Curr Gastroenterol Rep (2014) 16:399 DOI 10.1007/s11894-014-0399-8
LARGE INTESTINE (B CASH, SECTION EDITOR)
Infectious Diarrhea: An Overview Brandon Dickinson & Christina M. Surawicz
Published online: 27 July 2014 # Springer Science+Business Media New York 2014
Abstract Diarrheal disease, which is most often caused by infectious pathogens, is a significant cause of morbidity and mortality worldwide, especially in children. This is particularly true in developing countries. Recent outbreaks of infectious diarrhea in developed countries, including the USA, are often attributed to food handling and distribution practices and highlight the need for continued vigilance in this area. Another common cause of infectious diarrhea, Clostridium difficile infection (CDI), has historically been associated with the use of antibiotics and exposure to a health-care setting but is now increasingly common in the community in persons who lack the typical risk factors. Recent scientific advances have also led to new and proposed new therapies for infectious diarrhea, including fecal microbiota transplant (FMT) for recurrent C. difficile infection (RCDI), probiotics for prevention of antibiotic-associated diarrhea (AAD) and CDI, and the use of zinc supplementation in the treatment of acute diarrhea in children. Other therapies that have been in use for decades, such as the oral rehydration solution (ORS), continue to be the targets of scientific advancement in an effort to improve delivery and efficacy. Finally, post-infectious irritable bowel syndrome (PI-IBS) is an increasingly recognized occurrence. Attempts to understand the mechanism behind this phenomenon are underway and may provide insight into potential treatment options.
This article is part of the Topical Collection on Large Intestine B. Dickinson Department of Medicine, University of Washington School of Medicine, Seattle, USA C. M. Surawicz (*) Division of Gastroenterology, Department of Medicine, University of Washington School of Medicine, 325 9th Ave, Box 359773, Seattle, WA 98104, USA e-mail: [email protected]
Keywords Infectious diarrhea . Clostridium difficile infection (CDI) . Recurrent Clostridium difficile infection (RCDI) . Fecal microbiota transplant (FMT) . Oral rehydration solution (ORS) . Zinc . Probiotics . Post-infectious irritable bowel syndrome (PI-IBS)
Introduction According to the World Health Organization, diarrheal disease is the second leading cause of death in children under 5 years old and kills around 760,000 children in that age group and over 2 million people overall, per year. There are an estimated 1.7 billion cases of diarrheal disease every year [1]. While infections with viral, bacterial, and parasitic pathogens are not the only cause of diarrhea, they are certainly the most common. This article focuses on recent developments within the field of infectious diarrhea, including recent outbreaks, Clostridium difficile infection (CDI), as well as proposed new therapies.
Epidemiology of Infectious Diarrhea In developed countries, widespread dissemination of infectious agents can often be linked to contamination during food and water handling and distribution practices of a region. Foodborne infectious agents are also responsible for a significant number of cases of infectious diarrhea in the USA. The Foodborne Diseases Active Surveillance Network (FoodNet) is a collaboration among the CDC, 10 state health departments, the U.S. Department of Agriculture’s Food Safety and Inspection Service (USDA-FSIS), and the Food and Drug Administration (FDA) that conducts surveillance for laboratory-confirmed infections caused by Campylobacter, Cryptosporidium, Cyclospora, Listeria, Salmonella, Shiga
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toxin-producing Escherichia coli (STEC) O157 and nonO157, Shigella, Vibrio, and Yersinia. In 2012, FoodNet identified 19,531 laboratory-confirmed cases of infection. For Campylobacter and Vibrio, the incidence of infection in 2012 was higher than in years 2006–2008, but for other pathogens, it was unchanged. According to FoodNet, the incidence of Campylobacter infection has increased to its highest level since 2000. In addition, the incidence of STEC O157, which had declined since 2006, was no longer declining in 2012. That these increases occurred in the setting of stricter food handling regulations than ever before highlights the need for continued vigilance and improvements in the area of food safety [2].
Specific Pathogens Shiga Toxin-Producing Escherichia coli There are over 100 serotypes of STEC that cause human disease and include both the O157 and the non-0157 strains. Although the organism is not itself invasive, it produces a Shiga-like toxin that leads to symptomatic disease and can contribute to the development of hemolytic uremic syndrome (HUS). HUS involves the combination of renal failure, microangiopathic hemolytic anemia, and thrombocytopenic purpura [3]. Non-0157 strains may account for 20–50 % of STEC infections worldwide. In 2011, an outbreak involving 3,816 patients (including 51 deaths) of gastroenteritis and hemolytic-uremic syndrome (HUS) caused by STEC O104:H4 in Germany was attributed to the consumption of sprouts. This particular outbreak was unique in that it primarily affected adults (median age of 42), women were overrepresented (68 %), and a larger number than expected of patients went on to develop HUS (>20 %). STEC O157:H7, the predominant virulent strain in the USA, primarily affects children and leads to the development of HUS in only about 6 % of cases [4]. The O104:H4 strain was found to have virulence properties of both enteroaggregative E. coli and STEC, which may have led to its increased virulence (49, 50) [5, 6]. Listeria Although Listeria monocytogenes is a fairly infrequent cause of foodborne illness, infections can be severe with an overall case fatality rate of up to 17 %, which is the highest among foodborne bacterial pathogens [7]. There is both a noninvasive form of Listeria, which typically causes a febrile illness, and an invasive form that can cause meningitis, bacteremia, and fetal loss. Diabetics, pregnant women, persons who are immunocompromised, and newborn infants are at particularly high risk of invasive disease. Listeria has historically been
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implicated in outbreaks of gastroenteritis associated with contaminated deli meats and unpasteurized dairy products. However, an outbreak of Listeria in the USA in 2011 was attributed to cantaloupe, an unusual vehicle for listeriosis, which was contaminated from a single farm in Colorado. Of the 145 patients for whom information about the hospitalization was available, 33 (22 %) died [8]. Shigella Infection with Shigella is very common worldwide. It causes infection both by direct invasion of the colonic epithelium and by production of an enterotoxin. In the USA, infection with Shigella sonnei is the most common. It typically occurs in children under 5 years of age and has been associated with day-care centers [9]. Historically, infection was treated primarily with quinolone antibiotics, but given the increased prevalence of quinolone resistance, the use of azithromycin is increasing. However, a recent outbreak of diarrhea caused by S. sonnei in California demonstrated the bacteria to have reduced susceptibility to azithromycin. This was the first outbreak of Shigella isolates to display such reduced susceptibility [10]. Clostridium difficile C. difficile infection (CDI) places a burden on the health-care system that has been estimated at 3.2 billion dollars annually [11, 12]. It has historically been thought of as an infection affecting those within the health-care setting, including those who are currently or have recently been treated with antibiotics, the elderly, those with chronic kidney disease (CKD), malignancy, and the immunosuppressed. Rates of CDI have been increasing since the year 2000, and C. difficile has become an emerging pathogen in populations who were previously felt to be low risk. This is due, at least in part, to the emergence of an epidemic strain, Nap1 B1/O27 [13]. This strain possesses a gene deletion that causes increased production of toxins A and B presumably contributing to its increased virulence. It has been associated with quinolone and clindamycin resistance [14]. Such resistance among widespread use of quinolones in the community may explain, in part, the increasing prevalence of CDI in the community. Other contributing factors include recent health-care exposure other than hospitalization and asymptomatic carriers in the community [15–20]. Studies estimate that communityacquired CDI accounts for 20–27 % of all CDI [15]. Those with community-acquired infection, when compared to hospital-acquired infection, were younger, more likely to be female, had fewer comorbidities, and had less severe infection [15, 21]. Studies have also shown that the incidence in children has increased up to 12.5-fold [19].
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There is increasing evidence that proton pump inhibitor (PPI) therapy predisposes to CDI. Two meta-analyses concluded that PPI therapy is associated with an estimated 70 % increased risk of developing CDI and that that risk was further increased when PPIs were used concomitantly with antibiotics [22, 23]. It should be noted that both studies found statistically significant heterogeneity among their included studies. Simply the use of PPIs and the duration of use have also independently been shown to increase the risk of developing CDI in hospitalized patients [24]. In addition, a recent study in an ICU setting showed that PPI therapy was an independent risk factor for CDI in ICU patients [25], in whom PPIs are often used for stress ulcer prophylaxis. These studies, and others, contributed to the Food and Drug Administration issuing a warning in February 2012 that PPI therapy may predispose to CDI [26]. It should be noted that expert opinion regarding the risk of recurrent CDI with PPI use is divided [27, 28]. New guidelines from the American College of Gastroenterology for the diagnosis, treatment, and prevention of CDI have recently been published [29•]. Recurrent CDI (RCDI) is an increasingly recognized problem and poses a treatment challenge. Studies show approximately 15–30 % of patients develop recurrence of CDI following treatment of a first infection [30, 31]. Patients with RCDI are often treated with prolonged tapering or pulsed doses of antibiotics. More than two decades ago, Tvede and Rask-Madsen used a mixture of 10 different bacterial species to successfully treat five patients with RCDI who were deficient in Bacteroides bacteria [32•, 33]. Fecal microbiota transplant (FMT) has been proposed as an alternative to the more traditional treatments for RCDI. FMT involves the transfer of stool from a healthy donor into the gastrointestinal tract of the patient via enema, nasogastric tube, or endoscopically. Small case series have shown significant success rates [34, 35], even in patients infected with the virulent Nap1 BI/027 strain, suggesting FMT appears to be an effective therapy for RCDI. A systematic review included 317 patients across 27 case series with RCDI treated with FMT. Disease resolution occurred in 92 % of cases [36]. The first randomized controlled trial of FMT for RCDI was recently published. Patients with RCDI (defined as relapse of CDI after at least one course of adequate antibiotic therapy) were randomized to one of three treatment groups: an initial vancomycin regimen followed by bowel lavage and subsequent infusion of donor feces, a standard vancomycin regimen, or a standard vancomycin regimen with bowel lavage. Resolution of C. difficile-associated diarrhea occurred in 81 % of patients in the infusion group after the first infusion, 31 % of patients in the vancomycin only group, and 23 % of patients in the vancomycin with bowel lavage group. No significant differences in adverse events among the three study groups were observed except for mild diarrhea and abdominal cramping in the infusion group on the infusion day [37•]. While the study was stopped early, could not be blinded by its nature, and has
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been criticized for its small numbers of patients, it remains the first randomized controlled trial of FMT for RCDI. An additional NIH-funded trial is underway using colonoscopy to deliver the FMT (personal communication, Dr. Colleen Kelley, Providence RI). Conceptually, FMT is used in an effort to reconstitute the disrupted intestinal microbiota of a patient and thus provide protection against infection. Khoruts et al. assessed the intestinal microbiome of CDI patients both pre- and post-FMT and found that 2 weeks after transplant, the recipient’s microbiota was similar to that of the donor stool with a dominance of Bacteroides sp. These effects were demonstrated to last up to 33 days [38]. Attempts are being made to elucidate the mechanism by which disruption of the normal intestinal flora increases susceptibility to CDI. Antibiotic-mediated depletion of bacteria involved in the modification of bile acids [32•, 39, 40], depletion of other bacteria involved in the production of short-chain fatty acids (SCFAs) [32•, 41], and increased production of sialic acids, which may serve as an energy source of C. difficile, following antibiotic use have all been proposed as mechanisms by which alteration of the normal gut microbiota leads to increased susceptibility to CDI [42, 43•].
Therapy Oral Rehydration Therapy Oral rehydration solution (ORS) has been a key resource in the treatment of acute diarrhea in the developing world since the 1970s. An excellent review has recently been published [44•]. The initial solution, referred to as the WHO-ORS, was iso-osmolar and provided Na (and thus fluid) and glucosemediated Na absorption in the small intestine via a cyclic AMP-independent process [45, 46]. It was later demonstrated that hypo-osmolar solutions performed better than the initial iso-osmolar solution [47]. However, despite long-standing proven efficacy in limiting dehydration and metabolic acidosis (MA) in acute diarrhea, the use of ORS has been somewhat limited. The lack of widespread use of ORS has been postulated to be due, in part, to its inability to reduce stool output dramatically. This has led to efforts to develop a solution that not only treats dehydration and MA but also reduces stool output. As previous solutions aimed to increase fluid absorption in the small intestine only, reducing stool output necessitates developing a solution that also increases fluid absorption in the colon. The use of resistant starches (RS) [48–50] and fermentable substances (FS) [51] has been proposed as mechanisms by which SCFAs could be delivered to the colon, instead of being digested in the small intestine, taking advantage of SCFA-mediated Na absorption in the colon. A specific RS (high-amylose maize starch or HAMS-ORS) was shown
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in three studies to be associated with a 30–50 % reduction in time to first stool [48–50]. The mechanism includes glucosemediated absorption of Na in the small intestine, with the addition of HAMS fermentation to SCFA in the colon stimulating colonic Na absorption and reduction of stool output [44•]. Efforts are ongoing to develop a HAMS-ORS that can be further tested for efficacy and safety prior to implementation in the developing world.
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0.34; 95 % confidence interval (CI), 0.24–0.49]. There were no significant differences in adverse events between the two groups [62•]. However, a recent large, randomized, doubleblinded, placebo-controlled trial (PLACIDE trial) showed that a multi-strain preparation of lactobacilli and bifidobacteria showed no benefit when compared to placebo at preventing AAD or CDI [63]. Given these findings, the use of probiotics for prophylaxis or treatment of a first case of AAD or CDI is controversial.
Zinc Zinc is emerging as an adjunct therapy in the treatment of acute diarrheal illness. It is estimated that zinc deficiency may contribute to 176,000 diarrhea-related deaths in children under 5 years of age per year [52]. Multiple reviews in the early 2000s demonstrating the benefit of zinc supplementation in the setting of acute diarrhea led to the WHO-UNICEF joint statement in 2004 recommending the use of zinc supplementation for 10–14 days for the clinical management of acute diarrhea [53]. In 2013, a Cochrane review of 24 randomized trials comparing oral zinc supplementation with placebo in children aged 1 month to 5 years with acute or persistent diarrhea was published. Nine thousand one hundred twenty eight children were included in the trials, which demonstrated that in children older than 6 months with acute diarrhea, zinc supplementation may shorten the duration of diarrhea by about 10 h and probably reduces the number of children whose diarrhea persists until day seven. In children with signs of moderate malnutrition, the effect appears greater, reducing the duration of diarrhea by about 27 h [54]. The mechanisms by which zinc supplementation provides benefit in acute diarrhea are under extensive review. Enteric pathogens cause diarrhea by altering fluid secretion via four intracellular signaling pathways: cAMP, cGMP, intracellular calcium, and nitric oxide [55, 56]. Studies have shown that zinc interferes with at least three of these pathways [57, 58]. Other proposed mechanisms include the role of zinc in intestinal mucosal integrity [59] and its role in generalized immunity [60]. Probiotics Multiple studies since have also sought to identify specific bacteria that, when given, confer protection against antibioticassociated diarrhea (AAD) or CDI. Meta-analyses have demonstrated efficacy of probiotics in the prevention of AAD [61]. A Cochrane review in 2012 included 20 randomized controlled trials with adult or pediatric patients receiving antibiotics. These trials compared any strain or dose of a probiotic with placebo or with no treatment control and reported the incidence of CDI. Three thousand eight hundred eighteen patients met eligibility criteria. Probiotics were shown to reduce the incidence of CDI by 66 % [pooled relative risk of
Post-infectious Irritable Bowel Syndrome Post-infectious irritable bowel syndrome (PI-IBS) has been defined as the onset of new IBS-like symptoms (by Rome criteria for IBS) in an individual who has not previously met the Rome criteria, following an acute illness characterized by two or more of the following: fever, vomiting, diarrhea, or a positive bacterial stool culture [64]. PI-IBS was first recognized in 1950 [65] and has gained more recognition in recent years. Multiple studies from the mid-1990s to present report that 6–17 % of patients with IBS symptoms developed their symptoms after an episode of gastroenteritis, either bacterial or viral [66]. The mechanisms by which patients develop PI-IBS may include changes in the microbiota, inflammation, and motility. It has long been known that acute diarrheal illness can change the gut microbiota [67], and alterations in gut microbiota have been shown to occur in patients with IBS [68]. PI-IBS may be related to continued low-grade inflammation of the GI tract following an episode of infective diarrhea, as inflammation of the GI tract has been shown to affect its sensorimotor function and development of functional bowel disease [66, 69]. Pimentel et al. developed a rat model of PI-IBS in which they colonized rats with Campylobacter jejuni and showed that 3 months after clearance of the infection, the rats demonstrated altered stool frequency, consistency, and gut lymphocytosis using real-time PCR, all findings that have been demonstrated in patients with IBS [70]. Further efforts to elucidate the mechanism by which patients develop PI-IBS are underway and may provide insight into potential treatment options.
Conclusion The field of infectious diarrhea continues to evolve. Recent outbreaks highlight this as pathogens demonstrate new virulence properties, new vehicles for infection, and increasing antibiotic resistance. Other common infections, such as CDI, have demonstrated a change in epidemiology. In addition, new scientific advances continue to provide greater understanding of the mechanism by which infectious agents cause
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diarrhea, have led to new therapies such as fecal microbiota transplant, and have identified targets for future areas of research.
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Compliance with Ethics Guidelines Conflict of Interest Brandon Dickinson and Christina M. Surawicz have nothing to disclose.
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Human and Animal Rights and Informed Consent This article does not contain any studies with animal subjects performed by any of the authors. With regard to the authors’ research cited in this paper, all procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000 and 2008.
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Raghupathy P, Ramakrishna BS, Oommen SP, et al. Amylaseresistant starch as adjunct to oral rehydration therapy in children with diarrhea. J Pediatr Gastr Nutr. 2006;42:362–8. Balakrishnan BS, Venkataraman S, Mohen V, et al. Amylase resistant starch in hypo-osmolar oral rehydration solution for the treatment of acute severe watery diarrhea in adults. PLoS ONE. 2008;3:e1587. Subramanya S, Balakrishnan BS, Ramakrishna S, et al. Evaluation of oral rehydration solution by whole gut perfusion in rats: effects of osmolarity, sodium concentration and resistant starch. J Pediatr Gastroenterol Nutr. 2006;43:568–77. Penny ME. Zinc supplementation in public health. Ann Nutr Metab. 2013;62(1):31–42. WHO/UNICEF joint statement: clinical management of acute diarrhoea. The United Nations Children's Fund/World Health Organization, 2004. http://whqlibdoc.who.int.offcampus.lib. washington.edu/hq/2004/WHO_FCH_CAH_04.7.pdf (accessed April 3, 2014). Lazzerini M, Ronfani L. Oral zinc for treating diarrhoea in children. Cochrane Database Syst Rev. 2013;1, CD005436. Fasano A. Toxin and the gut: role in human disease. Gut. 2002;50: 9–14. Surawicz CM. Mechanisms of Diarrhea. Curr Gastroenterol Rep. 2010;12(4):236–41. Berni Canani R, Cirillo P, Buccigrossi V, et al. Zinc inhibits cholera toxin-induced, but not Escherichia coli heat-stable enterotoxininduced, ion secretion in human enterocytes. J Infect Dis. 2006;191:1072–7. BerniCanani R, Secondo A, Passariello A, et al. Zinc inhibits calcium-mediated and nitric oxide-mediated ion secretion in human enterocytes. Eur J Pharmacol. 2010;626:266–70. Berni Canani R, Buccigrossi V, Passariello A. Mechanisms of action of zinc in acute diarrhea. Curr Opin Gastroenterol. 2011;27:8–12. Salgueiro MJ, Zubillaga M, Lysionek A, et al. Zinc status and immune system relationship: a review. Biol Trace Elem Res. 2000;76:193–205. McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol. 2006;101:812–22. Johnston BC, Ma SS, Goldenberg JZ, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. Ann Intern Med. 2012;157(12):878–88. Recent Cochrane review looking at the use of probiotics in the prevention of Clostridium difficile infection. Allen SJ, Wareham K, Wang D, et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older patients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2013;382(9900):1249–57. Spiller R, Garsed K. Postinfectious irritable bowel syndrome. Gastroenterology. 2009;136:1979–88. Stewart GT. Post-dysenteric colitis. Br Med J. 1950;1:405–9. Ghoshal UC, Ranjan P. Post-infectious irritable bowel syndrome: the past, the present, the future. J Gastroenterol Hepatol. 2011;26(3):94–101. Gorbach SL, Neale G, Levitan R, et al. Alterations in human intestinal microflora during experimental diarrhoea. Gut. 1970;11:1–6. Krogius-Kurikka L, Lyra A, Malinen E, et al. Microbial community analysis reveals high level phylogenetic alterations in the overall gastrointestinal microbiota of diarrhoea-predominant irritable bowel syndrome sufferers. BMC Gastroenterol. 2009;9:95. Gwee KA, Collins SM, Read NW, et al. Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome. Gut. 2003;52:523–6. Pimentel M, Chatterjee S, Chang C, et al. A new rat model links two contemporary theories in irritable bowel syndrome. Dig Dis Sci. 2008;53(4):982–9.
LARGE INTESTINE (B CASH, SECTION EDITOR)
Infectious Diarrhea: An Overview Brandon Dickinson & Christina M. Surawicz
Published online: 27 July 2014 # Springer Science+Business Media New York 2014
Abstract Diarrheal disease, which is most often caused by infectious pathogens, is a significant cause of morbidity and mortality worldwide, especially in children. This is particularly true in developing countries. Recent outbreaks of infectious diarrhea in developed countries, including the USA, are often attributed to food handling and distribution practices and highlight the need for continued vigilance in this area. Another common cause of infectious diarrhea, Clostridium difficile infection (CDI), has historically been associated with the use of antibiotics and exposure to a health-care setting but is now increasingly common in the community in persons who lack the typical risk factors. Recent scientific advances have also led to new and proposed new therapies for infectious diarrhea, including fecal microbiota transplant (FMT) for recurrent C. difficile infection (RCDI), probiotics for prevention of antibiotic-associated diarrhea (AAD) and CDI, and the use of zinc supplementation in the treatment of acute diarrhea in children. Other therapies that have been in use for decades, such as the oral rehydration solution (ORS), continue to be the targets of scientific advancement in an effort to improve delivery and efficacy. Finally, post-infectious irritable bowel syndrome (PI-IBS) is an increasingly recognized occurrence. Attempts to understand the mechanism behind this phenomenon are underway and may provide insight into potential treatment options.
This article is part of the Topical Collection on Large Intestine B. Dickinson Department of Medicine, University of Washington School of Medicine, Seattle, USA C. M. Surawicz (*) Division of Gastroenterology, Department of Medicine, University of Washington School of Medicine, 325 9th Ave, Box 359773, Seattle, WA 98104, USA e-mail: [email protected]
Keywords Infectious diarrhea . Clostridium difficile infection (CDI) . Recurrent Clostridium difficile infection (RCDI) . Fecal microbiota transplant (FMT) . Oral rehydration solution (ORS) . Zinc . Probiotics . Post-infectious irritable bowel syndrome (PI-IBS)
Introduction According to the World Health Organization, diarrheal disease is the second leading cause of death in children under 5 years old and kills around 760,000 children in that age group and over 2 million people overall, per year. There are an estimated 1.7 billion cases of diarrheal disease every year [1]. While infections with viral, bacterial, and parasitic pathogens are not the only cause of diarrhea, they are certainly the most common. This article focuses on recent developments within the field of infectious diarrhea, including recent outbreaks, Clostridium difficile infection (CDI), as well as proposed new therapies.
Epidemiology of Infectious Diarrhea In developed countries, widespread dissemination of infectious agents can often be linked to contamination during food and water handling and distribution practices of a region. Foodborne infectious agents are also responsible for a significant number of cases of infectious diarrhea in the USA. The Foodborne Diseases Active Surveillance Network (FoodNet) is a collaboration among the CDC, 10 state health departments, the U.S. Department of Agriculture’s Food Safety and Inspection Service (USDA-FSIS), and the Food and Drug Administration (FDA) that conducts surveillance for laboratory-confirmed infections caused by Campylobacter, Cryptosporidium, Cyclospora, Listeria, Salmonella, Shiga
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toxin-producing Escherichia coli (STEC) O157 and nonO157, Shigella, Vibrio, and Yersinia. In 2012, FoodNet identified 19,531 laboratory-confirmed cases of infection. For Campylobacter and Vibrio, the incidence of infection in 2012 was higher than in years 2006–2008, but for other pathogens, it was unchanged. According to FoodNet, the incidence of Campylobacter infection has increased to its highest level since 2000. In addition, the incidence of STEC O157, which had declined since 2006, was no longer declining in 2012. That these increases occurred in the setting of stricter food handling regulations than ever before highlights the need for continued vigilance and improvements in the area of food safety [2].
Specific Pathogens Shiga Toxin-Producing Escherichia coli There are over 100 serotypes of STEC that cause human disease and include both the O157 and the non-0157 strains. Although the organism is not itself invasive, it produces a Shiga-like toxin that leads to symptomatic disease and can contribute to the development of hemolytic uremic syndrome (HUS). HUS involves the combination of renal failure, microangiopathic hemolytic anemia, and thrombocytopenic purpura [3]. Non-0157 strains may account for 20–50 % of STEC infections worldwide. In 2011, an outbreak involving 3,816 patients (including 51 deaths) of gastroenteritis and hemolytic-uremic syndrome (HUS) caused by STEC O104:H4 in Germany was attributed to the consumption of sprouts. This particular outbreak was unique in that it primarily affected adults (median age of 42), women were overrepresented (68 %), and a larger number than expected of patients went on to develop HUS (>20 %). STEC O157:H7, the predominant virulent strain in the USA, primarily affects children and leads to the development of HUS in only about 6 % of cases [4]. The O104:H4 strain was found to have virulence properties of both enteroaggregative E. coli and STEC, which may have led to its increased virulence (49, 50) [5, 6]. Listeria Although Listeria monocytogenes is a fairly infrequent cause of foodborne illness, infections can be severe with an overall case fatality rate of up to 17 %, which is the highest among foodborne bacterial pathogens [7]. There is both a noninvasive form of Listeria, which typically causes a febrile illness, and an invasive form that can cause meningitis, bacteremia, and fetal loss. Diabetics, pregnant women, persons who are immunocompromised, and newborn infants are at particularly high risk of invasive disease. Listeria has historically been
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implicated in outbreaks of gastroenteritis associated with contaminated deli meats and unpasteurized dairy products. However, an outbreak of Listeria in the USA in 2011 was attributed to cantaloupe, an unusual vehicle for listeriosis, which was contaminated from a single farm in Colorado. Of the 145 patients for whom information about the hospitalization was available, 33 (22 %) died [8]. Shigella Infection with Shigella is very common worldwide. It causes infection both by direct invasion of the colonic epithelium and by production of an enterotoxin. In the USA, infection with Shigella sonnei is the most common. It typically occurs in children under 5 years of age and has been associated with day-care centers [9]. Historically, infection was treated primarily with quinolone antibiotics, but given the increased prevalence of quinolone resistance, the use of azithromycin is increasing. However, a recent outbreak of diarrhea caused by S. sonnei in California demonstrated the bacteria to have reduced susceptibility to azithromycin. This was the first outbreak of Shigella isolates to display such reduced susceptibility [10]. Clostridium difficile C. difficile infection (CDI) places a burden on the health-care system that has been estimated at 3.2 billion dollars annually [11, 12]. It has historically been thought of as an infection affecting those within the health-care setting, including those who are currently or have recently been treated with antibiotics, the elderly, those with chronic kidney disease (CKD), malignancy, and the immunosuppressed. Rates of CDI have been increasing since the year 2000, and C. difficile has become an emerging pathogen in populations who were previously felt to be low risk. This is due, at least in part, to the emergence of an epidemic strain, Nap1 B1/O27 [13]. This strain possesses a gene deletion that causes increased production of toxins A and B presumably contributing to its increased virulence. It has been associated with quinolone and clindamycin resistance [14]. Such resistance among widespread use of quinolones in the community may explain, in part, the increasing prevalence of CDI in the community. Other contributing factors include recent health-care exposure other than hospitalization and asymptomatic carriers in the community [15–20]. Studies estimate that communityacquired CDI accounts for 20–27 % of all CDI [15]. Those with community-acquired infection, when compared to hospital-acquired infection, were younger, more likely to be female, had fewer comorbidities, and had less severe infection [15, 21]. Studies have also shown that the incidence in children has increased up to 12.5-fold [19].
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There is increasing evidence that proton pump inhibitor (PPI) therapy predisposes to CDI. Two meta-analyses concluded that PPI therapy is associated with an estimated 70 % increased risk of developing CDI and that that risk was further increased when PPIs were used concomitantly with antibiotics [22, 23]. It should be noted that both studies found statistically significant heterogeneity among their included studies. Simply the use of PPIs and the duration of use have also independently been shown to increase the risk of developing CDI in hospitalized patients [24]. In addition, a recent study in an ICU setting showed that PPI therapy was an independent risk factor for CDI in ICU patients [25], in whom PPIs are often used for stress ulcer prophylaxis. These studies, and others, contributed to the Food and Drug Administration issuing a warning in February 2012 that PPI therapy may predispose to CDI [26]. It should be noted that expert opinion regarding the risk of recurrent CDI with PPI use is divided [27, 28]. New guidelines from the American College of Gastroenterology for the diagnosis, treatment, and prevention of CDI have recently been published [29•]. Recurrent CDI (RCDI) is an increasingly recognized problem and poses a treatment challenge. Studies show approximately 15–30 % of patients develop recurrence of CDI following treatment of a first infection [30, 31]. Patients with RCDI are often treated with prolonged tapering or pulsed doses of antibiotics. More than two decades ago, Tvede and Rask-Madsen used a mixture of 10 different bacterial species to successfully treat five patients with RCDI who were deficient in Bacteroides bacteria [32•, 33]. Fecal microbiota transplant (FMT) has been proposed as an alternative to the more traditional treatments for RCDI. FMT involves the transfer of stool from a healthy donor into the gastrointestinal tract of the patient via enema, nasogastric tube, or endoscopically. Small case series have shown significant success rates [34, 35], even in patients infected with the virulent Nap1 BI/027 strain, suggesting FMT appears to be an effective therapy for RCDI. A systematic review included 317 patients across 27 case series with RCDI treated with FMT. Disease resolution occurred in 92 % of cases [36]. The first randomized controlled trial of FMT for RCDI was recently published. Patients with RCDI (defined as relapse of CDI after at least one course of adequate antibiotic therapy) were randomized to one of three treatment groups: an initial vancomycin regimen followed by bowel lavage and subsequent infusion of donor feces, a standard vancomycin regimen, or a standard vancomycin regimen with bowel lavage. Resolution of C. difficile-associated diarrhea occurred in 81 % of patients in the infusion group after the first infusion, 31 % of patients in the vancomycin only group, and 23 % of patients in the vancomycin with bowel lavage group. No significant differences in adverse events among the three study groups were observed except for mild diarrhea and abdominal cramping in the infusion group on the infusion day [37•]. While the study was stopped early, could not be blinded by its nature, and has
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been criticized for its small numbers of patients, it remains the first randomized controlled trial of FMT for RCDI. An additional NIH-funded trial is underway using colonoscopy to deliver the FMT (personal communication, Dr. Colleen Kelley, Providence RI). Conceptually, FMT is used in an effort to reconstitute the disrupted intestinal microbiota of a patient and thus provide protection against infection. Khoruts et al. assessed the intestinal microbiome of CDI patients both pre- and post-FMT and found that 2 weeks after transplant, the recipient’s microbiota was similar to that of the donor stool with a dominance of Bacteroides sp. These effects were demonstrated to last up to 33 days [38]. Attempts are being made to elucidate the mechanism by which disruption of the normal intestinal flora increases susceptibility to CDI. Antibiotic-mediated depletion of bacteria involved in the modification of bile acids [32•, 39, 40], depletion of other bacteria involved in the production of short-chain fatty acids (SCFAs) [32•, 41], and increased production of sialic acids, which may serve as an energy source of C. difficile, following antibiotic use have all been proposed as mechanisms by which alteration of the normal gut microbiota leads to increased susceptibility to CDI [42, 43•].
Therapy Oral Rehydration Therapy Oral rehydration solution (ORS) has been a key resource in the treatment of acute diarrhea in the developing world since the 1970s. An excellent review has recently been published [44•]. The initial solution, referred to as the WHO-ORS, was iso-osmolar and provided Na (and thus fluid) and glucosemediated Na absorption in the small intestine via a cyclic AMP-independent process [45, 46]. It was later demonstrated that hypo-osmolar solutions performed better than the initial iso-osmolar solution [47]. However, despite long-standing proven efficacy in limiting dehydration and metabolic acidosis (MA) in acute diarrhea, the use of ORS has been somewhat limited. The lack of widespread use of ORS has been postulated to be due, in part, to its inability to reduce stool output dramatically. This has led to efforts to develop a solution that not only treats dehydration and MA but also reduces stool output. As previous solutions aimed to increase fluid absorption in the small intestine only, reducing stool output necessitates developing a solution that also increases fluid absorption in the colon. The use of resistant starches (RS) [48–50] and fermentable substances (FS) [51] has been proposed as mechanisms by which SCFAs could be delivered to the colon, instead of being digested in the small intestine, taking advantage of SCFA-mediated Na absorption in the colon. A specific RS (high-amylose maize starch or HAMS-ORS) was shown
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in three studies to be associated with a 30–50 % reduction in time to first stool [48–50]. The mechanism includes glucosemediated absorption of Na in the small intestine, with the addition of HAMS fermentation to SCFA in the colon stimulating colonic Na absorption and reduction of stool output [44•]. Efforts are ongoing to develop a HAMS-ORS that can be further tested for efficacy and safety prior to implementation in the developing world.
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0.34; 95 % confidence interval (CI), 0.24–0.49]. There were no significant differences in adverse events between the two groups [62•]. However, a recent large, randomized, doubleblinded, placebo-controlled trial (PLACIDE trial) showed that a multi-strain preparation of lactobacilli and bifidobacteria showed no benefit when compared to placebo at preventing AAD or CDI [63]. Given these findings, the use of probiotics for prophylaxis or treatment of a first case of AAD or CDI is controversial.
Zinc Zinc is emerging as an adjunct therapy in the treatment of acute diarrheal illness. It is estimated that zinc deficiency may contribute to 176,000 diarrhea-related deaths in children under 5 years of age per year [52]. Multiple reviews in the early 2000s demonstrating the benefit of zinc supplementation in the setting of acute diarrhea led to the WHO-UNICEF joint statement in 2004 recommending the use of zinc supplementation for 10–14 days for the clinical management of acute diarrhea [53]. In 2013, a Cochrane review of 24 randomized trials comparing oral zinc supplementation with placebo in children aged 1 month to 5 years with acute or persistent diarrhea was published. Nine thousand one hundred twenty eight children were included in the trials, which demonstrated that in children older than 6 months with acute diarrhea, zinc supplementation may shorten the duration of diarrhea by about 10 h and probably reduces the number of children whose diarrhea persists until day seven. In children with signs of moderate malnutrition, the effect appears greater, reducing the duration of diarrhea by about 27 h [54]. The mechanisms by which zinc supplementation provides benefit in acute diarrhea are under extensive review. Enteric pathogens cause diarrhea by altering fluid secretion via four intracellular signaling pathways: cAMP, cGMP, intracellular calcium, and nitric oxide [55, 56]. Studies have shown that zinc interferes with at least three of these pathways [57, 58]. Other proposed mechanisms include the role of zinc in intestinal mucosal integrity [59] and its role in generalized immunity [60]. Probiotics Multiple studies since have also sought to identify specific bacteria that, when given, confer protection against antibioticassociated diarrhea (AAD) or CDI. Meta-analyses have demonstrated efficacy of probiotics in the prevention of AAD [61]. A Cochrane review in 2012 included 20 randomized controlled trials with adult or pediatric patients receiving antibiotics. These trials compared any strain or dose of a probiotic with placebo or with no treatment control and reported the incidence of CDI. Three thousand eight hundred eighteen patients met eligibility criteria. Probiotics were shown to reduce the incidence of CDI by 66 % [pooled relative risk of
Post-infectious Irritable Bowel Syndrome Post-infectious irritable bowel syndrome (PI-IBS) has been defined as the onset of new IBS-like symptoms (by Rome criteria for IBS) in an individual who has not previously met the Rome criteria, following an acute illness characterized by two or more of the following: fever, vomiting, diarrhea, or a positive bacterial stool culture [64]. PI-IBS was first recognized in 1950 [65] and has gained more recognition in recent years. Multiple studies from the mid-1990s to present report that 6–17 % of patients with IBS symptoms developed their symptoms after an episode of gastroenteritis, either bacterial or viral [66]. The mechanisms by which patients develop PI-IBS may include changes in the microbiota, inflammation, and motility. It has long been known that acute diarrheal illness can change the gut microbiota [67], and alterations in gut microbiota have been shown to occur in patients with IBS [68]. PI-IBS may be related to continued low-grade inflammation of the GI tract following an episode of infective diarrhea, as inflammation of the GI tract has been shown to affect its sensorimotor function and development of functional bowel disease [66, 69]. Pimentel et al. developed a rat model of PI-IBS in which they colonized rats with Campylobacter jejuni and showed that 3 months after clearance of the infection, the rats demonstrated altered stool frequency, consistency, and gut lymphocytosis using real-time PCR, all findings that have been demonstrated in patients with IBS [70]. Further efforts to elucidate the mechanism by which patients develop PI-IBS are underway and may provide insight into potential treatment options.
Conclusion The field of infectious diarrhea continues to evolve. Recent outbreaks highlight this as pathogens demonstrate new virulence properties, new vehicles for infection, and increasing antibiotic resistance. Other common infections, such as CDI, have demonstrated a change in epidemiology. In addition, new scientific advances continue to provide greater understanding of the mechanism by which infectious agents cause
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diarrhea, have led to new therapies such as fecal microbiota transplant, and have identified targets for future areas of research.
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Compliance with Ethics Guidelines Conflict of Interest Brandon Dickinson and Christina M. Surawicz have nothing to disclose.
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Human and Animal Rights and Informed Consent This article does not contain any studies with animal subjects performed by any of the authors. With regard to the authors’ research cited in this paper, all procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000 and 2008.
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