Comment

Escherichia coli O104, Germany 2011

Published Online June 23, 2011 DOI:10.1016/S14733099(11)70166-9 See Online/Articles DOI:10.1016/S14733099(11)70165-7

In The Lancet Infectious Diseases, Helge Karch and colleagues1 characterise the virulence proles of E coli O104:H4 isolates from 80 patients in the large outbreak in Germany. The researchers show that all the isolates belong to a clone (HUSEC041) rst isolated in Germany from a patient with haemolytic uraemic syndrome in 2001. The members of this clone have virulence proles that combine those of two dierent enterovirulent E colienterohaemorrhagic E coli and enteroaggregative E coli. They have the stx2 locus typical of the rst and the so called stackedbrick aggregative adherence typical of the second. The outbreak isolates (but not the 2001 strain) also have an extended spectrum -lactamase (ESBL) antibiotic resistance prole. Karch and colleagues speculate very reasonably that the blending of enterohaemorrhagic and enteroaggregative virulence traits could explain why so manyabout 30% of those infectedin the German outbreak have developed haemolytic uraemic syndrome (a variable combination of renal impairment, thrombocytopaenia, haemolytic anaemia, and CNS and myocardial damage). About 1000 symptomatic Shiga-toxin-producing E coli infections and 60 cases of haemolytic uraemic syndrome are notied in Germany every year.3 But by June 20 this year, the numbers notied were 2684 and 810 respectively.2 Haemolytic uraemic syndrome linked to the outbreak have also occurred in elsewhere in Europe and in North America. Since late May, no shortage of information about the causative organism and the epidemiology has been published.37 And work proceeds too fast to reference comprehensively. The epidemiological evidence
Culture conrmed Location cases 143 595 242 231 2764 126 85 9 UK Sweden, Finland USA, Finland USA UK Sakai City, Japan Japan USA USA
10,11

Pathogen 1988 1994 1995 1996 2010 1996 1997 1997 1998 Salmonella Saintpaul Salmonella Bovismorbicans Salmonella Stanley Salmonella Bareilly Escherichia coli O157:H7 E coli O157:H7 E coli O157:H7 E coli O157

Sprout type Mung Alfalfa Alfalfa Alfalfa Mung Radish Radish Alfalfa Alfalfa, clover

Salmonella Montevideo and Meleagridis ~500

Table: Notable outbreaks of food borne illness linked to seed sprouts

implicating bean sprouts as the vector is strongin particular the results of a cohort study done by the Robert Koch Institute.8 More than 100 individuals in ve groups (including 19 with an infection with Shigatoxin-producing E coli) who had eaten in one restaurant provided food histories. To supplement memories, menus were scrutinised and choices identied from receipts. The kitchen provided information about ingredients in the chosen foods and their preparation. As a nal check photographs taken in the restaurant were analysed to identify foods, including garnishes, on the plates. Those who ate bean sprouts had a risk of haemolytic uraemic syndrome or illness caused by Shigatoxin-producing E coli almost nine-times higher than for people who had not had bean sprouts. All of those who fell ill had eaten bean sprouts. The size, geographical distribution, health impact, and cause of food-borne outbreaks of Shiga-toxinproducing E coli are largely determined by the vector. Most have been caused by E coli O157:H7,9 and typically haemolytic uraemic syndrome develops mostly in young children and elderly people. In this large outbreak in Germany, most cases of the syndrome have been in young and middle-aged adults, particularly women. Two factors probably explain this scenario: the patterns of consumption of the vector and an increased likelihood of developing haemolytic uraemic syndrome because of the high virulence of the clone. Outbreaks of infection associated with the consumption of raw seed sprouts are not rare (table).10,11 In some outbreaks, women have been most aected, and young adults have predominated in many. Epidemiological evidence implicating seed sprouts has been strong but the causative pathogen has not been found on them. Because investigations only started in the current outbreak as a rare microbial strain became common, a large number of infections related to bean sprouts might go undetected. Bean sprouts are high-risk foods: contamination usually starts with contaminated seeds and sprouting is triggered with incubation at high humidity, ideal conditions for bacterial multiplication. No secure way has so far been found to decontaminate beans completely, and I await with interest information about the risk-reduction strategies12 used by the German producers of bean sprouts.
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Comment

Hugh Pennington
Aberdeen, Scotland, UK t.h.pennington@abdn.ac.uk
I declare that I have no conicts of interest. 1 Bielaszewska M, Mellmann A, Zhang W, et al. Characterisation of the Escherichia coli strain associated with an outbreak of haemolytic uraemic syndrome in Germany, 2011: a microbiological study. Lancet Infect Dis 2011; published online June 23. DOI:10.1016/S1473-3099(11)70165-7. Robert Koch Institute. Informationen zum EHEC/HUS-Ausbruchsgeschehen. http://www.rki.de/nn_217400/DE/Home/Info-HUS.html. Frank C, Faber MS, Askar M, et al, on behalf of the HUS investigation team. Large and ongoing outbreak of haemolytic uraemic syndrome, Germany, May 2011. Euro Surveill 2011; 16: pii=19878. Askar M, Faber MS, Frank C, et al. Update on the ongoing outbreak of haemolytic uraemic syndrome due to Shiga toxin-producing Escherichia coli (STEC) serotype O104, Germany, May 2011. Euro Surveill 2011; 16: pii=19883. European Centre for Disease Prevention and Control and European Food Safety Authority. Shiga toxin/verotoxin-producing Escherichia coli in humans, food and animals in the EU/EEA, with special reference to the German outbreak strain STEC O104. Stockholm: ECDC, 2011.

8 9 10 11

2 3

12

Scheutz F, Mller Nielsen E, Frimodt-Mller J, et al. Characteristics of the enteroaggregative Shiga toxin/verotoxin-producing Escherichia coli O104:H4 strain causing the outbreak of haemolytic uraemic syndrome in Germany, May to June 2011. Euro Surveill 2011; 16: pii=19889. Struelens MJ, Palm D, Takkinen J. Enteroaggregative, Shiga toxin-producing Escherichia coli O104:H4 outbreak: new microbiological ndings boost coordinated investigations by European public health laboratories. Euro Surveill 2011; 16: pii=19890. Robert Koch Institute. Information update on EHEC outbreak. http://www. rki.de/nn_217400/EN/Home/PM082011.html (accessed June 20, 2011). Pennington TH. Escherichia coli O157. Lancet 2010; 376: 142835. Taormina PJ, Beuchat LR, Sluttsker L. Infections associated with eating seed sprouts: an international concern. Emerg Infect Dis 1999; 5: 62634. Cleary P, Browning L, Coia J, et al, on behalf of the outbreak control team. A foodborne outbreak of Salmonella Bareilly in the United Kingdom, 2010. Euro Surveill 2010; 15: pii=19732. Beales N. Review of microbiological risks associated with sprouted seeds: review 41. Chipping Campden: Campden & Chorleywood Food Research Association Group, 2004.

Use of chloroquine in viral diseases

In The Lancet Infectious Diseases, Paton and colleagues1 report results of a clinical trial investigating chloroquine for prevention of inuenza, which show that this antimalarial drug had no eect on disease acquisition and clinical course. Chloroquine, and its hydroxyl analogue hydroxychloroquine, became plausible candidates for treatment of several viral diseases after many reports of their in-vitro inhibitory eects on dierent viruses.2 Although these eects proved highly reproducible,2 the antiviral eects of chloroquine in vivo have been shown only in a mouse model for coronavirus infection.3 The antiviral eect of hydroxychloroquine was shown in two clinical trials of individuals infected with HIV-1;4,5 the results, however, could not be reproduced with an equivalent dose of chloroquine.6 Several possible reasons exist for the failure of translation of the in-vitro eects to in-vivo settings: narrow therapeutic indexes (ie, the ratio between the 50% cytotoxic concentration [CC50] and the 50% antivirally eective concentration [EC50]); EC50 in the micromolar range (about three orders of magnitude greater than that necessary to inhibit chloroquinesensitive malaria parasitesthe microorganisms against which the drug was originally prescribed); poor penetration in specic tissues; and high interstrain variability of the eects of chloroquine on inuenza A viruses.7 Maybe, in the future, chloroquine derivatives with improved pharmacokinetics will be able to bridge the gap between the in-vitro and in-vivo eects.
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For treatment of RNA-virus infections, I think that monotherapy should be avoided because of the potential for rapid development of drug resistance. Therefore, chloroquine and hydroxychloroquine could still be considered for treatment in combination with other antiviral drugs. An eect that merits consideration is inhibition, by chloroquine, of some cellular proteins, including the P-glycoprotein and multidrug-resistanceassociated proteins, which extrude drugs from the cells and other anatomic compartments.8 Although current anti-inuenza drugs act on extracellular or transmembrane targets, new intracytosolic drug targets in the viral life cycle are being explored.9 My colleagues and I proposed the use of chloroquine as a therapeutic agent for some viral infections (eg, SARS and AIDS; the pathogenesis of which is characterised by deleteriously strong or persistent immune activation).2 Chloroquine is a well known immunomodulatory agent, as shown by its continued use for treatment of rheumatoid arthritis and other immune-mediated diseases.2 In this context, poor ecacy of this drug against pandemic inuenza disease severity shown by Paton and colleagues1 can be explained not only by absence of an antiviral eect in vivo, but also by the fact that pandemic inuenza shows, in most patients, a benign clinical course and is generally uncomplicated by immune-mediated damage. In individuals with HIV/AIDS, chloroquine was repeatedly reported to be eective in counteracting

Published Online May 6, 2011 DOI:10.1016/S14733099(11)70092-5 See Online/Articles DOI:10.1016/S14733099(11)70065-2

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