Journal of Pediatric Gastroenterology and Nutrition 39:S711S716 June 2004 Lippincott Williams & Wilkins, Philadelphia

Persistent and Chronic Diarrhea and Malabsorption: Working Group Report of the Second World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition
Zulfiqar A. Bhutta (Coordinator), Fayez Ghishan, Keith Lindley, Iqbal A. Memon, Santosh Mittal, and J. Marc Rhoads
Commonwealth Association of Paediatric Gastroenterology and Nutrition (Z.A.B., S.M.); North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (F.G., J.M.R.); European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (K.L.); and Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology and Nutrition (I.A.M.).

Research 1. Assessment of mucosal immuno-pathology and molecular and cellular biology of persistent diarrhea in representative populations in developing countries. 2. Studies of small bowel microbiology in PD, especially in at-risk populations e.g., malnourished children and HIV endemic areas. 3. Evaluation of the link of micronutrient deficiencies with PD and their relationship with intestinal repair mechanisms. Intervention 1. Improved facility-based approaches and algorithms for the nutritional management of PD and malnutrition. 2. Diagnosis and management of PD in public health system and primary care (including domiciliary) settings. 3. Scaling-up environmental control measures and safe water and hygiene strategies. Education 1. Continuing medical education strategies to educate medical students and physicians in the recognition, management and prevention of PD. 2. Education of nursing and paramedical personnel in the recognition and management of PD in ambulatory and health system settings. 3. Community and public health education strategies for increased awareness of the prevention of PD and optimal management of acute and prolonged diarrheal episodes.

INTRODUCTION Despite considerable advances in the understanding and management of diarrheal disorders in childhood, they are still responsible for an estimated 2.2 million childhood deaths worldwide (1). In 1980, the World Health Organization calculated that there were >700 million episodes of diarrhea annually in children <5 years of age in developing countries (excluding China), with >4.6 million deaths (2). More recent reviews indicate that although global mortality has decreased, the incidence remains unchanged at >3.2 episodes per child-year (3). These findings indicate the continuing need to focus on the prevention and management of acute and chronic diarrhea in children in developing countries.

Address correspondence and reprint requests to Dr. Bhutta (e-mail zulfiqar.bhutta@aku.edu).

Diarrheal disorders form a continuum, the majority of cases resolving within the first week of the illness. However, a smaller proportion of diarrheal illnesses may fail to resolve and persist for >2 weeks. Persistent diarrhea (PD) may be defined as the passage of 3 watery stools per day for >2 weeks in a child who either fails to gain or loses weight. PD identifies children with a substantial diarrhea-related morbidity and accounts for between 36% and 54% of all diarrhea-related deaths (4). Many infants and toddlers in developing countries may have frequent recurrent episodes of acute diarrhea or PD, resulting in nutritional compromising and/or predisposing these children to PD. The bulk of epidemiological data on the relationship between acute diarrheal disorders and PD are from studies undertaken > 10 to 15 years ago. There is a paucity of recent data on this subject, especially from nonHIVendemic areas. However, chronic enteropathy and PD have been increasingly recognized as manifestations of advancing HIV infection and AIDS. S711

S712 ETIOLOGY

BHUTTA ET AL. mal delayed-type hypersensitivity reactions and specific immune deficiencies such as HIV infection and severe combined immunodeficiency are particularly prone to PD. Diarrheal disease is closely related to malnutrition, but the causal nature of this association has been challenged. The relationship between PD and malnutrition is less controversial because it is commonly associated with significant malnutrition. In a verbal autopsy study of diarrheal deaths in Bangladesh, almost half the deaths were in malnourished children with PD, and the relative risk of dying of PD and severe malnutrition was 17-fold higher than in children with lesser degrees of malnutrition (6). There is a wealth of experimental and clinical evidence that improved nutrition hastens recovery from protracted diarrheal diseases. There are several reasons why malnutrition should both predispose to and follow PD. These range from achlorhydria with increased risk of small bowel contamination, systemic immune deficiency, intestinal and pancreatic enzyme deficiency, and altered intestinal mucosal repair mechanisms after an infectious insult. An independent relationship has also been demonstrated between cutaneous anergy and the subsequent risk of PD (7). There has been much interest in the possibility that such transient immune deficiency may be a marker of concomitant micronutrient deficiency (8,9). The most striking example of the critical role that the immune system plays in the pathogenesis of PD is the relationship between HIV/AIDS and PD. This is exemplified by the plethora of studies linking PD with cryptosporidiosis (10) and other parasitic infections in Africa and Asia. Poor intestinal repair is regarded as a key component of the abnormal mucosal morphology. However, the factors underlying this ineffective repair process and continuing injury are poorly understood. The result of this mucosal derangement is poor absorption of luminal nutrients and increased permeability of the bowel to abnormal dietary or microbial antigens. Alterations of intestinal permeability in early childhood may reflect changes in intestinal mucosal maturation and may be affected by concomitant enteric infections. Key micronutrient deficiencies may contribute to poor intestinal repair. Recent meta-analyses of zinc supplementation in diarrheal illnesses indicate a significant reduction in the duration and severity of diarrheal illnesses (11). Thus, zinc deficiency may significantly contribute to the prolongation of mucosal injury and delayed intestinal repair mechanisms. Given the close relationship between diarrheal disorders and malnutrition, it is not surprising that PD is widely recognized as a nutritional disorder and that optimal nutritional rehabilitation is considered the cornerstone of its management (12). A clear understanding of alterations in intestinal morphology and molecular mechanisms underlying the pathophysiology of PD in developing countries is crucial for the development of interventional strategies. However, in contrast to the progress made in understanding

Broadly speaking, the origins of diarrhea may lie primarily within the small intestine, large intestine, or accessory digestive organs (pancreas and hepatobiliary tract). Disorders of the large intestine usually cause diarrhea through defective water salvage, whereas disorders of the small intestine can be either secretory or osmotic (in association with malabsorption). Secretory and osmotic processes may be present concurrently (eg, with rotavirus enteritis). Protracted diarrhea may arise from a large number of conditions. Globally, the most important trigger for PD is an acute diarrheal episode caused by an enteric infection. In areas in which HIV infection is endemic, chronic infection of the gastrointestinal tract (eg, cryptosporidiosis) is an important cause. In the absence of an infective etiology, other specific disease entities associated with PD in children should be sought. The most common are dietary protein intolerances, celiac disease, and secondary disaccharide (lactose) intolerance. In a large historical series in Europe, these diagnoses accounted for 56% of cases of PD in infancy (5). In these infants with severe PD, 24% had other diagnoses, but in 30%, no specific diagnosis was reached despite extensive investigation. Now, the subgroup of children with PD and no identifiable diagnosis accounts for <2% of cases in large European centers (K. Lindley, unpublished data, 2003). It is useful to have a diagnostic algorithm as an aid to diagnosis that (in a necessarily arbitrary and mutually nonexclusive fashion) categorizes PD either by age of onset (in utero, neonatal, infantile, or older) or into congenital/inherited and acquired disorders. It is also useful to group the patients into those with secretory diarrhea and those with predominantly osmotic diarrhea on the basis of response to fasting and of stool electrolytes. Although from a global public health perspective these cases of protracted diarrhea are not important, an understanding of their underlying cellular and genetic mechanisms may provide invaluable insight into enterocyte pathophysiology, with potential implications for therapy. The diagnosis and management of these disorders, however, will not be discussed in depth in this report. Risk Factors and Pathophysiology for PD in Developing Countries The most important epidemiological risk factor for PD is malnutrition. Zinc deficiency, lack of breastfeeding, male sex, infection with enteropathogenic or enteroaggregative Escherichia coli or Cryptosporidium, and a history of intrauterine growth retardation are other important associated conditions. A recent acute diarrheal episode (within the past 2 months) is common in PD. Also important is immune status. Children with abnor-

J Pediatr Gastroenterol Nutr, Vol. 39, Suppl. 2, 2004

PERSISTENT AND CHRONIC DIARRHEA AND MALABSORPTION the hereditary disorders causing protracted or intractable diarrhea in infancy, there has been little progress in understanding the pathophysiology of this problem in developing countries beyond descriptive studies. Priority Goals in Research Appropriate and well-directed research is required to clarify the pathogenesis of PD and to develop sound public health preventive and treatment strategies. Among the several aspects of PD that merit further in-depth research, the following emerge as priority issues for the immediate future. 1. Assessment of mucosal immunopathology in PD and its relationship with malnutrition and malabsorption. These studies need to be undertaken in both HIVinfected children and noninfected children. We need to understand the interactions between specific pathogens and altered mucosal repair mechanisms. Suitable animal models to assess prolonged diarrheal episodes do not exist, and the models available have been used largely to assess the interaction between malnutrition and intestinal function. A clear understanding of the elements that underlie persistent mucosal injury is fundamental to the development of prevention and intervention strategies. There is a need to better define the inflammatory process within the lamina propria in tissues obtained at intestinal biopsy. In addition to research initiatives, this should facilitate accurate diagnosis and, when diagnosis is indeterminate, permit a logical approach to therapy. Mucosal immunopathology research should go beyond a simple description of inflammatory infiltrate and should clarify the basis of the inflammatory process (ligands involved, etc). Important areas of research are the interaction between innate and acquired immune responses in intestinal inflammation, the effects of inflammation on (enterocyte) gene expression and digestive/absorptive apparatus, and intestinal neuroimmune interactions. 2. Studies of small bowel microbiology in PD. Although PD has been associated with specific pathogens, eg, enteroaggregative E. coli, there is no consensus on this issue. Up to two thirds of children with PD have small bowel bacterial overgrowth, but it is not known whether small bowel bacterial overgrowth is a cause of PD or the result of impaired immunity and/or contaminated water. Several other pathogens have been associated with PD, especially in HIV-endemic populations. A wealth of data demonstrate that the innate immune response to bacteria and bacterial products is an important trigger in the pathogenesis of autoimmune and other gut diseases (13). Thus, studies of small bowel bacterial overgrowth and host-pathogen interactions at the molecular and cellular levels in the gut should be high priority in the quest to understand the origins of protracted diarrheal disease.

S713

3. Evaluation of the link between micronutrient deficiencies and PD. Although the causal relationship between PD and micronutrient, especially zinc, malnutrition is well recognized, little is known about the mechanisms underlying this process. Nor is it known how micronutrients affect intestinal mucosal repair and recovery patterns. Zinc deficiency may well be a key factor in the widespread prevalence of PD in zincdeficient populations, and research should be undertaken to evaluate the magnitude and the mechanisms of action of this effect. Priority Goals for Medical Interventions Although parenteral nutrition has been occasionally life-saving in selected cases in developing countries, it is clearly an impractical option for most of the developing world. There is now clear evidence supporting the enteral route for nutritional rehabilitation of malnourished children with PD (4,12). Starvation has been shown to have deleterious effects on the intestinal mucosa, thereby causing a reduction in the nutritive transporters for glutamine and arginine. It is thus imperative that malnourished children with PD receive enteral nutrition during their rehabilitation. Continued breastfeeding is universally accepted and recommended during diarrhea, and the disorder is frequently seen in the wake of lactation failure or after weaning. The choice of an appropriate diet or feeding regimen for these children is much debated because the diet offered must be well tolerated and of a sufficient nutritional quality to ensure adequate absorption without an osmotic penalty. Regardless of the cellular mechanisms and structural alterations in malnourished children with PD, the result is one of altered brush border and luminal enzymes and consequent malabsorption. Despite the aforementioned alterations in digestive and absorptive mechanisms, analysis of metabolic balance studies in children with PD indicates that satisfactory carbohydrate, protein, and fat absorption can take place on a variety of diets (14). Postinfectious cases of PD can usually be managed by dietary measures, including provision of dietary complex carbohydrates, eg, cereals such as rice, maize, lentils, or legumes, bananas, vegetable oil, and milk as a source of protein (human or cows milk, the former being preferable). Soy formulas may be acceptable but are significantly more expensive and in some studies were less effective than the cereal-lentilbased diets (4). Generally, the goal is to provide at least 150 kcalkg1d1 enterally. Research is underway to determine which complex carbohydrate is optimal for enhancing absorption (colonic) and bowel repair in PD. Candidates are maize, green banana fibers, pectin, and guar gum. Other potentially effective treatments are L-glutamine, which provides intestinal fuel, nucleotides for proliferating enterocytes, corticosteroids for children with protein-losing

J Pediatr Gastroenterol Nutr, Vol. 39, Suppl. 2, 2004

S714

BHUTTA ET AL. cile enterocolitis, cryptosporidial enteritis, and giardiasis. The role of antibiotics in the treatment of associated systemic infections that are seen in almost 30% to 40% of children with PD is poorly appreciated. Management protocols designed for facility settings in developing countries (4) need to be widely disseminated and used. Efforts should be made to devise agreed-on and appropriate diagnostic algorithms that reflect contemporary management strategies, ie, the place of parenteral nutrition, the place of specific therapies, and the place/timing of intestinal transplantation in intractable early-onset severe diarrheal diseases. 2. Diagnosis and management of PD in public health system and primary care (including domiciliary) settings. Although the fundamental principles of nutritional rehabilitation of PD are well recognized, optimal dietary treatment modalities for poor communities remain a challenge, especially for health system and primary care settings. These include the development of algorithms for management in ambulatory care, especially domiciliary settings, where referral to facility settings may not be possible. Although further research is needed to develop optimal, cost-effective strategies for the prevention and treatment of PD in children in such settings in developing countries, enough is known to design interventions, especially preventive strategies. However, these strategies need to be evaluated in large effectiveness studies. As noted, the early and unhygienic introduction of milk other than mothers milk and poorly managed recurrent acute diarrheal episodes are important predisposing factors for PD and should be prevented if possible. Thus, promotion of exclusive breastfeeding for at least 6 months, avoidance of formula feeding, and timely and adequate weaning with hygienic nutritious foods will help to prevent episodes of postinfectious PD. 3. Scaling-up of environmental control measures and safe water and hygiene strategies. Both macroenvironmental measures (provision of a safe and adequate water supply, hygienic waste disposal, etc) and microenvironmental measures (hand washing, hygienic storage and use of water, avoidance of stale/coldstorage infant foods in tropical environments) will help to prevent acute diarrhea and consequently PD. Although the benefit of hand washing strategies for the prevention of diarrhea is well recognized (19), the challenge is to introduce these measures on a scale that is meaningful and sustainable. In addition, rational and prompt management of acute diarrheal episodes, including use of oral rehydration solution, avoidance of unnecessary antimicrobial agents, early and adequate feeding during and after the episode of diarrhea, and possibly micronutrient supplementation (11,20), will contribute to early recovery from acute diarrheal episodes. These measures will also help to

enteropathy and bowel inflammation, preparations containing growth factors for ostensible intestinal trophic effects, and immunoglobulins (eg, bovine colostrum or bovine serum concentrate) for their antirotavirus effects. When this is unsuccessful, replacement of milk with another protein source, eg, egg white or chicken, is often effective. Most nutritional rehabilitation protocols for the treatment of PD in developed countries entail the administration of specialized enteral formulations, mainly lactose-free formulations or semielemental diets. However, these are beyond the reach of health resources in developing countries. They are also frequently unpalatable, require continuous administration, and thus are not appropriate in ambulatory settings. Because most PD cases occur in the community and parents frequently hesitate to seek help, the challenge is to develop a form of dietary therapy using inexpensive, home-available, and culturally acceptable ingredients. Recent data indicate that it may be entirely feasible to do so in community settings (15). The key role of micronutrients, especially zinc, in the treatment and prevention of PD is also well recognized. However, zinc supplementation is not included in public health programs in developing countries. Zinc supplementation during acute episodes has been shown to reduce the duration and severity of diarrhea (16), and when administered as part of a community treatment package for diarrhea, it reduces mortality and the rates of prescribing antimicrobials (17). As stated earlier, the biggest public health challenge is the development and widespread implementation of evidence-based strategies to treat PD. However, these must be based on information from intervention protocols in other settings. Too much emphasis is placed on developing new strategies when the technology and information needed to prevent most child deaths resulting from diarrhea are widely available (18). 1. Improved facility-based approaches and algorithms for the nutritional management of PD and malnutrition. Good nutrition is central to rapid and complete recovery from PD. Thus, the development and assessment of cost-effective enteral multinutrient formulations for the nutritional rehabilitation and therapy of children with PD and malnutrition remain a priority. These formulations need to be based on our understanding of the gut absorptive capacity and the critical nutrients required for repair and should consist of an appropriate balance of macronutrients and micronutrients. Although past dietary approaches have included soy formulations and elemental diets, they have not been shown to be superior to other diets or combinations validated in facility settings in developing countries. Oral antibiotics, either singly or in combination, have not been proven useful, but antimicrobial therapy is required for proven Clostridium diffi-

J Pediatr Gastroenterol Nutr, Vol. 39, Suppl. 2, 2004

PERSISTENT AND CHRONIC DIARRHEA AND MALABSORPTION prevent diarrhea-associated malnutrition and the occurrence of PD. It is beyond the scope of this report to evaluate how these basic needs can be met within public health and diarrheal disease control programs, but they require a combination of appropriate resources for public health and basic needs, staff training, and community mobilization. Priority Goals for Medical Education Information about potential preventive and intervention strategies for the reduction of the burden of PD should be incorporated into medical education programs. This should not be limited to medical and pediatric training curricula but should be extended to large-scale continuing medical education initiatives for the training of health professionals and workers. In addition, there must be commensurate moves toward public education so that a combination of push and pull strategies can be used. The priorities are the following: 1. Continuing medical education strategies. The important role that pediatricians play in child health notwithstanding, family physicians and public health officers represent the backbone of most primary care health services. Development of standardized education modules for the training of primary care physicians and health workers in the prevention, recognition, and management of PD and malnutrition is a priority. These educational strategies can thus consist of development of continuing medical education on the prevention and treatment of malnutrition and diarrheal diseases in childhood by colleges and professional societies, articles on clinical care and practice in journals devoted to standard general practice and family medicine, and manuals with simplified diarrhea prevention and treatment protocols for healthcare professionals at different levels. These should include simplification and improvement of the current World Health Organization/United Nations Children Fund integrated management of the sick child modules that concern the recognition, resuscitation and treatment of the malnourished child with PD. Web-based training modules are an excellent vehicle for spreading information. Some of these materials should be targeted to medical students and pediatric trainees and should focus on the recognition, management, and prevention of PD and malnutrition. They should consist of Web-based self-learning and educational materials, CD ROMs of background material and guidelines for treatment and prevention, and publication of standard case definitions and problems (vignettes or representative cases and photographs) in core pediatric texts and materials. 2. Education of nursing and paramedical personnel in ambulatory and health system settings. Given the in-

S715

creasing role of nursing and paramedical personnel in service delivery and health systems, it is important that they be well versed in the recognition and management of diarrhea, including PD. Development of protocols for the integrated management of the sick child in public health and community settings offers an important opportunity for training. These educational opportunities can also be extended to community health workers, given their increasing role in primary care settings. 3. Community and public health education strategies are important in educating families and parents in the recognition and management of diarrhea. They should be based on social marketing strategies for improved breastfeeding practices, domiciliary hygiene, and home-based management of diarrheal illnesses and should be reinforced through the mass media. Simple messages on diarrhea prevention, appropriate management, and early recognition of complicated diarrhea and PD may yield considerable dividends. Empowering parents and families with the skills for prompt recognition of problems and care seeking will lead to improved outcomes in children with recurrent diarrhea and PD. CONCLUSIONS In summary, PD is still a major cause of morbidity and mortality in the developing world and usually follows acute infectious diarrhea. Despite considerable progress in the understanding of the basic mechanisms and pathophysiology of prolonged diarrhea in infancy and related syndromes in the developed world, not even a fraction of comparable research has taken place in the developing world, where it is needed most. Thus, the challenge is to develop appropriate research, management, and education strategies to prevent and manage PD. REFERENCES
1. Black RE, Morris SS, Bryce J. Where and why are 10 million children dying every year? Lancet 2003;361:222634. 2. Snyder JD, Merson MH. The magnitude of the global problem of acute diarrheal disease: a review of active surveillance data. Bull World Heath Organ 1982;60:60513. 3. Kosek M, Bern C, Guerrant RL. The global burden of diarrheal disease as estimated from studies published between 1990 and 2000. Bull World Health Organ 2003;81:197204. 4. International Working Group on Persistent Diarrhoea. Evaluation of an algorithm for the treatment of persistent diarrhoea: a multicentre study. Bull World Health Organ 1996;74:479489. 5. Larcher VF, Shepherd R, Francis DE, et al. Protracted diarrhoea in infancy: analysis of 82 cases with particular reference to diagnosis and management. Arch Dis Child 1977;52:597605. 6. Fauveau V, Henry FJ, Briend A, et al. Persistent diarrhea as a cause of childhood mortality in rural Bangladesh. Acta Paediatr Suppl 1992;381:124. 7. Baqui AH, Black RE, Sack RB, et al. Malnutrition, cell-mediated immune deficiency and diarrhea: a community-based longitudinal

J Pediatr Gastroenterol Nutr, Vol. 39, Suppl. 2, 2004

S716

BHUTTA ET AL.
lentil-yogurt-milk diet with soy formula. J Pediatr Gastroenterol Nutr 1994;18:4552. Valentiner-Branth P, Steinsland H, Santos G, et al. Communitybased controlled trial of dietary management of children with persistent diarrhea: sustained beneficial effect on ponderal and linear growth. Am J Clin Nutr 2001;73:96874. Sazawal S, Black RE, Bhan MK, et al. Zinc supplementation in young children with acute diarrhea in India. N Engl J Med 1995; 333:83944. Baqui AH Black RE, El Arifeen S, et al. Effect of zinc supplementation started during diarrhea on morbidity and mortality in Bangladeshi children: community randomized trial. BMJ 2002; 325:1059. Jones G, Steketee RW, Black RE, et al, for the Bellagio Child Survival Study Group. How many child deaths can we prevent this year? Lancet 2003;362:6571. Curtis V, Cairncross S. Effect of washing hands with soap on diarrhoea risk in the community: a systematic review. Lancet Infect Dis 2003;3:27581. Bhutta ZA, Black RE, Brown KH, et al. Prevention of diarrhea and pneumonia by zinc supplementation in children in developing countries: pooled analysis of randomized controlled trials. J Pediatr 1999;135:68997.

8.

9.

10.

11.

12.

13.

14.

study in rural Bangladeshi children. Am J Epidemiol 1993;137: 35565. Azim T, Ahmad SM, Sefat-E-Khuda, et al. Immune response of children who develop persistent diarrhea following rotavirus infection. Clin Diagn Lab Immunol 1999;6:6905. Taniguchi K, Rikimaru T, Yartey JE, et al. Immunological background in children with persistent diarrhea in Ghana. Pediatr Int 1999;4:1627. Amadi B, Kelly P, Mwiya M, et al. Intestinal and systemic infection, HIV, and mortality in Zambian children with persistent diarrhea and malnutrition. J Pediatr Gastroenterol Nutr 2001;32: 5504. Bhutta ZA, Bird SM, Black RE, et al. Therapeutic effects of oral zinc in acute and persistent diarrhea in children in developing countries: pooled analysis of randomized controlled trials. Am J Clin Nutr 2000;72:151622. Bhutta ZA, Hendricks KH. Nutritional management of persistent diarrhea in childhood: a persistent from the developing world. J Pediatr Gastroenterol Nutr 1996;22:1737. Maiuri L, Ciacci C, Ricciardelli I, et al. Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. Lancet 2003;362:307. Bhutta ZA, Molla AM, Isani Z, et al. Nutrient absorption and weight gain in persistent diarrhea: comparison of a traditional rice-

15.

16.

17.

18.

19.

20.

J Pediatr Gastroenterol Nutr, Vol. 39, Suppl. 2, 2004