Bacteria and Diseases of Unknown Cause: Hemolytic‐Uremic Syndrome

Hemolytic-uremic syndrome (HUS), which is characterized by acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia, was first described in 1955 [1]. Although the cause of occasional cases of HUS could be ascribed [2], most cases of HUS resulting in renal failure during childhood were of uncertain etiology [3]. Its occurrence in outbreaks suggested an infectious etiology in at least some cases [4, 5], especially infections with Shigella dysenteriae type 1 (Shiga bacillus), a high-level producer of Shiga toxin. Between 1955 and 1983, case reports associated at least a dozen infectious agents with HUS; one prevailing notion was that HUS was a multifactorial disease (final common pathway) that could be triggered by a variety of infectious agents In 1982, outbreaks of bloody diarrhea involved patrons of a large chain of fast-food restaurants in 2 widely separated parts of the United States; this illness, termed “hemorrhagic colitis,” was found to be due to an Escherichia coli strain of serotype O157:H7 [6]. In the many years during which the Centers for Disease Control (CDC) kept records of E. coli strains associated with disease, this serotype was reported only once, in 1975, from a woman with the acute onset of bloody diarrhea [6] In 1977, the Canadian microbiologists Konowalchuk et al. reported that certain E. coli strains had cytotoxic activity toward African green monkey kidney (Vero) cells unlike that produced by any of the known E. coli toxins [7]. Also in 1977, Martin Skirrow, in England, reported that an obscure bacterium, Campylobacter jejuni was an important and essentially unrecognized cause of acute enteritis [8]. Spurred by Skirrow’s report, a young Canadian physician, Mohamed A. Karmali, began to study whether C. jejuni was important as a cause of acute diarrheal illnesses among patients seen at the Hospital for Sick Children in Toronto. His studies, conducted in the Clinical Microbiology Laboratory under the guidance of Peter Fleming, established C. jejuni as an etiologic agent in this population [9]. More importantly, this work brought Karmali into the study of diarrheal diseases Within several weeks during the summer of 1981, 14 children with HUS were admitted to the Hospital for Sick Children. This was an extraordinary event in Toronto, and all local scientists were committed to understanding its pathogenesis and etiology. Because he was a Canadian microbiologist, Karmali was aware of the findings of Konowalchuk et al. [7]; so, as part of the work-up to evaluate the role of E. coli infections in these case subjects, Karmali et al. sought to determine whether the activity that Konowalchuk et al. had reported was involved [10]. Surprisingly, in the majority of the children with HUS, they did indeed find evidence for (Vero−) toxin activity in E. coli isolates from stool specimens, directly in the stool specimens themselves, or from neutralizing antibody (i.e., serologic) responses in affected children [10]. Almost simultaneously, Johnson et al. reported toxigenic E. coli 0157:H7 in stool specimens from nursing-home patients with hemorrhagic colitis [11], and O’Brien et al. reported that 3 E. coli 0157:H7 isolates from the US outbreaks being investigated by the CDC produced the same toxin, which could be neutralized by antiserum to the Shiga toxin produced by S. dysenteriae [12]. Thus, each of these investigations coalesced around E. coli strains producing a cytotoxin (called “Verotoxin” [VT] by some [10, 11] and “Shiga-like toxin” [SLT] by others [12]). On the basis of the extant literature and the observations of the Canadian and US investigators, Karmali et al. hypothesized that these toxin-producing E. coli strains could cause a spectrum of illness ranging from mild diarrhea to hemorrhagic colitis to HUS [13] On this basis, Karmali and his colleagues (Martin Petric, Corazon Lim, Peter C. Fleming, Gerald S. Arbus, and Hermy Lior), who were all Canadians working in either Toronto or Ottawa, began a systematic study to determine the relationship between these VT-producing E. coli (VTEC) strains and HUS [14]. In total, 40 patients with idiopathic HUS were examined along with an equal number of age- and sex-matched control subjects. Either VTEC or neutralizable VT was present, or both were, in stool specimens from 24 (60%) of the case subjects, but not in any of the stool specimens from the control subjects. Ten of 15 of these case subjects developed serologic responses to VT, as did 6 others. In total, 30 (75%) of the 40 case subjects and none of the control subjects had evidence of VTEC infection [14] The results were clear, coherent, internally consistent, biologically plausible, and built on the prior literature [6, 7, 10–12]. Almost immediately, the concept that toxigenic E. coli were the major trigger for HUS became widely accepted. Once a disease of uncertain etiology, HUS was now viewed in a new way by medical science. The work of Karmali et al. was submitted for publication in August 1984 and was published in The Journal of Infectious Diseases the following May. During the nearly 20 years since this work was done, there have been many advances. In this perspective, I will address 4 major areas The linking of a causative microbe to a disease has allowed medical scientists to uncover the intermediate steps of that disease. The problem of enterohemorrhagic E. coli (EHEC) pathogenesis now has been attacked by physicians, microbiologists, cell biologists, and others, with great progress. The original description of SLTs has led to the uncovering of 2 major families of toxins (now referred to as “Stx1” and “Stx2”); >200 different E. coli serotypes produce these molecules, but not all have been associated with human disease [15]. We now know that these EHEC have evolved in a stepwise fashion, involving acquisition of bacteriophages that encode the relevant toxins, as well as high–molecular weight plasmids and other virulence factors [16]. Another major virulence strategy is the attaching and effacing lesion encoded by the locus of enterocyte effacement (LEE) pathogenicity island [17]. Recently, stcE, a C1 esterase inhibitor–specific metaloprotease, has been identified to have been acquired early in the evolution of O157:H7 strains toward their full virulence [18]. Understanding the role of the SLTs has led to identification of the glycolipid receptor (globotriosyl ceramide [GB3]) [18]. The presence of GB3 on the endothelial cells of glomerular capillaries explains the occurrence of acute renal failure, as well as microangiopathic hemolytic anemia and thrombocytopenia of HUS [19]. The SLTs are toxins arresting protein synthesis through the catalytic inactivation of the 60S ribosomal subunit [20], which leads to the injury and/or death of affected endothelial cells [21]. Development of neutralizing antibodies occurs in most persons before the age of 10, but they wane during old age. Persons lacking these antibodies at the extremes of age are the most common victims of the infection [15]. Thus, the major characteristics of the disease and of its natural protection have been determined. This knowledge led quickly to the development of new diagnostics, but development of effective treatments has lagged [15]. An interesting chicken-and-egg question concerns how individuals develop protective antibodies if colonization of a nonimmune host by an stx-producing strain is potentially disease producing With the great advances related to the discovery and use of antibiotics, it was widely assumed that all the medically important bacteria had been discovered and that the illnesses they cause had been characterized. We now know that this view is not correct. The identification of E. coli as the cause of HUS, along with C. jejuni as the cause of many cases of Guillain-Barré syndrome [22] and Helicobacter pylori as a risk factor for both peptic ulcer disease and gastric cancer [23], has changed our thinking about diseases of unknown etiology [24]. One corollary is that microbial pathogens are “great” cell biologists, immunologists, and physiologists. We now better realize that nature has selected our important pathogens because of their virulence. In each case, these microbial properties imply sufficient adaptation to breach human defenses and/or use them to the microbe’s advantage. That EHEC are able to use host-derived epinephrine to adapt to their in vivo environment is one recent example [25]. Not long ago, the entire genomic sequence of 2 E. coli O157:H7 strains were solved; comparison of the sequences of the chromosome and the large virulence plasmid with those from other virulent and avirulent E. coli strains will permit insights into mechanisms of colonization and pathogenesis [26, 27]. The identification of plasmid-encoded hemolysins, serine proteases, and the C1 esterase inhibitors, as well as at least 7 new chromosomal pathogenicity islands, shows our broadening knowledge of EHEC pathogenesis beyond the SLTs One further corollary is that the site of tissue injury need not be the site of infection. As with streptococcal pharyngitis and the subsequent development of acute rheumatic fever, primary EHEC infection of the colon is distant from the renal glomerular endothelium. These examples suggest that other infections at mucosal surfaces may result in distant tissue injury and, together, suggest a new paradigm for the etiology of chronic inflammatory disorders in tissues removed from a microbially colonized lumen. If an acute, transient gastrointestinal infection can lead to HUS or Guillain-Barré syndrome (at distant sites), could subacute or persistent infections lead to other autoimmune diseases?. There are many potential candidates Uncovering the important role that EHEC play in HUS, the most common form of acute renal failure during childhood in most developed countries, has stimulated investigation of the sources of the infection in the community. The initial association of hemorrhagic colitis with consumption of hamburgers provided the clue that HUS is a zoonotic disease, chiefly acquired from cattle. Now we understand that the early outbreaks of HUS associated with consumption of fresh apple juice were due to cattle grazing in orchards, with fecal contamination of the fallen apples that typically are used in juice production [28]. Such investigations have led to the widespread pasteurization of apple juice and to the progressive elimination of this problem [15]. Since O157:H7 strains in humans were rare before 1981, scientists have asked whether changes in animal husbandry could explain the increased incidence of human cases. We now know that E. coli O157:H7 strains are more resistant to low pH than are most competing E. coli strains; the change in cattle feeding in the United States from hay to grain has lowered colonic pH, giving O157:H7 strains a selective advantage over other E. coli strains [29]. Thus, the increase in HUS parallels changes in animal-husbandry practices and, thus, ecology on the farm! Similarly, with improved standards at fast-food restaurants, EHEC epidemiology is increasingly changing from a “hamburger disease” to a waterborne and vegetable-associated illness; a preference for organic foods has led to increased use of animal manure, rather than chemicals, as fertilizer. It is unlikely that Karmali et al. had considered these possibilities when beginning their studies, yet determining that a microbe plays a pathogenic role in an important human disease focused efforts to comprehend the underlying ecology of the microbe The relationship between EHEC and HUS has mobilized food-safety advocates as no previous food-safety cause has done. In 1993, an outbreak of food poisoning due to EHEC that occurred at a different fast-food chain serving hamburgers sickened >700 persons, and 4 died from HUS. This outbreak caught the national attention and has led to the creation of grass-roots organizations such as S.T.O.P. (Safe Tables Our Priority). HUS, with its devastating consequences, has served as a lightning rod to mobilize parents and consumers to embrace the cause of safe foods. Over the last 20 years, dramatic foodborne outbreaks of hemorrhagic colitis and HUS, with permanent disability or death of young children, have served as important catalysts for food safety in the United States, Canada, Japan, Europe, and other locales. Our public safety regulations are reflecting this pressure [30]. In 2001, Kevin Kowalcyk died as a result of ingesting E. coli O157:H7 in food, and food-safety advocates have concentrated efforts around his case. In May 2003, the US Congress reintroduced the “Meat and Poultry Pathogen Reduction and Enforcement Act of 2003,” also known as “Kevin’s Law.” In summary, the paper by Karmali et al. in the Journal in May 1985 [14] has advanced basic medical science, broadened our views of pathogenesis, led to new understandings of microbial ecology, and mobilized advocates for food safety. By any of these criteria, it was a landmark paper.

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