SUMMARY OF THE PROBLEM
Acute gastroenteritis (AGE) is an extremely frequent problem in childhood with 2 distinct consequences in rich and poor countries: hospital admissions and costs in the former, and death in the latter. AGE is the second leading cause of death in childhood, pneumonia being the first (1). The most frequent and dangerous agent is rotavirus, an infection with a typical target age distribution between 6 and 24 months of age and no specific geographical distribution.
The severity of AGE in poor countries results from a number of factors, primarily poverty and lack of education, and also limited access to health care requiring sick children and their mothers often to travel great distances to reach a physician.
A number of worldwide initiatives have been launched to reduce poverty and improve education and security. The Millenium Development Goals (MDG), a joint venture by the United Nations and the International Monetary Fund, the World Bank, and other organizations/agencies, are a series of 8 aims that have been established to reduce poverty and improve education, shelter, and security. The MDG number 4 (MDG4) is to reduce mortality in children younger than 5 years by two-thirds, between 1990 and 2015. One of the major causes of mortality in this age group is diarrhea. The MDG report in 2011 describes the success that has been obtained particularly in northern Africa and eastern Asia (2). Overall, the mortality rate has declined from 89 deaths per 1000 live births in 1998 to 60 in 2009 (ie, from 12.4 million in 1990 to 8.1 million in 2009, corresponding to 12,000 fewer children dying each day). The report stresses the role of infectious diseases as a major cause of death, in sub-Saharan Africa and southern Asia, Oceania, and southeast Asia. Children in rural areas have higher mortality, even in regions where overall child mortality is low. Mortality is associated with poverty, but the education of the mother is a powerful determinant of the survival of the child. According to the 2011 report, a child's chance of survival can also be improved by increasing equity in all social services.
Initiatives such as MDGs have been successful in part because of the massive investments of human and material resources. Part of the success is related to the large scale of the interventions and the relatively long time frame that allows time for global progress.
Several lessons have been learned from these programs. First, improvement in the quality of care in both primary health settings, and in hospitals, does increase survival; however, these interventions alone are ultimately insufficient to attain the objective. Second, the education of mothers (girls), parental networks for social support, and sustained economic equity among men and women are all essential. Third, strategies that have been tested in pilot studies with substantial success may not be effective when expanded to a larger group. The lack of monitoring and coordination of initiatives often results in termination of the project before achieving the primary objective. New knowledge is needed to develop effective strategies to treat AGE.
Because MDG4 is not likely to be reached, in 2009 UNICEF and WHO proposed a new plan to reduce diarrhea by applying a global approach that exploits multiple strategies including improving access to free water, community-wide promotion of sanitation, mass rotavirus immunization, support of breast-feeding, Vitamin A supplementation, and treatment of diarrhea with oral rehydration solution (ORS) and zinc (3).
An effective approach to improve quality care is the Plan Do Study Act (PDSA) model (4,5). This model supports the combined application of multiple strategies to reach objectives that are clearly stated and quantitatively monitored, through well-defined actions (Fig. 1). The barriers that prevent a goal to be reached are identified, described, and resolved before new actions to overcome those barriers being put forward to reach the goals. This continuing process allows a progressive improvement of health care (5).
A major aspect of large-scale programs is monitoring. Establishing baseline values for causes of death associated with AGE and evaluating the effect of interventions are difficult, yet essential issues. Recently, an instrument called Lives Saved Tools was developed to measure not only country-specific causes of death, but also the effect of specific interventions, such as those proposed by MDG4 (6). Using Lives Saved Tools, it was estimated that if 7 interventions in prevention and 3 for treatment were applied in 68 countries in which 95% of child deaths occur, mortality would decrease by 78% by 2015, in keeping with the MDG4 aim and schedule (Table 1) (6).
A FISPGHAN working group comprising representatives from each pediatric gastroenterology society was charged with identifying the top priorities in medical intervention, education, and research that may affect on AGE (Table 1). The working group used evidence and expert opinion related to the diagnosis, prevention, and treatment of AGE. Consensus was reached on priorities that were considered of relevance to obtaining the goals indicated by MDG4.
FISPGHAN working group members agreed to contribute to an ongoing coordinated program such as the MDG4, rather than promote another initiative. The report includes the identification of priorities in terms of medical interventions, education, and research, but the working group felt that there was a synergy by the interrelation of the priorities of medical intervention and education. The research agenda is intended to produce new knowledge that will form the basis of future priorities for intervention and education.
PRIORITIES FOR MEDICAL INTERVENTIONS
Number 1 Priority Is to Implement Immunization Against Rotavirus
This is supported by the following considerations: The number of deaths from AGE independent of the etiology was 1.8 million in 2003 and 1.3 million in 2008 in children younger than 5 years (7). The decrease in the death rate from diarrhea was largely the result of sanitation and hygiene that reduced intestinal infections caused by bacteria and parasites that are predominantly spread through food and water. In contrast, viral diarrhea is transmitted from person to person, and rotavirus still has a major effect on the death rate from AGE. Despite a progressive decrease in diarrhea-related mortality during 30 years, rotavirus mortality actually increased. In the last published report, the estimated deaths caused by rotavirus were 453,000, corresponding to 37% of diarrhea-related deaths, and to 5% of all deaths in children younger than 5 years (7). This problem is amenable to a solution, as 95% of rotavirus-induced deaths occurred in 72 countries all of whom were eligible to receive Global Alliance for Vaccine Immunization (GAVI) support. The highest absolute number of deaths (99,000) was recorded in India (22%) and >50% were recorded in 5 countries, including India, Nigeria, Pakistan, Congo, and Ethiopia (7); however, India has a rising per capita income projection that will soon exclude it from eligibility for GAVI, resulting in many children becoming vulnerable to rotavirus-induced gastroenteritis.
There are public health barriers to the implementation of rotavirus immunization, but all of the authorities recommend universal immunization and recently WHO recommendations were expanded to all countries with a particular emphasis on countries at highest risk of mortality (8).
Rotavirus vaccination is safe, prevents the vast majority of severe disease, has few adverse effects, and has been effective in reducing the burden of rotavirus infection in countries that introduced mass vaccination (8). The available vaccines even may be administered to HIV-positive babies. Thus far, rotavirus vaccines have been introduced in United States, selected European countries, and Oceania and are being implemented in selected countries in Asia; however, many countries in Asia and virtually all of Africa are still waiting for programs to be initiated. The major barriers against large-scale immunization are the need for administration within a limited time frame corresponding to the first 6 to 8 weeks following birth and a vaccination schedule that needs to be completed by 6 months of age to decrease the risk of intussusception. The likelihood of intussusception following rotavirus immunization is low based on large clinical trials and postmarketing data. Furthermore, the benefit in lives saved by broadening age restrictions for immunization may exceed the risk of potential deaths related to intussusception (9). The consensus of the working group is to provide specific immunization programs in areas of high mortality because of AGE by immunizing children to rotavirus at the times of scheduled immunizations. This would likely result in significant protection and in the substantial reduction of mortality because of rotavirus, but more data are needed to test the hypothesis that delayed administration of rotavirus vaccine would increase immunization coverage, thereby resulting in substantially better coverage of the population at risk.
A workshop with representatives of countries seriously affected by rotaviral disease should be convened to discuss whether this “rescue strategy” would be worth pursuing in terms of risk/effectiveness and investment. Because of the large contribution of Indian children to deaths caused by rotavirus, programs focused on regions most in need should be offered by GAVI.
Number 2 Priority Is the Promotion of ORS Administration
This priority is well known to be effective in reducing the death rate (Table 2); however, resources should be allocated to support the education of mothers and girls who are the primary providers for infants. Early recognition of the signs and symptoms of diarrhea and dehydration and rapid introduction of ORS has the potential, if applied routinely, to save an enormous number of lives at very little cost (10).
ORS has been called the most important “drug” of the 20th century because this simple, easily available, and extremely inexpensive solution has saved the lives of millions of children. Despite all of the success, there are barriers to administration of ORS and dehydration remains as the major cause of death from AGE. The obstacles to success are linked to inadequate education and insufficient information provided to mothers and girls resulting in delays in recognizing the severity of diarrhea, as well as poor access to health care services (10), Education of women and girls is essential in maintaining the health of a family.
The optimal composition of ORS has been extensively discussed elsewhere and there are 3 primary options: the Classic WHO/UNICEF ORS with 90 mOsm/L Na concentration; the so-called hypo-osmolal ORS with 75 mOsm/L Na; and the Zn-enriched ORS, recently proposed by WHO/UNICEF by adding Zn to hypo-osmolal ORS. Lower-osmolality ORS has better palatability and is consumed more easily by mildly dehydrated infants, whereas children with severe dehydration will drink the more salty-tasting ORS. The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition solution contains 60 mOsm/L of Na and is recommended for children of Europe, but it seems to be effective in children living in developing countries (11). The efficacy of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition solution in children with cholera needs to be determined.
ORS is underused in both resource-sufficient and resource-poor countries. Several studies suggest that one reason for underuse of ORS is the belief that “replacement” of fluid losses with a simple solution of salt and sugar is perceived as ineffective by both families as well as physicians. The addition of Zn to ORS potentially addresses this perception because Zn facilitates intestinal ion absorption and is effective in vivo and in vitro against 3 of the 4 mechanisms of infectious diarrhea (12). In addition, Zn stimulates enterocyte growth, helping to restore epithelial damage, and potentiates immune function. When Zn is added to ORS, the correct dose remains an issue because there is a narrow range between efficacy and toxicity. Presently, as adjunctive treatment during episodes of acute diarrhea, WHO recommends 10 mg of Zn per day in infants younger than 6 months and 20 mg in children older than 6 months (13). Such scheme is extremely simple but it may be worth reviewing, to see whether it is possible to find an equally safe and simple scheme but a more effective result. Either the amount of Zn or the optimal way to administer it could probably be optimized in the future. The form and dose of Zn administration in AGE could be reevaluated by an expert committee.
Effective strategies to support ORS implementation rely on universal availability, early use, and education and empowerment of women and girls. Public health strategies should be put forward to instruct mothers at their initial infant visit how to recognize the symptoms of diarrhea and promptly to start rehydration, while continuing with breast-feeding or formula if breast milk is not feasible (see Priorities for Education).
Number 3 Priority Is the Reduction of Inappropriate Medical Interventions for AGE
Excessive interventions for gastroenteritis such as hospitalization, microbiological investigations, dietary modifications, as well as administration of drugs are not necessarily effective, may detract from giving ORS, and are not included in the guidelines (14). Controlling unnecessary medical interventions goes along with the implementation of ORS. When a child with AGE is first evaluated by a physician, hospital admission is often considered despite the lack of evidence for benefit (11). In many countries in Europe, North America, and Australia, hospitalization removes the child from the family, results in increased medical costs, and exposes the child to nosocomial infections. The value of hospital admission in resource-poor countries, in which many children die because of limited access to care, is difficult to know. This is an area of health care use worth exploring.
Dietary interventions are often recommended for infants with acute diarrhea, but most of these suggestions are not evidence-based. Rice, the BRAT diet (a mnemonic for bananas, rice, apple sauce, and toast), the use of local cereals, and other options based on local traditions have been proposed. The major risks associated with the use of elimination diets are that they increase weight loss and may trigger a vicious cycle of diarrhea and malnutrition (15). Breast milk should always be continued and offered without limitations.
Medications have been recommended to treat AGE, but few have compelling evidence of efficacy based on reliable data (16). Any drug that is used to treat gastroenteritis should come with information that it should be used as an adjunct to ORS. Limiting medical intervention is difficult to achieve because there often is pressure for intervention by parents of sick children. Evidence-based guidelines may empower health care providers to follow effective management strategies and improve quality of care (4). The working group members agreed that convening a task force to investigate the value of developing universal evidence-based guidelines for the management of AGE would be of value to health care providers. The guidelines should take into consideration differences in epidemiology and availability of local and regional resources. Causes of AGE, including cholera, local traditions, and beliefs, and the cost involved in delivery of care should be considered. The availability of universal guidelines supported by all of the major pediatric gastroenterology societies, including emphasis of the importance of educating women and girls, would fill an unmet need in improving the outcomes for children with AGE and increase the likelihood of meeting goals indicated by MDG4.
PRIORITIES FOR EDUCATION
The working group members discussed priorities to correct gaps in education that would be synergetic with priorities for medical intervention. In the 2011 Millenium Development Goal report (2), there was recognition that the “mother's education is a powerful determinant of child survival” (goal 4, page 26). The report stated that “Empowering women, removing financial and social barriers, encouraging innovations to make critical services more available to the poor, and increased accountability of health systems at the local level are examples of policy interventions that could improve equity with benefits for child survival.”
Targets of education programs should include the general population, but in particular mothers of newborn infants and their families, the healthcare providers who evaluate infants and young children with AGE, and social workers, nurses, and other healthcare professionals at the local level. School teachers and those involved in mass media should also be recruited to provide education on the care and management of gastroenteritis. Although mortality from AGE is an international problem, resources should be allocated to those countries where mortality from acute diarrhea is the highest (6).
Priority Number 1 Is to Provide a Global Education Package to Mothers and Girls on Gastroenteritis Prevention and Management
The top priority is to prepare a set of key messages (a global education package) to educate mothers and girls about how to prevent AGE, to recognize the signs and symptoms of diarrhea and dehydration, and to effectively treat the problem.
The few key messages crucial to limit the spread and consequences of AGE are the following:
1. Hand washing with soap
2. Family education and promotion of oral rehydration provided during well visits
3. Construction of toilets
4. Implementation of breast-feeding
These issues play a major role in the prevention of gastroenteritis and were highlighted in the 2009 report published by WHO and UNICEF on diarrhea in children (2); however, they require a broad-based strategy because hand washing depends not only on an understanding of personal hygiene but also on the availability of clean water.
As a strategy to disseminate information, pamphlets with signs of dehydration and instructions of how to prepare ORS and a sachet of ORS should be given to each mother at the time of her first medical contact. Mothers, physicians, nurses, social workers, and other health care providers should be the targets of this initiative. The approach should include a “train the trainer” approach and use e-learning where feasible to reach the widest audience. Application of the PDSA model should be considered as a strategy to change behaviors (5).
Priority Number 2 Is Dissemination of Guidelines
Increasing awareness of the value of ORS and the need to reduce inappropriate medical interventions will result in lowering mortality. The present widespread use of medications decreases the use of ORS. Creation and dissemination of universal guidelines could be accomplished by collaboration among the pediatric gastroenterology societies comprising FISPGHAN. Many of the societies already have educational initiatives, and increasing awareness of the importance of effectively treating AGE could become a top priority. Programs could be developed for physicians, nurses, and health care providers in countries with the greatest needs to spread the key messages on prevention and management of AGE until 2015, when MDG4 goal is expected to be reached.
PDSA is a model of quality care improvement based on ongoing reassessment of interventions. Implementation of the methodology at the national and local levels will result in adoption of guidelines and incremental change directed at achieving the MDG4 goal. Partnering with agencies and institutes to initiate these programs is a critical priority.
Priority Number 3 Is to Use e-Learning to Promote Education
The internet is an important instrument that is underused in resource-poor communities to promote education. e-Learning is an inexpensive resource that not only can be used to disseminate information but also through the Internet's capability of linking individuals with audio and video health care providers can share experiences about effective strategies and interventions. Networks may already exist that could be expanded and focused to meet the MDG4 goal. Collaboration with agencies and foundations that share this mission is essential.
PRIORITIES FOR RESEARCH
The microbial ecosystem that resides in the gastrointestinal tract exists in a symbiotic relationship with the host. During times of undernutrition, the host is able to sustain this community by providing nutrients. Similarly, the microbiome may affect metabolic networks to protect the host at times of stress. Little is known about the perturbations of this intestinal ecosystem during AGE. Eradication of specific viral, bacterial, or parasitic pathogens had been the goal of recent treatment intervention. To change this paradigm, 3 priorities are proposed.
Priority Number 1 Is to Understand the Perturbations of the Intestinal Microbiome and the Metabolome That Occur During Episodes of AGE
Although implementation of vaccines is a top priority in preventing known causes of AGE, changing the focus from specific pathogens to better understand the role of the intestinal microbiota in the host response is critical for the discovery of new treatment modalities. Knowledge about the ways in which this intestinal ecosystem communicates with the host through locally produced metabolites will enable novel effective therapeutic interventions to be tested.
Priority Number 2 Is to Investigate Environmental and Host Factors, Such as Immune Function, That May Affect Outcomes in Children With AGE
Much has been learned in the last decade about the relation between malnutrition and host immune function from the HIV pandemic. Intestinal infection leads to nutrient malabsorption and eventual malnutrition. Individuals who are malnourished become more susceptible to infections because of immune dysregulation and the cycle is completed. Maternal health is a critical factor that affects these interrelationships (Fig. 2). Research focused on the environmental and host factors that potentiate malnutrition, and immune dysregulation in children with AGE will disrupt this cycle and help children regain their health.
Priority Number 3 Is to Apply Systems Biology Methodology Integrating Host, Microbial, Immunologic, Genetic, and Epigenetic Factors to Identify Novel Metabolic Pathways That Will Lead to the Discovery of New Therapeutic Interventions and More Effective ORS
Knowledge derived from cancer research about alterations in metabolic pathways has led to the discovery of new treatments. Understanding the relationships between the environment, intestinal microbiota, and immunologic, genetic, and epigenetic host factors has its own set of unique issues, but application of systems biology methodology to the problems encountered in acute diarrheal disease may lead to the discovery of novel therapies and a better understanding of the value of ORS.
AGE affects children in every country and is the second leading cause of death in childhood. In resource-sufficient countries, hospital admissions for management of diarrheal disease add significant expense to health care costs. For these reasons, every country has a reason to improve the care of children with AGE. Immunization against pathogens, early use of ORS, and reduction of inappropriate and unnecessary medical interventions are critical priorities. Education of women and girls about hygiene and recognition of the signs and symptoms of diarrhea and dehydration through creation of targeted programs are needed. Research focused on understanding the relationships between the intestinal microbiota and the host through a systems biology approach may lead to new therapeutic interventions and more effective ORS.