In the 50 years since ESPGHAN's inception the field of intestinal infectious diarrhoea has changed considerably. It is important to remember that ESPGHAN was a small society at the beginning and it is only in the last few years that the membership has expanded to 800 plus including trainees and allied health professionals (and an expanding emeritus category). There has been a huge expansion in the numbers of nonmembers attending the annual ESPGHAN meetings, dramatically changing the more informal atmosphere of earlier years to the formality of a major scientific congress. Around the 1980s and beyond ESPGHAN was largely driven by leading figures in centres of excellence, each with their own mix of areas of interest, which they independently investigated and funded having to satisfy their own Institutions’ demands of scientific activity and output. ESPGHAN's strength at that time, in terms of infectious diarrhoea, was largely as a network of clinical expertise, a platform to present research for debate, rather than a source of funding or a stimulus of novel research. So it is not surprising that there was an uneven scientific interest in infective diarrhoea, which did not match the more widespread commitment to clinical areas of research such as coeliac disease. However, the Group led by John Walker-Smith at the Queen Elizabeth Hospital for Children in London had been involved in the field of infectious diarrhoea from an early stage. In recent years, the ESPGHAN Gastroenteritis Working group, involving especially Hania Szajewska and Alfredo Guarino, provided important work for establishing guidelines (see Chapter 5.4.1).
THE PRE-ESPGHAN PERIOD
Evidence of Viral Diarrhoea
In 1968 no viral causes of acute diarrhoea had been identified and presumed cases were called nonbacterial gastroenteritis. This was a result of using isolation and culture when viral culture was impossible. Coincidentally, the outbreak of acute diarrhoea from which the Norwalk Agent was detected, occurred in 1968, but the virus was not identified until 1972 when immune electron microscopy was applied to stored faecal samples (1). Shortly afterwards Bishop et al used thin section electron microscopy to study small intestinal biopsies taken from children with acute diarrhoea and identified viral particles (rotavirus) within enterocytes (2). It was also found that negative staining stool electron microscopy could be used on crude faecal extracts to identify viral particles (3) (Fig. 1). This paved the way for rapid viral diagnosis, and allowed several morphologically distinct viruses to be identified (rotavirus, adenovirus, astrovirus, small round structured viruses (Norwalk-like), small round viruses, and coronavirus). From a clinical point of view, having the ability to make rapid viral diagnoses gave an understanding of the prevalence of viral diarrhoea, especially rotavirus-related, permitted an analysis of whether there were particular diagnostic clinical associations and gave an important analytical tool in children with the postenteritis syndrome. Stool electron microscopy (EM) was taken over by immune based identification tests; subsequently, molecular biological analysis using polymerase chain reaction methods provided rapid and sensitive viral identification and has become the method of choice.
Contribution of Intestinal Biopsies
Although Bishop et al performed small intestinal biopsies in children with acute diarrhoea, in clinical practice intestinal biopsy was restricted to cases of chronic (>14 days) diarrhoea (2). The application of EM to an abnormal biopsy from a case of chronic diarrhoea in 1980 demonstrated a distinctive microvillous-effacing lesion at sites of bacterial adhesion (4). The bacteria were identified as enteropathogenic Escherichia coli (EPEC). The observation that host cell actin accumulated at sites of EPEC (and enterohaemorrhagic E coli (EHEC) infection both in vivo and in vitro, provided a host, cell-based virulence test, which handed to molecular biologists the key that unlocked the incredible bacterial processes underlying pathogenesis (5) (Fig. 2). Another major advance was the finding in the early 1980s that EHEC produced Shiga toxin explaining the association of haemorrhagic colitis and the haemolytic uraemic syndrome with infection (6). Advances were also made in the identification and understanding of a range of other bacterial toxins (7).
In terms of parasites, although Giardia lamblia is a frequent stool and intestinal biopsy finding, the identification of Cryptosporidium as a cause of acute and chronic infectious diarrhoea was perhaps a more important finding (8) (Fig. 3).
Geographical and Interdisciplinary Approach
It is clear that infectious diarrhoea is a particular problem in developing countries and is integral to the downward spiral of infection and malnutrition that blights populations and is responsible for high levels of morbidity and mortality. In Europe, a direct interest in these areas is particularly fostered by historical links with countries in the process of development, for example, the British Commonwealth, the French-speaking North African countries, and to population centres where immigration of people from these countries was prevalent. The Commonwealth Association of Paediatric Gastroenterology and Nutrition (CAPGAN) was founded to develop clinical and research links between developing and developed communities. Through FISPGHAN a similar interest was catalysed at the world congresses by ESPGHAN, and working group reports were published for the 2004 and 2008 World Congress meetings (9,10). It is clear that major advances are made when there is a high degree of interaction between clinicians and other disciplines with microbiological, basic scientific, and molecular biological expertise.
THE ESPGHAN PERIOD
Protracted Diarrhoea, Malnutrition, and Immune System
By the time of the founding of ESPGHAN, the relationship between repeated cycles of gastrointestinal infection and malnutrition diseases was just becoming appreciated (11). Although immune mechanisms were acknowledged, the importance of the lymphoid system was not then recognised. In the next 2 decades, the natures of T cells and B cells were clarified, and important peptide mediators of inflammation and the changes in malnutrition and chronic diarrhoea were discovered, such as interleukin (IL-1), IL-6, and tumor necrosis factor (12).
Collaboration between ESPGHAN and CAPGAN members in centres, including the Medical Research Council (MRC) Unit in The Gambia, contributed to changes in the nutritional management of infants with chronic diarrhoea (13), and identified that persistent increase in gut epithelial permeability predicted nutritional failure and death (14), associated with an unchecked TH1 immune response within the mucosa and failure of T regulatory responses (15). Consistent with this, it was confirmed that an elemental diet induced better weight gain than a traditional weaning diet (16). More recently, there has been recognition of the important role of the microbiome in malnutrition enteropathy (17). Thus, there has been a change of emphasis, away from a simple concept of undernutrition, towards recognition that mucosal immune responses and immune tolerance are critical players in determining outcome of infants with chronic diarrhoea in resource poor countries.
In the UK, both Sandy McNeish and John Walker-Smith encouraged younger scientists and electron microscopists (Alan Phillips and Stuart Knutton) to get involved in clinical concerns and this mentorship stimulated laboratory studies in viral, EPEC or Clostridium difficile diarrhoea which were presented at ESPGHAN meetings; it also helped clinicopathological studies in viral, bacterial, parasitic, and traveller's diarrhoea observations at Queen Elizabeth Hospital for Children, London (18–21). These observations were of relevance to developing and developed communities as the hospital served a deprived community in east London with significant numbers of immigrant children and children of immigrants, especially from the Indian subcontinent and Bangladesh. Extensive work achieved understanding in E coli–related infectious diarrhoea. This arose in part from national and international collaboration between like-minded individuals with a balance of expertise and contacts. While not directly resulting from ESPGHAN initiatives, those involved benefited from an understanding of the clinical importance of the diseases caused by E coli, the access to clinical material (intestinal biopsy samples) from cases being investigated for unrelated conditions, and the ESPGHAN annual meeting platform to present research to intellectual scrutiny. The work itself used molecular biological, cell culture, in vitro human intestinal organ culture, biochemical, and morphological techniques to gain an understanding of the molecular basis of the interaction between enteropathogenic, enterohaemorrhagic, and enteroaggregative E coli with the intestine (22–27).
Light was also thrown onto the postenteritis syndrome, that is, chronic diarrhoea as an apparent sequel to acute infection (28). Evidence was presented at ESPGHAN meetings of cow's milk sensitive enteropathy as a sequel to gastroenteritis, as well as persistent EPEC infection, and intercurrent and/or superimposed viral infections causing enteropathies and prolonging diarrhoeal episodes (28). This work alerted ESPGHAN members that there were important causes of small intestinal enteropathy apart from coeliac disease.
ESPGHAN CONTRIBUTION IN GASTROENTERITIS MANAGEMENT
In reality, identifying the aetiology of the acute diarrhoeal episode did not, in the majority of cases, alter management. This was based on the degree of dehydration and centred on oral, or, in severely dehydrated cases, intravenous rehydration therapy. Compared to the more individual Institution based studies on aetiology and pathogenesis, ESPGHAN has taken a more active involvement in studies on the management of acute diarrhoeal disease.
Oral Rehydration Therapy
In 1978 The Lancet stated that a method of rehydrating patients with acute diarrhoea by mouth was “potentially the most important medical advance in this century” (29). This method was based upon the discovery that glucose stimulated sodium transport across a piece of rat ileum (30). This approach was called Oral Rehydration Therapy (ORT). “It was a remarkable example of theoretical scientific knowledge being applied directly to a clinical problem”(31). The effectiveness of this approach in practice was dramatically demonstrated in a cholera epidemic in Bangladesh, with a dramatic fall in mortality (32,33).
In Europe, there was concern about the relatively high sodium levels of the original oral rehydration solution (ORS). This was at a time when hypernatraemic dehydration was an important problem for the children of Europe with gastroenteritis. Unlike children of the developing world who were malnourished, such children were often obese and fed with high solute milks. There was pressure upon paediatricians in developed countries such as those of Europe to set an example to their colleagues by using ORS but there were safety anxieties at a time when mortality from childhood gastroenteritis had fallen to low levels. ESPGHAN addressed these issues and the matter was discussed in detail at a workshop at the ESPGAN meeting in Copenhagen in 1988 (34).
ESPGHAN Gastroenteritis Working Group
There were 2 outcomes of this Copenhagen symposium in 1988. Firstly, an ESPGHAN working group was established as a collaboration between 13 ESPGHAN members from across Europe. This led to the publication of ESPGHAN recommendations for the composition of ORS for the children of Europe (35) promoting a solution containing 60 mmol/L sodium “to minimize the risk of hypernatraemia.” Secondly, intestinal perfusion models at St. Bartholomew's Hospital in London permitted physiological studies of ORT (30). This led to modifications of ORS composition in order to maximise water and electrolyte absorption. Basically hypo-osmolar solutions were recommended and they are now recommended worldwide by the WHO, effectively removing the risk of hypernatraemia.
Multicentre study with 18 collaborators across Europe established the value of early feeding in children with gastroenteritis. The ESPGHAN gastroenteritis working group continued and a medical position paper concerning recommendations for feeding in childhood gastroenteritis were published in JPGN in 1997 (36). A further collaborative ESPGHAN study investigated the value of adding lactobacillus GG to ORS (37) reporting some, but not dramatic, reduction of duration of diarrhoea. In a follow-up study, the group reported the practical success of the new recommendations for early feeding in gastroenteritis in a large Europe wide study (38). Other ESPGHAN studies in acute diarrhoea have included compliance with treatment guidelines (2001) (39), rotavirus vaccination (2008) (40), recommendations for management in Europe (2008, 2014) (41,42), and on the use of probiotics (2014) (43) (see Chapter 5.4.1).
The last 50 years has seen development from the identification of rotavirus as the most prevalent cause of acute gastroenteritis in children proceed to the production of effective vaccine treatment. ESPGHAN has been active in guiding management of acute gastroenteritis and has members that have been involved in advances in aetiology, pathogenesis, and physiologically based treatment. As ESPGHAN increases in size and influence perhaps there is a place for stimulating research, either by highlighting areas of concern to attract the consideration of funding bodies, or by directly funding studies which would require significant financial backing and an increase in the philosophy of looking outside its own geographical borders.
Addendum: We join to this ESPGHAN history of infectious diarrhoea some pictures of many of those who contributed in the work at the Royal Free Hospital and in the world in Fig. 4A and B and Fig. 5A–C.
1. Kapikian AZ, Wyatt RG, Dolin R, et al. Visualization by immune electron microscopy of a 27 nm particle associated with acute infectious non-bacterial gastroenteritis. J Virol
2. Bishop RF, Davidson GP, Holmes IH, et al. Virus particles in epithelial cells of duodenal mucosa from children with acute nonbacterial gastroenteritis. Lancet
3. Flewett TH, Bryden AS, Davies H. Diagnostic electron microscopy of faeces. II Acute gastroenteritis associated with reovirus-like particles. J Clin Pathol
4. Ulshen MH, Rollo JL. Pathogenesis of Escherichia coli
gastroenteritis in man – another mechanism. N Engl J Med
5. Knutton S, Baldwin T, Williams PH, et al. Actin accumulation at sites of bacterial adhesion to tissue culture cells: basis of a new diagnostic test for enteropathogenic and enterohemorrhagic Escherichia coli
. Infect Immun
6. Karmali MA, Steele BT, Petric M, et al. Sporadic cases of haemolytic-uraemic syndrome associated with faecal cytotoxin and cytotoxin-producing Escherichia coli
in stools. Lancet
7. Fasano A. Toxins and the gut: role in human disease. Gut
2002; 50 (suppl 3):iii9–iii14.
8. Phillips AD, Thomas AG, Walker-Smith JA. Cryptosporidium, chronic diarrhoea and the proximal small intestinal mucosa. Gut
9. Salazar-Lindo E, Allen S, Brewster DR, et al. Latin American Society for Pediatric Gastroenterology, Hepatology and NutritionIntestinal infections and environmental enteropathy: Working Group report of the second World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr
2004; 39 (suppl 2):S662–S669.
10. Bhutta ZA, Nelson EA, Lee WS, et al. Persistent Diarrhea Working GroupRecent advances and evidence gaps in persistent diarrhea. J Pediatr Gastroenterol Nutr
11. Scrimshaw NS, Taylor CE, Gordon JE. Interactions of nutrition and infection. Monogr Ser World Health Organ
12. Tracey KJ, Cerami A. Tumor necrosis factor in the malnutrition (cachexia) of infection and cancer. Am J Trop Med Hyg
1992; 47 (1 pt 2):2–7.
13. Hoare S, Poppitt SD, Prentice AM, et al. Dietary supplementation and rapid catch-up growth after acute diarrhoea in childhood. Br J Nutr
14. Lunn PG, Northrop-Clewes CA, Downes RM. Intestinal permeability, mucosal injury, and growth faltering in Gambian infants. Lancet
15. Campbell DI, Murch SH, Elia M, et al. Chronic T cell-mediated enteropathy in rural west African children: relationship with nutritional status and small bowel function. Pediatr Res
16. Amadi B, Mwiya M, Chomba E, et al. Improved nutritional recovery on an elemental diet in Zambian children with persistent diarrhoea and malnutrition. J Trop Pediatr
17. Blanton LV, Barratt MJ, Charbonneau MR, et al. Childhood undernutrition, the gut microbiota, and microbiota-directed therapeutics. Science
18. Calabi E, Calabi F, Phillips AD, et al. Binding of Clostridium difficile
surface layer proteins to gastrointestinal tissues. Infect Immun
19. Walker-Smith JA, Phillips AD. Is prolonged rotavirus infection a common cause of protracted diarrhoea? Arch Dis Child
20. Salim AF, Phillips AD, Walker-Smith JA, et al. Sequential changes in small intestinal structure and function during rotavirus infection in neonatal rats. Gut
21. Chan KN, Phillips AD, Knutton S, et al. Enteroaggregative Escherichia coli
: another cause of acute and chronic diarrhoea in England? J Pediatr Gastroenterol Nutr
22. Hicks S, Candy DC, Phillips AD. Adhesion of enteroaggregative Escherichia coli
to pediatric intestinal mucosa in vitro. Infect Immun
23. Phillips AD, Navabpour S, Hicks S, et al. Enterohaemorrhagic Escherichia coli
O157:H7 target Peyer's patches in humans and cause attaching/effacing lesions in both human and bovine intestine. Gut
24. Frankel G, Phillips AD. Attaching effacing E. coli
and paradigms of Tir-triggered actin polymerisation: getting off the pedestal. Cell Microbiol
25. Schuller S, Frankel G, Phillips AD. Interaction of Shiga toxin from Escherichia coli
with human intestinal epithelial cell lines and explants. Stx2 induces epithelial damage in organ culture. Cell Micro
26. Garmendia J, Phillips AD, Carlier MF, et al. TccP is an enterohaemorrhagic E. coli
O157:H7 type III effector protein that couples Tir to the actin-cytoskeleton. Cell Microbiol
27. Frankel G, Phillips AD. Attaching effacing Escherichia coli
and paradigms of Tir-triggered actin polymerisation: getting off the pedestal. Cell Microbiol
28. AD Phillips. Microscopical studies in chronic diarroea. PhD thesis, University of London; 1991.
29. Water with sugar and salt. Lancet
30. Schultz SG, Zalusky R. Ion transport in isolated rate ileum. II. The interaction between active sodium and active sugar transport. J Gen Physiol
31. Walker-Smith JA, Sandhu BK, Isolauri E, et al. Guidelines prepared by the ESPGAN Working Group on Acute DiarrhoeaRecommendations for feeding in childhood gastroenteritis. European Society of Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr
32. Mahalanabis D, Choudhuri AB, Bagchi NG, et al. Oral fluid therapy of cholera among Bangladesh refugees. Johns Hopkins Med J
33. Farthing MJG, Walker-Smith JA. Oral rehydration solutions for children of Europe Proceedings of a workshop held at XXI Annual Meeting of ESPGAN Copenhagen 1988. Acta Paediatr Scand Suppl
34. Elliott EJ, Watson AJM, Walker-Smith JA, et al. Search for the ideal oral rehydration solution: studies in a model of secretory diarrhoea. Gut
35. Booth I, Cunha Ferreira R, Desjeux J-F. Recommendations for composition of oral rehydration solutions for the children of Europe. ESPGAN Working Group on Oral Rehydration. J Pediatr Gastroenterol Nutr
36. Sandhu BK, Isolauri E, Walker-Smith JA, et al. A multicentre study on behalf of the European Society of Paediatric Gastroenterology and Nutrition Working Group on Acute Diarrhoea. Early feeding in childhood gastroenteritis. J Pediatr Gastroenterol Nutr
37. Guandalini S, Pensabene L, Zikri MA, et al. Lactobacillus GG administered in oral rehydration solution in children with acute diarrhoea: a multi-centre European Trial. J Pediatr Gastroenterol Nutr
38. Szajewska H, Hoekstra H, Sandhu BK. Management of Acute Diarrhoea in Europe and the impact of new recommendations. A multi-centre study. J Pediatr Gastroenterol Nutr
39. Hoekstra H. European Society of Paediatric Gastroenterology, Hepatology and Nutrition Working Group on Acute DiarrhoeaAcute gastroenteritis in industrialized countries: compliance with guidelines for treatment. J Pediatr Gastroenterol Nutr
40. Vesikari T, Van Damme P, Giaquinto C, et al. Expert Working Group; European Society for Paediatric Infectious Diseases/European Society for Paediatric GastroenterologyHepatology, and Nutrition evidence-based recommendations for rotavirus vaccination in Europe: executive summary. J Pediatr Gastroenterol Nutr
41. Guarino A, Albano F, Ashkenazi S, et al. European Society for Paediatric Gastroenterology, Hepatology, and Nutrition/European Society for Paediatric InfectiousDiseases evidence-based guidelines for the management of acute gastroenteritis in children in Europe. J Pediatr Gastroenterol Nutr
2008; 46 (suppl 2):S81–122.
42. Guarino A, Ashkenazi S, Gendrel D, et al. European Society for Paediatric GastroenterologyHepatology, and Nutrition/European Society for Paediatric Infectious Diseases evidence-based guidelines for the management of acute gastroenteritis in children in Europe: update 2014. J Pediatr Gastroenterol Nutr
© 2018 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
43. Szajewska H, Guarino A, Hojsak I, et al. European Society for Pediatric Gastroenterology, Hepatology, and NutritionUse of Probiotics for Management of Acute Gastroenteritis: A Position Paper by the ESPGHAN Working Group for Probiotics and Prebiotics. J Pediatr Gastroenterol Nutr