Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case-control study
BMJ 2012; 345 doi: https://doi.org/10.1136/bmj.e4565 (Published 19 July 2012) Cite this as: BMJ 2012;345:e4565
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Dear Editor,
We read the paper by Menne et al.[1] with great interest. This thorough dissection of enterohaemorrhagic E. coli (EHEC) associated haemolytic uremic syndrome (HUS) during the tragic E. coli O104:H4 outbreak is comprehensive and thoughtful. It will help improve care for years to come for individuals infected sporadically and in epidemics.
We find intriguing that antibiotics might improve the outcome of EHEC associated HUS. In our opinion, interventions to treat potential complications of EHEC infections depend on the phase illness. What may considered good care during prodromal phase might be quite problematic in the later phase. Current data on the harmful effects of antibiotics during EHEC infection relate only to the risk of developing acute kidney injury due to HUS, and not to later outcomes once HUS is clearly established. Until this paper, there have been no data to suggest that antibiotics reduce complications in patients with established EHEC-related HUS.
We caution against extrapolating the findings in this paper to the pre-HUS phase. The proposal by Menne, et al. for “... a randomised trial ... to assess whether antibiotic treatment is beneficial in patients with enterohaemorrhagic E. coli associated haemolytic uremic syndrome” is not justified in the initial management of EHEC infections. Among the published studies, consisting of ~1,000 patients with EHEC infections, none have demonstrated significant reduction in the rate of HUS with antibiotics, and most have demonstrated a higher rate of HUS in the treated groups[2-6].
Certainly, after HUS is established, particularly after anuria has ensued, we concur that if antibiotics are indicated due to critical illness they should be used; as may be the case in any critically ill patient regardless of primary diagnosis. Thus, it might be reasonable to consider a randomized controlled trial of antibiotics among the most seriously ill patients with HUS (i.e., with anuria) to determine if such an intervention hastens renal recovery and averts other complications.
We also wish to comment on the reported use of azithromycin during EHEC infections[7], which might be problematic during the course of EHEC infection. In our recent series, we note that one of four children who received azithromycin developed HUS versus only 12% among those not treated with antibiotics[8]. Thus, this antimicrobial agent might not be very effective in averting this outcome. During HUS, we are concerned about the arrythmogenic risk of this macrolide[9], especially since HUS mortality is sometimes attributed to sudden death[10].
In summary, Menne, et al. made a very valuable contribution to the care of patients with renal failure following EHEC infections. Antibiotics might be helpful among the most severely ill, but we do not believe that these or any other extant data justify consideration of a controlled trial of antibiotics during the diarrhea phase of EHEC infections. As Menne et al. note, HUS is a serious but self-limited disease. The risks of any intervention should be weighed against the heartening reality that most patients, even those most severely affected, make quite remarkable recoveries from EHEC-related HUS with conservative supportive care[11].
Sincerely,
Craig S. Wong, M.D., M.P.H.
Department of Pediatrics, Div of Nephrology
University of New Mexico Children’s Hospital
MSC10-5590 1 University of New Mexico
Albuquerque, NM 87131, USA
Phillip I. Tarr, M.D.
Department of Pediatrics, Div of Gastroenterology and Nutrition
Washington University School of Medicine
Campus Box 8208,
660 South Euclid Avenue,
St. Louis, MO 63110, USA
Michael E. Seifert, M.D.
Department of Pediatrics, Div of Nephrology
Southern Illinois University
301 North 8th St, Pavillion 3A130,
Springfield, IL 62701
1. Menne, J., et al., Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case-control study. BMJ, 2012. 345: p. e4565.
2. Carter, A.O., et al., A severe outbreak of Escherichia coli O157:H7--associated hemorrhagic colitis in a nursing home. N Engl J Med, 1987. 317(24): p. 1496-500.
3. Bell, B.P., et al., Predictors of hemolytic uremic syndrome in children during a large outbreak of Escherichia coli O157:H7 infections. Pediatrics, 1997. 100(1): p. E12.
4. Dundas, S., et al., The central Scotland Escherichia coli O157:H7 outbreak: risk factors for the hemolytic uremic syndrome and death among hospitalized patients. Clin Infect Dis, 2001. 33(7): p. 923-31.
5. Pavia, A.T., et al., Hemolytic-uremic syndrome during an outbreak of Escherichia coli O157:H7 infections in institutions for mentally retarded persons: clinical and epidemiologic observations. J Pediatr, 1990. 116(4): p. 544-51.
6. Smith, K.E., et al., Antibiotic treatment of Escherichia coli O157 infection and the risk of hemolytic uremic syndrome, Minnesota. The Pediatric infectious disease journal, 2012. 31(1): p. 37-41.
7. Nitschke, M., et al., Association between azithromycin therapy and duration of bacterial shedding among patients with Shiga toxin-producing enteroaggregative Escherichia coli O104:H4. JAMA : the journal of the American Medical Association, 2012. 307(10): p. 1046-52.
8. Wong, C.S., et al., Risk Factors for the Hemolytic Uremic Syndrome in Children Infected With Escherichia coli O157:H7: A Multivariable Analysis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2012. 55(1): p. 33-41.
9. Ray, W.A., et al., Azithromycin and the risk of cardiovascular death. The New England journal of medicine, 2012. 366(20): p. 1881-90.
10. Seifert, M.E. and P.I. Tarr, Azithromycin decolonization of STEC-a new risk emerges. Nature reviews. Nephrology, 2012. 8(7): p. 429.
11. Loos, S., et al., An Outbreak of Shiga Toxin-Producing Escherichia coli O104:H4 Hemolytic Uremic Syndrome in Germany: Presentation and Short-term Outcome in Children. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2012.
Competing interests: No competing interests
Re: Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case-control study
Dear Dr. Menne:
We would like to congratulate you and your colleagues on your recent experience in the 2011outbreak of Escherichi Coli O104:H4 induced Haemolytic Uremic Syndrome in 23 hospitals in Northern Germany. Your report outlines the difficulties of controlling selection bias in an observational study of a spontaneous outbreak of HUS in which clear RCT evidence about optimal therapy was absent. Your experience with selection bias, patient withdrawal, the use of combined therapies and variable reporting underline the value of simple objective well defined outcomes such as mortality.
Your mortality for an adult series of 4% is laudable. In Lanarkshire the mortality rate for adults was 45 %.(ref 1) The largest meta-analysis in the world of over 3400 children shows a mortality rate of 9% for DHUS.(ref2)
The information suggests a number of possibilities 1) O104:H4 is a milder disease, 2) your case description included milder cases of HUS or 3) you were providing more effective therapy? The largest single treatment group representing over 80% of your patients received plasma exchange (PLEX) and your mortality for PLEX in 251 patients was 3% and in 197 who had more aggressive PLEX therapy it was 2.5%. The group of 47 patients that were thought to have had milder disease and received conservative treatment had a mortality rate of 9%. In fact, the 54 patients that received less aggressive PLEX that you indicated had milder disease had a mortality rate of 6%.
The mortality gradient of your observational data is in sharp contrast to your conclusions that aggressive PLEX may be potentially harmful. Your observations support the need for a randomized control trial and your evidence, in terms of mortality, suggests a potential benefit for aggressive PLEX rather than harm in your largely adult patients who suffered DHUS.
References:
1) Dundas S, Todd WT, Stewart AI, Murdoch PS, Chaudhuri AK, Hutchison SJ. The central Scotland Escherichia coli O157:H7 outbreak: risk factors for the haemolytic uremic syndrome and death among hospitalized patients. Clin Infect Dis 2001;33:923-31.
2) Garg AX, Suri RS, Barrowman N, Rehman F, Matsell D, Rosas-Arellano MP, Salvadori M, Haynes RB, Clark WF. Long-term Renal Prognosis of Diarrhea-Associated Hemolytic Uremic Syndrome 2003;290(10):1360-1370.
Yours truly,
W. F. Clark, MD, FRCPC, FACP,FASN and
G.A. Rock, PhD, MD, FRCPC
Competing interests: No competing interests