of patients affected would have been ideal to test some of the questions and hypotheses about treatment strategies that existed at the start of the outbreak. As the outbreak began at the end of May and had almost finished by July, it was impossible to design a randomised trial and get approval within that time.
Haemolytic uraemic syndrome associated with E coli O104:H4 is an acute self limited disease with a high percentage of patients requiring dialysis and ventilation and having severe neurological impairment. Our retrospective analyses question the benefit of plasmapheresis and concomitant glucocorticoid treatment in adults with enterohaemorrhagic E coli associated haemolytic uraemic syndrome. Contrary to current belief, antibiotics do not seem to worsen the clinical course in patients with established haemolytic uraemic syndrome, but may be of clinical benefit. Further prospective, randomised investigations of antibiotic treatment and its timing in future cases of (enteroaggregative) enterohaemorrhagic E coli associated haemolytic uraemic syndrome and even outbreaks with the O157:H7 strain are required. We observed no significant short term benefit of eculizumab treatment.
Discussion
Current treatment recommendations for adults with haemolytic uraemic syndrome might need to be modified in light of the findings in this large cohort of patients from the outbreak of enterohaemorrhagic Escherichia coli associated haemolytic uraemic syndrome in northern German, 2011. Evidence of the benefits from plasmapheresis was not clear. Contrary to current notions, antibiotic treatment of established haemolytic uraemic syndrome is not harmful and might even improve the outcome.
Strengths and Limitations of the Study
The major strength of this study was the large number of patients and the extensive data available by database to describe the population. Another advantage was that not all the centres used the same treatment strategy. These differences allowed a retrospective analysis of treatment strategies. This non-randomised group assignment was also the major weakness of our study. Our comparisons involved imperfect controls and thus bias was introduced by indication. Such bias is obvious in the analysis of plasmapheresis, a treatment that was begun in patients with severe haemolytic uraemic syndrome but not in the less severely affected patients who served as controls. Whenever possible we used adjusted analyses to take into account the differences in baseline severity. Nevertheless, these results should be interpreted with caution. Comparisons are easier when baseline characteristics are similar, such as in patients who received limited plasmapheresis versus platelet guided plasmapheresis.
Importantly, differences in participation between the centres owing to the exclusion of patients taking part in the industry sponsored trial gives rise to bias. For example, none of the patients receiving the early antibiotic strategy were excluded, owing to participation in the eculizumab trial, but 28% were excluded in the respective control group when they received eculizumab ( Table 2 ). As patients receiving eculizumab were usually sicker than the rest of the study population this biases the analysis towards a smaller therapeutic effect of antibiotics. Limited plasmapheresis would be biased towards a more favourable outcome as only 49.1% of the patients in these centres were included in the present analysis.
Clinical Picture of Haemolytic Uraemic Syndrome in Adults
The 298 patients with haemolytic uraemic syndrome in the present study had a similar sex and age distribution to the adults with haemolytic uraemic syndrome reported by the Robert Koch Institute. Our figures for mortality were also in line with the national data (4.0% v 4.1%). Most of the formerly healthy patients were severely ill during the acute phase of the disease: 54% required dialysis, many had neurological problems, and more than 12% had seizures. Over half of the patients (n=156, 52%) were treated on an intensive care ward and more than 18% (n=54) required ventilation for an average of 10 days. Despite the severity of the disease during the acute phase, most of the patients recovered completely and only five were still receiving renal replacement therapy after nine months. A previous study reported that the neurological symptoms resolved completely in most patients.
Plasmapheresis
At the beginning of this outbreak the German Society of Nephrology recommended use of plasmapheresis, especially for cases of enterohaemorrhagic E coli associated haemolytic uraemic syndrome with neurological or severe renal involvement. This recommendation is supported by the American Society for Apheresis, which gives a low II-3 recommendation for the usage of plasmapheresis in patients with typical haemolytic uraemic syndrome. It is believed that plasmapheresis might remove the circulating shiga toxin or factors that damage the endothelium. Data to support such an assumption are, however, scarce. Firstly, shiga toxin has never been identified in the circulation. Secondly, the density of the infecting organism and concentration of toxin in stools diminish in the colon as haemolytic uraemic syndrome develops. Thirdly, there is ample evidence of vascular injury before haemolytic uraemic syndrome ensues, and the microvascular damage is possibly already manifested before the clinical manifestation of the disease. In addition, injected shiga toxin in animal models has shown a short half life in the circulation. Hence the evidence for plasmapheresis is based on empirical observations. In the Scottish outbreak overall mortality seemed better in the small number of patients treated with plasmapheresis, although statistically robust conclusions were not possible owing to lack of power. More recently, findings in five patients in the 2011 outbreak were published and it was suggested that plasmapheresis is beneficial. Furthermore, the authors of an accompanying editorial mentioned that plasmapheresis remains “the cornerstone of treatment.” We observed an improvement in the average platelet count and a drop in the levels of lactate dehydrogenase after initiation of plasmapheresis in 251 patients. However, our data also suggest that this might reflect the natural course of the disease, as plasmapheresis was usually started at the peak of disease activity, around days 6-8, misleading the observers to conclude that the improvement shortly after the start of therapy resulted from plasmapheresis. In our cohort, 47 patients were not treated with plasmapheresis. The time courses of platelet count and levels of lactate dehydrogenase, haemoglobin, and creatinine during recovery from the disease were similar to the group that received plasmapheresis. Secondly, the three centres that treated patients with limited plasmapheresis (3-5 sessions) had similar or better outcomes than centres that continued plasmapheresis until platelet counts had increased to more than 100/nL. These results question the current recommendation to use plasmapheresis as a standard treatment in adults with enterohaemorrhagic E coli associated haemolytic uraemic syndrome and are in agreement with the experience of paediatric nephrologists, who encounter shiga toxin induced haemolytic uraemic syndrome more often than doctors treating adults and use plasmapheresis only rarely. During the current epidemic, 17 of the 90 children were treated with plasmapheresis (data not shown) and the outcome was good.
According to the recommendation of the German Society of Nephrology, fresh frozen plasma should be used for plasmapheresis. No plasmapheresis was carried out with albumin in the adults, whereas albumin was mainly used in the children. We cannot exclude the possibility that fresh plasma enhanced the disease process—for example, through further complement activation. This needs further research.
We believe that a randomised trial analysing supportive treatment plus limited plasmapheresis (3-5 sessions using albumin) compared with no additional treatment is necessary for clarification. However, from our experience during the outbreak in Germany and the experience of the paediatricians in the routine treatment of children with typical haemolytic uraemic syndrome, we believe that no benefit or only a marginal benefit will be found.
Glucocorticoids With Plasmapheresis
Despite our finding that glucocorticoids had an effect on recovery of lactate dehydrogenase and creatinine levels and platelet counts, it was not significant and led to a higher number of patients requiring dialysis. As enterohaemorrhagic E coli associated haemolytic uraemic syndrome is an infectious disease, concomitant treatment with glucocorticoids might be harmful—an observation in keeping with a randomised trial from Italy, in which no benefit was found in children.
Antibiotic Treatment
The use of antibiotics to treat enterohaemorrhagic E coli infection is controversial. In theory antibiotic treatment may lead to higher toxicity through an intestinal Jarisch-Herxheimer reaction, with a massive release of shiga toxin through bacterial death during the prodromal phase of diarrhoea. This concept is supported by a mouse model with shiga toxin producing E coli, showing that treatment with fluoroquinolone resulted in a higher release of toxin and mortality. A report in 71 children with enterohaemorrhagic E coli O157:H7 induced diarrhoea described that five of nine children receiving antibiotics developed haemolytic uraemic syndrome compared with five of 62 children not receiving antibiotics. In our patient cohort, all but one medical centre did not use antibiotic treatment. In this centre patients were treated with a combination of at least two antibiotics sensitive to enterohaemorrhagic E coli (meropenem and ciprofloxacin and additionally rifaximin in patients on intensive care ward) after a diagnosis of haemolytic uraemic syndrome. None of the patients treated with antibiotics developed signs of toxic shock. Enterohaemorrhagic E coli was eradicated about eight days earlier than in the other centres and the rates of seizures and mortality were improved. None of the patients required intestinal surgery. In this centre the lower incidence of seizures might also be explained by a more aggressive use of prophylactic antiepileptics in patients with neurological symptoms. Nevertheless, the results are encouraging as they suggest that the production and potential drug induced release of shiga toxin might be irrelevant and that pre-emptive antibiotics do not worsen the clinical course of established haemolytic uraemic syndrome. Moreover, in contrast with previous studies the antibiotic strategy was more aggressive. Patients simultaneously received at least two (many even three) antibiotics effective against enterohaemorrhagic E coli, which might have contributed to the beneficial outcome. As antibiotics seem to improve, but definitely do not worsen, the course of the infection we believe that they are beneficial in the later stages of the disease when the prodromal phase with diarrhoea has nearly subsided. Mice infected with different enterohaemorrhagic E coli O157:H7 strains have shown lower mortality and weight loss if treated with rifampicin compared with placebo. Therefore it could be speculated that a suitable antibiotic combination strategy at the onset of bloody diarrhoea in (enteroaggregative) enterohaemorrhagic E coli infections might even prevent the development of haemolytic uraemic syndrome.
We believe that a randomised trial should be carried out to assess whether antibiotic treatment is beneficial in patients with enterohaemorrhagic E coli associated haemolytic uraemic syndrome.
Complement 5 Inhibition
Eculizumab was used widely as a compassionate treatment (that is, outside the currently accepted indication for atypical haemolytic uraemic syndrome and paroxysmal nocturnal haematuria) during the outbreak in Germany. Evaluations of treatment effects were prone to bias by indication, as most of the centres treated the least sick patients with supportive care only, sicker patients with plasmapheresis, and the sickest with eculizumab. The treatment patterns in the different centres were not uniform; one larger hospital did not give eculizumab at all and in other hospitals it was administered only later during the outbreak. This enabled us to identify a control group of similarly sick patients to compare eculizumab treatment with plasmapheresis. This evaluation cannot be a substitute for a randomised controlled trial, but we believe that this is the only way to get an impression of the true effect of eculizumab treatment. Based on the data presented, patients treated with eculizumab did not improve significantly compared with a control group of patients with the same severity of haemolytic uraemic syndrome. Patients treated with eculizumab still developed new complications, such as seizure or requirement for ventilation, and in more than 40% of the patients plasmapheresis was continued after eculizumab had been started. Data on long term (6-12 months) renal and neurological follow-up in all patients treated with eculizumab will be required to assess the effect of this treatment strategy. In addition, the effect of eculizumab might be confounded because more than 98% of patients who received the drug were simultaneously treated with the antibiotic azithromycin for meningococcal prophylaxis. Recently, this antibiotic has been shown to eradicate O104:H4 quickly and does not lead to shiga toxin release in vitro.
Lessons for Future Outbreaks
A major shortcoming of our analysis was that we did not carry out a randomised study. The large number of patients affected would have been ideal to test some of the questions and hypotheses about treatment strategies that existed at the start of the outbreak. As the outbreak began at the end of May and had almost finished by July, it was impossible to design a randomised trial and get approval within that time.
Conclusions and Policy Implications
Haemolytic uraemic syndrome associated with E coli O104:H4 is an acute self limited disease with a high percentage of patients requiring dialysis and ventilation and having severe neurological impairment. Our retrospective analyses question the benefit of plasmapheresis and concomitant glucocorticoid treatment in adults with enterohaemorrhagic E coli associated haemolytic uraemic syndrome. Contrary to current belief, antibiotics do not seem to worsen the clinical course in patients with established haemolytic uraemic syndrome, but may be of clinical benefit. Further prospective, randomised investigations of antibiotic treatment and its timing in future cases of (enteroaggregative) enterohaemorrhagic E coli associated haemolytic uraemic syndrome and even outbreaks with the O157:H7 strain are required. We observed no significant short term benefit of eculizumab treatment.
