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Background: Rome IV criteria for functional gastrointestinal disorders state that children suspected of having Irritable Bowel Syndrome (IBS) with Constipation (IBS-C) should be preliminarily treated for constipation. We aimed at verifying if functional constipation may indeed lead to an erroneous diagnosis of IBS with diarrhea (IBS-D) or IBS with mixed pattern of diarrhea and constipation (IBS-M)., Methods: We prospectively enrolled in an unblinded fashion 10 and 16 consecutive children referred to our center who met Rome IV criteria for a diagnosis of IBS-D and IBS-M, respectively. Patients who fulfilled criteria for suspect "occult constipation" were then given a bowel cleaning regimen with Polyethylene glycol 3350, re-evaluated at 2 months and followed up for at least 6 months. Sixteen additional patients with IBS with Constipation (IBS-C) referred in the same period served as control. The endpoints were: 1) a decrease of more than 50% in abdominal pain intensity and frequency scores; and 2) for patients with IBS-D and IBS-M: resolution of diarrhea., Results: The endpoints were met by 8 (80%) and 14 (87%) of the patients with IBS-D and IBS-M, respectively, with decrease of abdominal pain and resolution of "diarrhea". The response was not significantly different from that observed in 15 (93%) of the IBS-C control group., Conclusion: Acknowledging the limitations of the small number of patients and of the uncontrolled nature of the study, we suggest that a possibly large number of patients labeled as IBS-D or IBS-M may actually simply present functional constipation and should be managed as such.

Probiotics are increasingly used for prevention and treatment of diarrhea more in children than in adults. Given the broad spectrum of diarrhea, this review focuses on the main etiologies: acute gastroenteritis, antibiotic-associated diarrhea (AAD), and necrotizing enterocolitis (NEC). For each, we reviewed randomized controlled trials, meta-analyses, and guidelines. For acute gastroenteritis we found 12 guidelines: 5 recommended probiotics and 7 did not. However, the guidelines containing positive recommendations provided proof of evidence from clinical trials and meta-analyses. Lactobacillus rhamnosus GG (LGG) and Saccharomyces boulardii had the most compelling evidence of efficacy as they reduced the duration of the disease by 1 day. For AAD 4 meta-analyses were found, reporting variable efficacy of probiotics in preventing diarrhea, based on the setting, patient's age, and antibiotics. The most effective strains were LGG and S. boulardii. For NEC, we found 3 randomized controlled trials, 5 meta-analyses, and 4 position papers. Probiotics reduced the risk of NEC enterocolitis and mortality in preterm babies. Guidelines did not support a routine use of probiotics and asked for further data for such sensitive implications. In conclusion, there is strong and solid proof of efficacy of probiotics as active treatment of gastroenteritis in addition to rehydration. There is solid evidence that probiotics have some efficacy in prevention of AAD, but the number needed to treat is an issue. For both etiologies LGG and S. boulardii have the strongest evidence. In NEC the indications are more debated, yet on the basis of available data and their implications, probiotics should be carefully considered.

Probiotics have been extensively studied over the past several years in the prevention and, to a larger extent, in the treatment of diarrheal diseases, especially in pediatric populations. Diarrhea is a symptom, and not a disease. This review will not address chronic disorders associated with diarrhea, or Clostridium difficile-induced diarrhea. Rather it will focus on published clinical trials performed on acute-onset, likely infectious diarrhea occurring in the settings of day-care centers, in the community, acquired in the hospital, antibiotic-associated diarrhea, and treatment of acute infectious diarrhea. For prevention of diarrhea acquired in day-care centers, 9 randomized and placebo-controlled trials have been published, conducted in different parts of the world. Probiotics tested were Lactobacillus GG, Bifidobacterium lactis (alone or in combination with Streptococcus thermophilus, and Lactobacillus reuteri, Lactobacillus rhamnosus (not GG), and Lactobacillus acidophilus, in various trials either alone or in comparison with each other. The evidence of their efficacy in these settings is only modest for the prevention of diarrhea, although somewhat better for prevention of upper respiratory infections. In the community, new trails conducted in underprivileged areas of India, again with modest efficacy. Previous trials that examined the potential role of probiotics in preventing the spreading of diarrhea in hospitalized children had yielded conflicting results. More recently, a large trial in Poland showed, however, rather good evidence of efficacy for Lactobacillus GG. The prevention of antibiotic-associated diarrhea has been the subject of many investigations, both in children and in adults. Most commonly used probiotics were Lactobacillus GG, Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium ssp, Streptococcus ssp, and the yeast Saccharomyces boulardii. In general, most of these trials do show clear evidence of efficacy, with the 2 most effective strains being Lactobacillus GG and S. boulardii. Evidence is also emerging on the importance of the dose in reducing the incidence of this type of diarrhea, and the incidence of Clostridium difficile-associated postantibiotic diarrhea. As for treatment, a large body of data is available, especially in children, on the effect of several strains of probiotics in treating sporadic infectious diarrhea. The vast majority of the published trials show a statistically significant benefit and moderate clinical benefit of a few, well-identified probiotic strains-mostly Lactobacillus GG and S. boulardii-in the treatment of acute watery diarrhea, and particularly those due to rotavirus. Such a beneficial effect results, on average, in a reduction of diarrhea duration of approximately 1 day. The effect is strain-dependent and dose-dependent.

This review focuses on the efficacy of probiotics for diarrhea in children in different settings: day-care centers, diarrhea acquired in the hospital, antibiotic-associated diarrhea, and treatment of acute infectious diarrhea. For prevention of diarrhea acquired in day-care centers, 5 randomized and placebo-controlled trials have been published. Probiotics tested were Lactobacillus GG, Bifidobacterium lactis (alone or in combination with Streptococcus thermophilus), and Lactobacillus reuteri. The evidence of their efficacy in these settings is only modest: statistically significant for some strains only and in any case of minimal to mild clinical importance. Few trials have examined the potential role of probiotics in preventing the spread of diarrhea in hospitalized children, an event most commonly due to either rotavirus or Clostridium difficile, and they have yielded conflicting results. Overall, these studies provide only weak evidence on the efficacy of probiotics. On the other hand, a large number of trials on the role of probiotics in preventing the onset of antibiotic-associated diarrhea have been published. Most commonly employed probiotics were Lactobacillus GG, Bifidobacterium spp., Streptococcus spp., and the yeast Saccharomyces boulardii. In general, these trials do show clear evidence of efficacy, with the 2 most effective strains being Lactobacillus GG and S. boulardii. Today, we have a large number of published clinical trials on the role of probiotics in treating sporadic infectious diarrhea in children, and many of them are randomized, blinded, and controlled. They consistently show a statistically significant benefit and moderate clinical benefit of a few, well-identified probiotic strains-mostly Lactobacillus GG and S. boulardii, but also L. reuteri-in the treatment of acute watery diarrhea, primarily rotaviral, in infants and young children of developed countries. Such a beneficial effect seems to result in a reduction of diarrhea duration of little more than 1 day, and to be exerted mostly on diarrhea due to rotavirus. The effect is not only strain-dependent, but also dose-dependent, with doses of at least 10 billion/d being necessary.

The use of probiotics in diarrheal diseases of children is increasing. Probiotics, mostly lactic acid bacteria such as Lactobacilli and Bifidobacteria, but also the yeast Saccharomyces boulardii, have been tried in many double-blinded, randomized, placebo-controlled studies, and several well-conducted meta-analyses are now available. There is some evidence of efficacy in the prevention of community-acquired and nosocomial diarrhea. More solid evidence of efficacy is found in the treatment of sporadic, infectious diarrhea, where several probiotics, and especially Lactobacillus GG, have been found capable of reducing by approximately 1 day the duration of diarrhea, shorten the initial phase of watery stools, and reducing hospital stay in developed countries. The effect is best documented in viral diarrheas. Although there are valid conceptual premises for probiotics to be helpful in inflammatory bowel diseases, only 1 trial has been published in children, showing Lactobacillus GG not to be superior to placebo in maintaining remission of Crohn disease. All considered, more research is needed for a better understanding of the role of probiotics in gastrointestinal diseases of children, addressing issues such as pharmacokinetics, mechanism of action, and role of specific probiotics, alone or in combination, in different disorders.

Diarrheal diseases continue to be a major cause of morbidity and mortality worldwide. Although new, potentially useful drugs such as acetorphan are appearing at the horizon, the cornerstone of treatment remains a proper oral rehydration (ORT). Yet, the rates at which ORT is used are still disappointingly low. Despite dramatic progresses in the understanding of the pathophysiology of diarrhea, the list of available drugs is indeed short. Recently however, several new options have appeared that may bear a great potential in the near future. The first is a potential improvement of ORS. It was recently shown that the addition of a resistant starch to oral rehydration solution reduces fecal fluid loss and shortens the duration of diarrhea in patients with cholera. Starches that are resistant to hydrolysis by amylase in fact generate in the colon short-chain fatty acids, which are known to enhance sodium absorption. The second development in treating diarrheal disease is acetorphan (racecadotril). This enkephalinase inhibitor has in fact been shown to be effective in reducing by almost half the stool output of 135 young children with acute diarrhea. Finally, probiotics. In the last few years, they have attracted a great deal of renewed interest, particularly focusing on their effects in treating and preventing diarrheal diseases. Lactobacillus GG proved effective in several clinical trials, mostly randomized and placebo-controlled, in the prevention and/or treatment of acute diarrheal disease in children. We have recently shown (6) the safety and efficacy in its administration in the ORS, especially in Rotavirus-induced diarrheas, in a large multicenter, randomized, double blind and placebo-controlled study conducted on behalf of the ESPGHAN Working Group on Acute Diarrhea.

Background: Attaching and effacing Escherichia coli demonstrate marked species specificity in inducing diarrhea, although its mechanism remains largely unclear. The purpose of this study was to investigate the existence of a soluble, species-specific factor that induces diarrhea in an in vitro model., Methods: Stripped rabbit ileum was mounted in Ussing chambers, and changes in potential difference and short-circuit current were monitored after the addition of bacterial culture supernatant., Results: The culture supernatant from rabbit-specific strain RDEC-1, but not from human-specific enteropathogenic Escherichia coli strain E2348/69, induced an increase in potential difference and short-circuit current in rabbit ileum mounted in Ussing chambers. This electrical signal was related to chloride ion secretion, was absent in colonic tissue, and was retained in the 30 to 100-KDa fraction of the supernatant. Preliminary experiments failed to show an involvement of calcium or cyclic nucleotides as intracellular messengers. RDEC-1 cured of a 42-MDa plasmid lost the enterotoxicity whereas conjugation of the plasmid into the negative E. coli recipient HB101 resulted in the expression of toxicity., Conclusions: The authors describe a novel, species-specific factor that helps to explain RDEC-1 diarrhea, which may be relevant to the pathogenesis of enteropathogenic Escherichia coli infection.

Background: The probiotic Lactobacillus GG is effective in promoting a more rapid recovery of acute, watery diarrhea in children with rotavirus enteritis. Very limited information is available, however, on the potential role of such agents in non-rotaviral diarrheal episodes. Furthermore, no evidence is available concerning the efficacy of Lactobacillus GG administered in the oral rehydration solution during oral rehydration therapy. A multicenter trial was conducted to evaluate the efficacy of Lactobacillus GG administered in the oral rehydration solution to patients with acute-onset diarrhea of all causes., Methods: Children 1 month to 3 years of age with acute-onset diarrhea were enrolled in a double-blind, placebo-controlled investigation. Patients were randomly allocated to group A, receiving oral rehydration solution plus placebo, or group B, receiving the same preparation but with a live preparation of Lactobacillus GG (at least 10(10) CFU/250 ml). After rehydration in the first 4 to 6 hours, patients were offered their usual feedings plus free access to the same solution until diarrhea stopped., Results: One hundred forty children were enrolled in group A, and 147 in group B. There were no differences at admission between the groups in age, sex, previous types of feeding, previous duration of diarrhea, use of antibiotics, weight, height, weight-height percentile, prevalence of fever, overall status, degree of dehydration, and percentage of in- versus outpatients. Duration of diarrhea after enrollment was 71.9 +/- 35.8 hours in group A versus 58.3 +/- 27.6 hours in group B (mean +/- SD; P = 0.03). In rotavirus-positive children, diarrhea lasted 76.6 +/- 41.6 hours in group A versus 56.2 +/- 16.9 hours in groups B (P < 0.008). Diarrhea lasted longer than 7 days in 10.7% of group A versus 2.7% of group B patients (P < 0.01). Hospital stays were significantly shorter in group B than in group A., Conclusions: Administering oral rehydration solution containing Lactobacillus GG to children with acute diarrhea is safe and results in shorter duration of diarrhea, less chance of a protracted course, and faster discharge from the hospital.

Adequate nutritional intervention in diarrhoeal disease in children is crucial in obtaining optimal control of a disorder that may become life-threatening. During recent years, important advances have been made in our understanding of the pathophysiology of diarrhoeal states, in the formulation of oral rehydration solutions and in the role of micro- and macronutrients in diarrhoeal disorders. This chapter outlines some of the relevant concepts in the pathophysiology of diarrhoeal disease and provides a rationale for nutritional intervention. Guidelines for nutritional management in the settings of acute-onset diarrhoea, post-enteritis protracted diarrhoea and chronic non-specific diarrhoea are provided, mostly based on controlled clinical trials and meta-analyses of evidence-based medicine.

A potential aetiologic agent was detected in the stools of 56% of 118 children hospitalized in Naples for acute diarrhoea. Rotavirus and Salmonella were the agents most commonly associated with disease, accounting for 23 and 17 percent of cases, respectively. Campylobacter jejuni, enterotoxigenic Escherichia coli, Yersinia and Shigella were less frequently isolated (total, 11% of cases). These findings fit well with the epidemiological picture described for other developed countries, except for the isolation rate of Salmonella which widely exceeds that reported in other investigations. Cytotoxic strains of E. coli and other Gram-negative bacilli were identified in the stools of 18 children; the possible pathogenic role of these strains is unknown and needs further investigation.

Citrobacter species are often present in the stools of children and are generally considered a normal component of the intestinal microflora. Previous reports suggested that they might act as enteric pathogens. Aiming at defining the role of Citrobacter species in inducing diarrhea, we looked for their presence in the stools of 328 children with diarrhea and in 108 controls. Citrobacter strains were isolated from 46 patients (14%) and 7 controls (6.5%) (P less than 0.05). All isolates were tested for heat-stable (ST) and heat-labile (LT) enterotoxin. No LT-producing organisms were found. Three C. freundii strains, all isolated from children with diarrhea, elaborated an enterotoxin detected by the suckling mouse assay. A crude extract was prepared by acetone precipitation and a sequential ultrafiltration technique. The enterotoxin was heat stable, and its estimated molecular weight was between 2,000 and 10,000. Citrobacter enterotoxin was soluble in methanol and stable at acid and neutral pHs but not above pH 8, and its activity was destroyed by treatment with 2-mercaptoethanol. Citrobacter enterotoxin was inactive in the 18-h rabbit ileal loop test. All these characteristics closely resemble STa produced by Escherichia coli. The time course of Citrobacter enterotoxin-induced intestinal secretion in suckling mice was similar to that of E. coli STa. The enterotoxin produced by C. freundii cross-reacted with monoclonal antibodies raised against E. coli STa. These results suggest that C. freundii is capable of inducing diarrhea through the production of an E. coli-like STa, and its presence in the stools of patients with diarrhea should be considered as that of a possible etiologic agent.

Infant mortality from acute diarrhoea has sharply declined in the last few decades throughout Europe. However, acute diarrhoea is still a very common occurrence in European children, who experience, in their first 3 years of life, approximately 1 episode/year. The commonest agent responsible for infectious diarrhoeas appears to be rotavirus, followed by campylobacter. Although water loss may be high, the mean sodium loss is close to 40 mmol/l of stool in rotaviral diarrhoea, and to 60 mmol/l in diarrhoeas due to invasive pathogens such as campylobacter and salmonella. Larger fluid losses but a somewhat lower sodium loss accompanies non-cholera secretory diarrhoeas, which appear to be commoner in infants than in older children. This evidence indicates that an ORS for European children should have a sodium concentration lower than 90 mmol/l which was primarily intended for use in developing countries. Clearly, the glucose concentration is crucial, as it is now evident that concentrations higher than the recommended 110 mmol/l may lead, particularly in rotaviral enteritis, to worsening of diarrhoea and development of hypernatraemia. Finally, it appears that in Europe the use of commercially available ORS is strikingly low, so that infants and children are often given a variety of "clear fluids", generally inadequate to ensure proper rehydration or maintenance of hydration. Thus an effort should be made not only to devise the "ideal" solution, but also to effectively implement its use.

We screened 569 children with acute onset diarrhoea from five Italian towns for heat stable enterotoxin produced by Escherichia coli. We compared an enzyme linked immunoabsorbent assay (ELISA) with the standard suckling mouse assay for detection of the enterotoxin. A total of 31 (5.4%) children were found who had strains of E coli that produced heat stable enterotoxin: 26 strains were positive in both tests, four only in the suckling mouse assay, and one only in the ELISA. Compared with the suckling mouse assay the sensitivity of the ELISA was 87% and the specificity was 99.8%. The mean age of the children with E coli that produced heat stable enterotoxin was 22 months. Fifteen (48%) of the children had ingested potentially contaminated food and five (17%) had a previous contact with someone with diarrhoea. The clinical picture was milder than that described in developing countries. Faecal osmolality and the osmolal gap were consistent with a secretory diarrhoea in 12 out of 15 (80%) of these children. The mean duration of the diarrhoea was five days. Heat stable enterotoxin produced by E coli is a common cause of mild diarrhoeal illness in Italian children.

Absorption of water from the intestine occurs in response to the osmotic gradient as a passive consequence of the active transfer of solutes (nutrients and electrolytes, with Na absorption playing a key role) from the intestinal lumen to the serosal side. During intestinal infections, several possible derangements of such a situation may occur, ultimately leading to the shift of net water absorption to secretion and, thus, to diarrhoea. In rotaviral diarrhoea, the mature enterocytes are invaded by the virus and exfoliate, thus inducing villous atrophy and crypt hyperplasia. Consequently, undigested and unabsorbed nutrients cause an osmolar diarrhoea, while the ongoing process of crypt secretion contributes by adding active anion and water secretion. In bacterial intestinal infections, the pathogenetic mechanisms are essentially mucosal invasion, adherence, cytotoxicity or release of enterotoxins. The pathophysiology of bacterial diarrhoea is best known for the latter mechanism; heat-labile and heat-stable families of enterotoxins have been described and characterised that act by inducing, respectively, an increase in the enterocyte's cyclic AMP or cyclic GMP content. Such alteration leads, in a morphologically intact mucosa, to changes in the major electrolyte transport processes that reverse net absorption of ions and water to net secretion and thus to secretory diarrhoea. As for nutrient absorption, although experimental evidence indicates an impairment of glucose and amino acid absorption in rotaviral diarrhoea, many clinical trials have shown the successful use of oral rehydration solutions in such circumstances. The same applies to bacterial-induced diarrhoeas; the well-established observation that, in enterotoxic diarrhoea of all kinds, the coupled transport of Na and nutrients such as glucose or amino acids is intact has proved to be the cornerstone of the highly successful, widespread use of oral rehydration solutions.

One hundred and eighteen consecutive cases of childhood acute diarrhoea (mean age: 10.5 months) were studied after admission to our Pediatric Unit in Naples over a 13-month period. A diagnosis was established in 92 patients (78%): 55% of patients were found to have an infectious enteritis (among them, 5 had ETEC infections and 1 had an ST-producing Klebsiella infection), 12% a parenteral infection, 11% cow's milk intolerance. The occurrence of gross blood (P less than 0.01), leukocytes, and reducing substances in the stools was more commonly associated with infectious enteritis than with diarrhoea due to all other causes. In 14 patients (8 of whom were malnourished), diarrhoea ran a prolonged course. In all, the eventual outcome was favourable. Our findings, while confirming that infectious enteritides account for most of acute diarrhoeas in children, stress the importance of parenteral infections and cow's milk intolerance in this condition. Also, the need for an accurate search for enterotoxigenicity of enterobacteria before ruling out their pathogenetic role is stressed.

Escherichia coli heat-stable enterotoxins (ST) are classified into STa and STb according to their physicochemical and biologic characteristics. STa induces diarrhea, activating the guanylate cyclase-cGMP system. ST-like enterotoxins can be produced by bacteria other than E. coli, including Klebsiella pneumoniae. A Klebsiella ST has previously been shown to share some chemical and immunologic characteristics with E. coli ST. Aiming to define better the nature of Klebsiella ST, we have screened 237 children with diarrhea and 179 controls for ST-producing Klebsiella, using the SMA. We detected 26 Klebsiella strains from patients, two of which were positive in the SMA, and 36 from controls, all negative for ST. A partial purification was performed using an acetone precipitation followed by ultrafiltration and gel filtration techniques. Klebsiella toxin was heat-stable, methanol-soluble, sensitive to mercaptoethanol, active at acid pH values, but not at pH greater than 8. The time course of Klebsiella toxin in the SMA resembled that of E. coli STa. Klebsiella ST caused reduced Na absorption and net Cl secretion in rabbit ileal mucosa mounted in Ussing chambers. It was found to increase the cGMP but not the cAMP concentration. Finally, Klebsiella ST did not react with anti-E. coli STa MAb in a competitive ELISA. We conclude that K. pneumoniae may induce diarrhea through the production of an STa similar but not identical to E. coli STa.

To elucidate the pathophysiological changes leading to postantibiotic diarrhoea caused by Clostridium difficile and its cytotoxin, oral ampicillin was given to rabbits, and jejunal, ileal, and caecal segments of those that developed diarrhoea were investigated in vitro. The rabbits that, in response to treatment, harboured Clostridium difficile in their colonic lumen were studied, and the results expressed according to the presence or absence of Clostridium difficile and/or its cytotoxin. Thus, we refer to either CD+ or CD- segments. The influx of glucose, phenylalanine, glycylphenylalanine, and lysine across the brush border of jejunum and ileum of CD+ segments was severely impaired, while only slightly blunted in CD-. No significant change was detected in the influx of glutamic acid in the jejunum of all treated animals and in the CD- ilea. Morphologic damage in ileum and caecum of CD+ was also more evident than in CD-. Transepithelial ion transport across short circuited ileal mucosa (CD+ and CD-) revealed secretory changes in Cl net transport that were more marked in CD-. We conclude that: (1) Clostridium difficile may also colonise the upper intestinal tract, where it induces morphological and functional damage, severely impairing nutrient absorption; and (2) the ileum contributes to the diarrhoea caused by CD even when the micro-organism is confined to the more distal gut by showing moderate impairment of nutrient absorption and marked electrolyte secretion.

Unlabelled: A "quick" prevalence study of intractable diarrhoea (defined as diarrhoea lasting more than 3 weeks and dependent on parenteral nutrition [PN] for more than 50% of daily caloric intake) was conducted by FAX. All 35 paediatric gastroenterology services which had been contacted answered questionnaire sent by FAX. 20 cases of intractable diarrhoea were identified in 9 centres. In 12 cases PN was administered at home, the other 8 cases being treated as inpatients for an average duration of 9.5 months. A diagnosis had been established in 11 out of 20 cases. Auto-immune enteropathy was the most frequent diagnosis (5 cases); congenital microvillous atrophy (3 cases); chronic pseudo-obstruction (2 cases) and multiple food intolerance (1 case). Undefined 9/20 cases presented atrophy of intestinal mucosa. The age of the beginning of diarrhoea varied from 2 days to 12 years, but was more than 16 months only in some cases with auto-immune enteropathy.Conclusion: Intractable diarrhoea has a low prevalence in Italy and remains a rare but very intricating problem. Long-term PN is recommended in most cases: autoimmune enteropathy is the most frequent cause but in about half of the cases the aetiopathogenetic diagnosis is still not defined. [ABSTRACT FROM AUTHOR]