1980 SPILLER AND GARSED GASTROENTEROLOGY Vol. 136, No. 6 available for analysis; in this case, the diagnosis must rely on suggestive symptoms alone. E

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1 GASTROENTEROLOGY 2009;136: Postinfectious Irritable Bowel Syndrome Robin Spiller Klara Garsed Nottingham Digestive Diseases Centre Biomedical Research Unit, University Hospital, Nottingham, England Approximately 1 in ten patients with irritable bowel syndrome (IBS) believe their IBS began with an infectious illness. Prospective studies have shown that 3% to 36% of enteric infections lead to persistent new IBS symptoms; the precise incidence depends on the infecting organism. Whereas viral gastroenteritis seems to have only short-term effects, bacterial enteritis and protozoan and helminth infections are followed by prolonged postinfective IBS (PI-IBS). Risk factors for developing PI-IBS include, in order of importance, prolonged duration of initial illness, toxicity of infecting bacterial strain, smoking, mucosal markers of inflammation, female gender, depression, hypochondriasis, and adverse life events in the preceding 3 months. Age older than 60 years might protect against PI-IBS, whereas treatment with antibiotics has been associated with increased risk. The mechanisms that cause PI-IBS are unknown but could include residual inflammation or persistent changes in mucosal immunocytes, enterochromaffin and mast cells, enteric nerves, and the gastrointestinal microbiota. Adverse psychological factors contribute to persistent lowgrade inflammation. The prognosis for patients with PI-IBS is somewhat better than for those with unselected IBS, but PI-IBS can still take years to resolve. There are no specific treatments for PI-IBS; these should be tailored to the predominant bowel disturbance, which is most frequently diarrhea. Infectious enteritis is a common event with variable outcomes. Although in most cases a full recovery occurs rapidly, symptoms can persist for many years and some patients eventually meet the criteria for a diagnosis of irritable bowel syndrome (IBS). It is important to discuss the epidemiology and clinical features of postinfectious irritable bowel syndrome (PI-IBS) to understand the mechanisms that underlie it and the treatments available for patients with this disorder. IBS represents a substantial and often difficult clinical problem that accounts for up to 40% of gastroenterology outpatients. 1 Patients with IBS have a range of psychosocial and gastroenterological disturbances, but it is difficult to sort the causes from the effects, especially for chronic diseases. PI-IBS is important to study because its underlying mechanisms will help us understand other subtypes of IBS. The features of PI-IBS are similar to those of the IBS subgroup with diarrhea 2 ; 6% to 17% of patients with IBS believe their symptoms began with an infective illness. 3 PI-IBS can therefore be regarded as a natural experiment in which an insult in the form of an infective illness impacts on an individual with underlying genetic and psychosocial predispositions who then develops IBS. Unlike other patients with IBS, there is a clear onset in time and well-defined pathophysiological changes. Measuring the psychological and pathophysiological features has allowed us to compare the relative importance of these different factors. A patient s outcome depends on predisposing host factors, the nature of the infecting organism, and the host response to this insult. Definition For the purpose of this review, and in the absence of biomarkers, we will use the relevant Rome criteria for IBS. 4 We define PI-IBS as the acute onset of new IBS symptoms in an individual, who has not previously met the Rome criteria for IBS, immediately following an acute illness characterized by 2 or more of the following: fever, vomiting, diarrhea, or a positive bacterial stool culture. 5 Although studies should ideally identify patients with PI-IBS based on a combination of symptoms and positive stool cultures, many patients develop acute diarrhea while abroad, so positive stool cultures are not always Abbreviations used in this paper: 5-HT, 5-hydroxytryptamine; IBS, irritable bowel syndrome; IBS-D, irritable bowel syndrome with diarrhea; PI-IBS, postinfective irritable bowel syndrome; RR, relative risk by the AGA Institute /09/$36.00 doi: /j.gastro

2 1980 SPILLER AND GARSED GASTROENTEROLOGY Vol. 136, No. 6 available for analysis; in this case, the diagnosis must rely on suggestive symptoms alone. Epidemiology Infective diarrhea is one of the most common illnesses worldwide. Official statistics for infection substantially underrepresent the problem. A large community survey of 9776 individuals in England and Wales showed that the annual incidence of gastrointestinal infection was 19.4 per 100 person-years, of which only 1 in 136 was reported to a national surveillance database. 6 Approximately 35% of cases in this survey were caused by viral infections, mostly norovirus and rotavirus; bacterial infections are also important, with Campylobacter spp and Salmonella spp accounting for 10% and 3% of the cases, respectively. This has an important bearing on the probability of developing PI-IBS, because this disorder occurs less frequently following viral gastroenteritis than after infection associated with mucosal ulceration, such as Campylobacter jejuni and Escherichia coli O157:H7. Half of the reports documenting the occurrence of PI-IBS have been of outbreaks of infection with a single organism (Table 1). The percentage of infected individuals who develop PI-IBS varies from 3.7% to 36%. The study from the Walkerton outbreak 7 reported the highest incidence of PI-IBS, which was 36% at 24 months after a dual infection with both C jejuni and the particularly virulent form of E coli O157:H7. C jejuni infection was associated with a PI-IBS risk of 9% to 13%. 2,8 The only analysis of a viral outbreak suggested that although norovirus infection produced new IBS symptoms in about 25% of cases after 3 months, by 6 months the incidence was no different in infected versus control individuals, 9 suggesting that PI-IBS following viral gastroenteritis is a transient entity. This explains why PI-IBS is not more common since bacterial gastroenteritis occurs much more frequently than infective gastroenteritis. A community series study of unselected patients with bacterial infections, of which only 10% were admitted to the hospital, reported a PI-IBS incidence of 7%, 10 whereas the only other study of unselected patients with bacterial infections reported a much higher incidence (29%). However, this study was restricted to patients admitted to an infectious diseases hospital, who are likely to be much more severely affected. 11 These studies indicate that the varying incidence of PI-IBS associated with different infections reflects the variable severity of damage to the bowel. Recent norovirus studies have shown that although this infection causes villous blunting and a reduction in villous surface area, there is very little tissue destruction. 12 The main changes that occur are increases in intestinal permeability and numbers of intraepithelial lymphocytes but no ulceration and little tissue damage; the mucosal structure is likely to rapidly return to normal, as has been shown in rats. 13 Clinical Features of PI-IBS The majority (63%) of cases of PI-IBS following C jejuni associated enteritis meet the Rome II criteria for IBS with diarrhea (IBS-D), with predominantly loose stool passed more frequently than normal and with urgency. About 24% of cases have an alternating pattern, Table 1. Incidence of PI-IBS Author, year of publication Percentage with PI-IBS Follow-up period (mo) No. infected Organism Setting McKendrick and Read, S enteritidis Elderly care a Gwee et al, Mixed bacterial Infectious diseases hospital Neal et al, Mixed bacterial Community Thornley et al, C jejuni Community Dunlop et al, C jejuni Community Ilnyckyj et al, Traveler s diarrhea Travelers Okhuysen et al, Traveler s diarrhea Travelers Wang et al, Shigella spp Community a Ji et al, Shigella spp Community a Mearin et al, Salmonella Community a Marshall et al, C jejuni E coli O157 Community a Borgaonkar et al, Mixed Community Stermer et al, Traveler s diarrhea Travelers Moss Morris and Spence, C jejuni and Epstein Barr Community virus Dizdar et al, Giardia duodenalis Community a Soyturk et al, Trichinella britovi Community Marshall et al, Norovirus Travelers a 12 NS vs control Norovirus Travelers a C jejuni Community Saps et al, Mixed bacterial Pediatric hospital NOTE. There is a wide range of percentages developing PI-IBS that appears to be related to the type of organism. a Outbreak of infectious diarrhea.

3 May 2009 POSTINFECTIOUS IBS 1981 and 13% report constipation. 2 Bloating and increased frequency of passing mucus per rectum have also been reported. 10 Physiological studies show accelerated colonic transit and a decreased threshold for discomfort and pain during rectal balloon distention. 14,15 Risk Factors for PI-IBS As with IBS in general, understanding the risk factors for the syndrome is best considered using a biopsychosocial model that includes influences from both the brain and the gut 16 (see Figure 1). Genetic Factors Predisposition to different types of infections depends on genetic factors, such as polymorphisms in genes that encode cytokines. 17,18 Genetic studies of predisposition to IBS are limited; none have been specifically related to PI-IBS. One study reported that a heterozygous mutation that results in high-level expression of tumor necrosis factor (G/A polymorphism at position 308) was found in 41% of patients with IBS compared with 26% of controls (P.02). 19 The number of patients with PI-IBS included in this study was too small to show significant differences in the incidence of different genotypes compared with controls. A previous study had concluded that fewer patients with IBS compared with controls had a genotype that caused high-level expression of interleukin-10, 20 but this finding was not confirmed in a later study. 19 However, it is clear that there might be a genetic predisposition toward severe inflammation that contributes to an increased incidence of postinfective symptoms. Psychosocial Factors Childhood rearing practices have a strong effect on the chances that a person will develop IBS. Childhood IBS was more common in children who were frequently absent from school and those whose mothers made solicitous responses to complaints of illness. 21 A large twin pair study showed increased concordance for IBS in monozygotic compared with dizygotic twins (17.2% vs 8.4%), supporting a genetic component to IBS, but in that study having a mother or father with IBS was an independent predictor of IBS and a stronger predictor than having a twin with IBS. This indicates that social learning has an equal or greater influence than genetic factors. 22 Illness beliefs and behavior are usually established in childhood and might be expected to impact on the response to an infectious illness. One study that has examined this prospectively found that those who developed PI-IBS had greater anxiety and somatization and more negative illness beliefs. 23 Several psychological factors have been shown to affect the risk of developing PI-IBS. These include hypochondriasis, somatization, and neuroticism, although in multivariate analysis, only hypochondriasis was an independent risk factor (relative risk [RR], 2.0; 95% confidence interval [CI], ). 11 The same study showed that adverse life events in the preceding 3 months resulted in a similar increase in risk (RR, 2.0; 95% CI, ), 14 and other studies suggest depression is also an important factor; each standard deviation increase in depression score increased the risk of developing PI-IBS 3.2-fold. 2 Regrettably, few PI-IBS studies have included psycholog- Figure 1. Interaction between local inflammation and psychosocial factors in determining the risk of developing PI-IBS. Psychological and intestinal factors are both important determinants of PI-IBS risk. Several studies have evaluated risk levels associated with the following: adverse life events and hypochondriasis 14 ; depression, lymphocytosis, and enterochromaffin cell hyperplasia 2 ; age younger than 60 years, female gender, and duration of initial illness 3 weeks 10 ; and elongating toxin of C jejuni. 8

4 1982 SPILLER AND GARSED GASTROENTEROLOGY Vol. 136, No. 6 ical variables. However, in a large prospective populationbased study of the onset of IBS, psychosocial factors were found to be an important determinant. 24 A multivariate analysis of unselected patients with IBS showed that high levels of illness behavior such as visiting doctors, anxiety, sleep problems, and somatic symptoms were all independent predictors of new-onset IBS, 24 although it should be noted that these were not patients with PI-IBS. A study of patients in Nottingham showed that bowel dysfunction after C jejuni infection was associated with an increased somatization score, 25 suggesting that preexisting behavior patterns were important predictors of outcome. The more anxious and hypochondriacal patients are, the more likely they are to seek medical attention; patients with IBS are 4-fold more likely than those without IBS to present with stool culture positive gastroenteritis. 26 However, most studies on PI-IBS have been careful to exclude those with preexisting IBS, which should reduce this source of bias that could inflate the true incidence of PI-IBS. The effect of psychological factors should not, however, be overly emphasized. It is worth noting that the impact of anxiety and depression on the development of PI-IBS is much less than it is on the development of chronic fatigue syndrome. 27 In a large study comparing postinfectious syndromes after C jejuni infection with those that occur after Epstein Barr virus infection, significant anxiety was found to occur in 53% of individuals who developed chronic fatigue syndrome but only a minority (34%) of the patients who developed PI-IBS; this is a rate only slightly higher than the 21% incidence in infected controls, who did not develop any functional gastrointestinal symptoms. Similarly, the incidence of depression was 43% in the new chronic fatigue syndrome cases but only 17.6% in those with PI-IBS, which is only slightly greater than the 12.5% incidence of depression among the controls. Interestingly, smoking substantially increases the risk of PI-IBS, with an odds ratio of 4.8 (95% CI, ). 28 There are no obvious mechanisms by which smoking might directly cause PI-IBS. Nicotine has been suggested to have anti-inflammatory effects. 29 However, smoking is a marker of other factors, such as neuroticism, 30 that also contribute to the risk of PI-IBS, 14 so the effect could be indirect. Bacterial Factors A wide variety of infections have been associated with PI-IBS with differing incidence rates. However, comparison between studies at different sites is confounded by many other differences. Comparing infections within a single-center study is a more reliable way of assessing the RR associated with bacterial type. One study showed that C jejuni infection was associated with a 10% risk of PI-IBS, whereas the risk associated with Salmonella spp infection was substantially lower. 10 The importance of bacterial factors in the pathogenesis of PI-IBS becomes more clear when just a single organism is studied. We found that infection with C jejuni strains that produce a specific toxin that elongates Chinese hamster ovary cells increased the risk of developing persistently deranged bowel habits, with an RR of 12.8 (95% CI, ). 8 A surrogate marker for bacterial toxicity is the duration of the initial illness; an illness lasting more than 3 weeks had an RR of 11.4 (95% CI, ) for PI-IBS, compared with those with an illness lasting less than 8 days. 10 Likewise, a study of Shigella spp enteritis showed an illness lasting 14 days had an RR of 4.6 (95% CI, ) compared with an illness lasting 8 days. 31 Antibiotics Several studies have reported that patients who have received antibiotics had more and longer-lasting IBS symptoms. Thus, the prevalence of dyspepsia and IBS in patients who were given antibiotics following infection with Salmonella enteritidis was 17.6%, compared with 9.3% in those who did not receive antibiotics. 32 Although this difference was not significant, studies of a different S enteritidis outbreak found that persistent symptoms of vomiting, abdominal pain, and diarrhea were significantly increased in patients who received antibiotics compared with those who did not (9.5% vs 2.9%). 33 Likewise, the RR of developing IBS in individuals with traveler s diarrhea who received antibiotic treatment was 4.1 (95% CI, ). 34 It should be noted that without a randomized placebo-controlled study, it is not clear whether the association of PI-IBS with antibiotic therapy is direct or is confounded by premorbid hypochondriasis or more severe illnesses that lead to antibiotic prescriptions. Sex and Age The majority of the studies discussed found that women were at increased risk for PI-IBS compared with men. Noted exceptions occurred during outbreaks of S enteritidis infection in Spain, 32 Shigella spp in China, 31 and traveler s diarrhea in Israel. 34 The odds ratios in other studies ranged from 2 to 3. However, there is a confounding factor; female patients have a higher incidence of psychological disorders, including anxiety and depression. When multivariate analysis was performed, the effect of gender disappeared from 2 studies 2,14 but not from another large study that showed that female gender was an independent factor, even when anxiety was factored in, resulting in a PI-IBS RR of 2.36 (95% CI, ). This study also showed that the RR was 1.82 (95% CI, ) for patients with anxiety. 27 In patients with severe infections, such as during the Walkerton outbreak, female gender had a smaller effect; the RR was just 1.5 (95% CI, ) for PI-IBS. 35 Very old or young age does not exclude people from developing PI-IBS; the first report of this disorder came from an elderly persons home. 36 However, in a large community survey, age older than 60 years was found to

5 May 2009 POSTINFECTIOUS IBS 1983 be protective, with an RR of 0.36 (95% CI, ) for developing persistent changes in bowel habit, although this might be related to immunity due to prior exposure. 10 However, other studies have failed to show an age effect. 27,32 Mechanisms Acute infectious diarrhea is rarely investigated invasively because the illness often resolves without specific treatment. Therefore, little is known about its pathogenesis. Mucosal Injury and Inflammation Studies of the norovirus indicate that acute villous blunting and infiltration with intraepithelial lymphocytes are associated with increased gut permeability and loss of villous surface area. 12 The brunt of the infection in giardiasis is born in the proximal part of the small intestine with acute lymphocytic infiltration, 37 whereas in cases of bacterial enteritis, inflammation and ulceration occurs more distally, with involvement of the terminal ileum and proximal colon in Salmonella spp and C jejuni enteritis and more distal colonic disease in Shigella spp enteritis. 38 The different distribution of inflammation influences symptoms both during and after infection. Postinfectious symptoms are predominantly dyspepsia, early satiety, and anorexia following giardiasis, 39 whereas diarrhea dominates after shigellosis. 31 The recovery process depends on the severity of initial mucosal damage and, as already mentioned, occurs most rapidly in patients with viral gastroenteritis. A systematic prospective study of the recovery process has rarely been performed, but in one study of patients following C jejuni enteritis, serial biopsy specimens were collected at 2, 6, and 12 weeks after infection. This study showed increases in numbers of macrophages, T lymphocytes, and enteroendocrine cells at 2 weeks with a gradual return to normal levels thereafter. 40 Biopsy specimens were also collected 1 year after infection from a small subgroup with persistent symptoms; analyses of these revealed persistent increases in numbers of enteroendocrine cells and an increase in the proportion that were serotonin positive. 40 Persistent enterochromaffin cell hyperplasia was also observed in another study of patients at 3 months after C jejuni infection, 2 but the effects were reported to be less striking in a subsequent study. 41 No changes in enterochromaffin cell numbers were found in an unselected group of patients with IBS from the United States, 42 although increased numbers were seen in patients with the irritable pouch syndrome following colectomy and those with ileal pouch formation who had diarrhea, even in the absence of inflammation. 43 Another study found no difference in enterochromaffin cell counts in patients with IBS and diarrhea compared with controls but did find an inverse relationship between the number of enterochromaffin cells in the rectum and maximally tolerated pressures during rectal distention, suggesting that these cells have a role in visceral hypersensitivity, a feature that is characteristic of IBS. 44 Infection of mice with Trichinella spiralis is a model that has similarities with PI-IBS; these mice develop disordered motility and increased visceral hypersensitivity that lasts for many weeks after the infection has been cleared. 45 T spiralis infection is followed by enterochromaffin cell hyperplasia, which is mediated by T lymphocytes. 46,47 The enterochromaffin cell hyperplasia in this model is associated with increased 5-hydroxytryptamine (5-HT) content and release, together with increased afferent nerve firing following distention. These effects are likely to be mediated by 5-HT because they can be blocked by the 5-HT 3 receptor antagonist ondansetron. 48 The functional significance of increased enterochromaffin cells in humans is uncertain, but one study showed that postprandial blood levels of serotonin increased in a small group of patients with PI- IBS. 41 However, it should be noted that enterochromaffin cell hyperplasia is not a universal response to infection; infection of mice with Citrobacter rodentium, a model of enteropathogenic E coli infection, actually reduces enterochromaffin cell counts. 49 Mast Cell Hyperplasia Mast cell hyperplasia is commonly observed following infection with T spiralis or Shigella spp; the effect is most marked in the terminal ileum but found equally in those with PI-IBS and non PI-IBS. 31 This increase in mast cell numbers could be important because other studies have related mast cell proximity to enteric nerves with the severity of abdominal pain in patients with IBS. 50 Analysis of mucosal biopsy samples has shown that the mucosa releases mediators that activate afferent nerves 51 and might therefore mediate the visceral hypersensitivity that is characteristic of PI-IBS 14,15 and other subtypes of IBS, 52 particularly in female patients 53 and those with diarrhea. 53,54 Mast cell activation might be a means whereby psychological factors perpetuate mucosal inflammation; in animal studies, stress was observed to increase mast cell counts and activation. 55 Human studies support this finding indirectly; thus, in IBS, both fatigue and depression scores correlated significantly with the cellularity of the lamina propria and mast cell counts. 56 Other human studies have reported mast cell hyperplasia in jejunal biopsy specimens of stressed patients with IBS. 57 Changes in Enteric Nerves Animal models of infection have shown that significant changes occur in enteric nerves, with alterations in neurochemical coding, including increased production of substance P. 58 Chemical inflammation also up-regulates tachykinins and other neuropeptides in the mucosa and myenteric muscle. 59 Similar changes, observed through increased staining for the paneuronal markers neuron-specific

6 1984 SPILLER AND GARSED GASTROENTEROLOGY Vol. 136, No. 6 enolase and substance P, were observed in the terminal ileum and rectum tissues of patients with PI-IBS after Shigella spp infection. 31 However, in this study, similar changes were seen in non PI-IBS patients, so these effects might not be specific. Recently, another group has shown increased TRPV-1 positive neuronal fibers in the rectum tissues of unselected patients with IBS, 60 a change that was also reported in patients with inflammatory bowel disease (IBD). 61 Inflammatory Cytokines T-lymphocyte infiltration has been reported in several studies of patients with IBS-D 62 as well as PI- IBS. 2,14 Several recent studies have also shown increased inflammatory cytokines in serum (increases in interleukin-6 and interleukin-8) 63 and peripheral blood mononuclear cells, 64 although it is not clear whether these reflect immune activation within the intestine. One study showed that production of the cytokines interleukin-1, tumor necrosis factor, and interleukin-10 increased in peripheral blood mononuclear cell samples from patients with PI-IBS, although these also increase in patients with IBS-D and no history of infection. 65 It is not clear whether these changes originate from inflammation in the gastrointestinal tract or result from psychological stressors, because peripheral blood mononuclear cell production of cytokines is also altered by psychological stress. 66 The interactions between the nervous and immune systems make it vital that future studies include analyses of both psychological and immunologic parameters. Changes in Gastrointestinal Microbiota Following Infective Enteritis The acute diarrhea that is associated with infective gastroenteritis leads to a profound depletion of the commensal flora, 67 followed by a loss of normal fermentation products, particularly short-chain fatty acids, with an associated increase in luminal ph. This allows overgrowth of organisms that are usually inhibited by the abundant short-chain fatty acids. 68 Animal studies have shown that S enteritis infection results in a depletion of the colonic microbiota that is believed to result from the host immune response as well as the associated diarrhea. 69 Similar changes were observed in mouse models developed using C rodentium or chemical-induced colitis. 70 Seven days after infection with C rodentium, bacterial counts decreased to 20% that of control levels and only slowly recovered. The depletion appeared to result from intestinal inflammation, because colonization by similar numbers of C jejuni in mice, which does not induce inflammation, did not deplete the microbiota. Salmonella infection appeared to induce a preferential elimination of the Cytophagia-Flavobacter-Bacteroides class of bacteria. Similar changes were observed in mice with dextran sulfate sodium induced colitis, but there was also an associated overgrowth of Enterobacteriaceae. 70 Inflammation and associated diarrhea induced changes in the intestinal microbiota by allowing colonization by aerotolerant bacteria, a feature that has been frequently reported in patients with Crohn s disease. 71 Recent studies in animal models have suggested that in the rat, C jejuni infection can lead to bacterial overgrowth in the small bowel 72 ;itis important to determine if this also occurs in humans. Also, some infections, such as with T spiralis, lead to a prolonged disturbance in intestinal motility 45 that might interfere with the normal protective mechanisms that prevent bacteria growth in the small intestine. In human disorders, disruption of normal fasting motility and loss of the migrating motor complex are associated in other conditions with small intestinal bacterial overgrowth. 73 Studies of small intestinal bacterial overgrowth associated with postgastrectomy blind loops and duodenal and jejunal diverticulosis originally reported the classic clinical features of abdominal pain, nausea, bloating, and obvious malabsorption with anemia, hypocalcemia, and fat malabsorption. Patients with IBS, by definition, lack these classic features. Reports of small intestinal bacterial overgrowth in patients with IBS relied on the lactulose breath hydrogen test, 74 which most researchers agree has a high false-positive rate. 75,76 Other studies have suggested that the incidence of small intestinal bacterial overgrowth in unselected patients with IBS is low (approximately 4%) and not significantly different from that of controls, 77 although little is known about small intestinal bacterial overgrowth in patients with PI-IBS. Several clinical trials have been performed using antibiotics with the intention of eradicating small intestinal bacterial overgrowth, and although some have shown significant differences from the placebo group, 78,79 the trials have used unvalidated end points and the significance of any effect remains uncertain. 80 It remains unproven whether the antibiotic benefits via action on the small bowel or the colonic microbiota; suppression of microbiota activity by metronidazole or a low-fiber diet can also improve symptoms of bloating and abdominal pain. 81 Given the known association between antibiotic consumption and IBS, 82,83 along with the deleterious and potentially dangerous disturbance of the gastrointestinal microbiota and overgrowth of C difficile that occurs following broad-spectrum antibiotic use, 84 antibiotic therapy cannot be recommended for patients with PI-IBS until there is better evidence of benefit. Furthermore, as already discussed, some studies have reported that antibiotic treatment significantly increases the risk of PI-IBS. Differential Diagnosis of PI-IBS: Lactose Intolerance, Bile Acid Malabsorption, and Rare Postinfection Syndromes Acute acquired hypolactasia following gastroenteritis is well recognized in children, and its effects are

7 May 2009 POSTINFECTIOUS IBS 1985 usually short lived. 85 There is only one study in adults with PI-IBS; it found that lactose intolerance did not occur in any of the 24 adults with PI-IBS 3 to 6 months following infection, 86 suggesting that testing for lactose intolerance is unlikely to be useful in management of this condition. The occurrence of bile acid malabsorption following infectious gastroenteritis has been well documented. 87,88 One characteristic feature that can distinguish cases of bile acid malabsorption from those of PI-IBS is nocturnal, high-volume diarrhea. Patients with bile acid malabsorption often show markedly abnormal retention of the Selenium 75 -labeled bile salt, Se 75 -homocholic acid taurine, with 5% retained 1 week after dosing. 88 The same study showed that these patients all had positive responses to the bile salt binding agent cholestyramine. IBD, particularly ulcerative colitis, can begin acutely; in 3% of patients, enteric infections are detected in stool cultures. 89 However, the true incidence at which IBD develops after acute enteritis is hard to assess. It appears to be an extremely rare event, according to at least one study of the United Kingdom General Practice Research Database of 4113 patients with acute infectious gastroenteritis whose records were available for a mean of 3.5 years after the infection. 90 The study found an increased incidence of IBD at 68 of 100,000 person-years compared with the controls (30 of 100,000 person years), with the odds ratio for developing IBD following gastroenteritis found to be 2.4 (95% CI, ). The risk of developing IBD doubled in patients who received antibiotics; this association might reflect an increased severity infection. However, it could also be causal if antibiotics allow overgrowth of certain organisms such as C difficile, which has been associated with exacerbation of IBD. 91 However, it should be emphasized that the absolute rate of 1 in 1000 personyears is extremely low compared with the rate of approximately 10% of patients who develop IBS after infection. Lymphocytic colitis is a rare condition (annual incidence of 5 per 100,000 people) that has been reported at least in one individual to follow gastroenteritis caused by infection with C jejuni 92 ; furthermore, a large survey reported that 25% of all cases of lymphocytic colitis presented acutely. Because 63% of lymphocytic colitis cases occurred as only a single attack, it is possible that these were caused by an unrecognized infection. 93 Other differential diagnoses might include celiac disease, which can mimic IBS, 94 but again this is probably extremely rare because in our experience of more than 450 cases of PI-IBS following C jejuni infection studied from 1997 to 2007, only one such case has been detected. Diverticulitis is another acute gastrointestinal infection that is frequently followed by recurrent abdominal pain and diarrhea and can mimic IBS. 95 Its pathogenic mechanism is unclear, but after resolution of the acute infection, tissue samples from patients with persisting symptoms have been shown to have increases in staining for substance P and galanin in enteric nerves in the mucosa and muscle. 96 Tropical sprue is another diarrheal disease that might mimic PI-IBS and has been reported to occur in epidemics, suggesting an infectious origin, 97 but this is not well documented and further studies are needed. Prognosis of PI-IBS Prolonged follow-up studies of PI-IBS are scarce. One of the earliest studies reported that 5 years after onset, 5 of 11 patients with PI-IBS after S enteritidis infection still had diarrhea more than once each week. 98 Other studies found that 8 of 14 patients still had persistent symptoms 5 years after infection. 99 According to this study, patients with a history of treatment for anxiety or depression were unlikely to recover, a conclusion similar to that of a much earlier study. 100 A recent metaanalysis gives some indication as to the evolution of symptoms; it showed that the risk of PI-IBS decreases substantially with time after infection. Odds ratios were 7.6 at 3 months, 5.0 at 6 months, 6.4 at 12 months, and 3.8 at 36 months, suggesting that patients with PI-IBS can expect a gradual recovery. 99 Management of PI-IBS Therapy for PI-IBS should be adjusted to the severity of the patient s symptoms. Once the diagnosis has been formally established, the patient should be reassured that the prognosis is likely to be one of improvement rather than deterioration. Patients for which urgency and diarrhea are main concerns should be given loperamide, titrating the dose to obtain optimum effect. Patients with painful symptoms are often given low doses of amitriptyline. Although there have been no randomized controlled trials of this agent in patients with PI-IBS or IBS-D, clinical consensus supports its use for pain relief in those with IBS and its mild tranquilizing effect could also help reduce stool frequency. 101 Prednisolone was shown to be ineffective in reducing pain in one of the few randomized placebo-controlled trials in PI-IBS, although it did show an anti-inflammatory effect, reducing mucosal lymphocyte counts. 102 Recently, mesalazine has been proposed as a possible anti-inflammatory agent; preliminary results from a small randomized clinical trial showed that it reduced pain and stool frequency and improved stool consistency in patients with PI-IBS or IBS without an infectious origin. 103 Given the increase in postprandial 5-HT levels in patients with PI-IBS 41 and that 5-HT stimulate intestinal motility and secretion via the 5-HT 3 receptor, specific 5-HT 3 receptor antagonists would be a logical choice for therapy, although they have never been tested specifically in patients with PI-IBS. Alosetron, a 5-HT 3 receptor antagonist, was shown to be efficacious in patients with unselected IBS-D, reducing stool frequency and improving stool consistency. 104 Al-

8 1986 SPILLER AND GARSED GASTROENTEROLOGY Vol. 136, No. 6 though this study involved patients with unselected IBS-D, previous studies suggested that 6% to 17% of patients with IBS have PI-IBS 3 ; it is not known if these patients will have a better than average response to alosetron. However, given the importance of psychological disturbance in the prognosis of patients with PI-IBS, 99,100 antidepressants or psychotherapy might be indicated when psychological issues are prominent. Potential areas for future therapeutic development for PI-IBS include agents with anti-inflammatory effects, such as mesalazine, and those designed to correct a disturbance in the colonic microbiota, such as probiotics or poorly absorbed antibiotics. Additional high-quality randomized controlled trials are needed to enable gastroenterologists to recommend effective evidence-based treatment for patients with PI-IBS. References 1. Wells NE, Hahn BA, Whorwell PJ. 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