Transmission

Diarrhea is caused by infectious organisms, including viruses, bacteria, protozoa, and helminths, that are transmitted from the stool of one individual to the mouth of another, termed fecaloral transmission. Some are well known, others are recently discovered or emerging new agents, and presumably many remain to be identified. They differ in the route from the stool to the mouth and in the number of organisms needed to cause infection and illness. Among bacteria, the ability to survive stomach acid is an important determinant of the inoculum size required to cause illness. For example, Shigella bacteria are resistant to low pH, and a few thousand organisms suffice, which are readily transferred by direct person-to-person contact or through contamination of inanimate objects, such as a cup. In contrast, bacteria readily killed by acid, such as Vibrio cholerae, require millions of organisms to cause illness, and therefore must first multiply in food or water to an infectious dose. Some pathogens, such as rotavirus, display a sharp host species preference, and others have a broad host range. Among Salmonella bacteria, certain bio-serotypes are adapted to infect animals and pose no threat to humans, and others are adapted to humans and do not infect animals. The majority, however, are not adapted to a specific host and can infect either humans or domestic animals, thus facilitating transmission of these organisms to humans. Less than a dozen of the more than 2,500 individual Salmonella cause the majority of human infections, reflecting the requirement for genes that encode essential virulence factors.

The ability to identify virulence genes and their products has led to new molecular approaches to epidemiology and diagnosis, and undoubtedly will lead to new measures to prevent and treat diarrhea. Molecular methods also allow the separation of organisms that otherwise appear to be identical. Nonpathogenic Escherichia coli in normal stool cannot be separated from diarrhea-causing E. coli by standard methods; however, identification of virulence genes or factors distinguishes five groups of E. coli that cause illnesses ranging from cholera-like watery diarrhea to neonatal diarrhea, persistent diarrhea, and bloody diarrhea (Nataro and Kaper 1998).

Laboratory Diagnosis

Etiologic diagnosis of diarrhea is valuable for public health interventions and case management. Microbiological culture and microscopy remain the standard, despite their limited sensitivity. Their effectiveness is further reduced by antibiotic use, and patients with severe illness are more likely both to be cultured and to have taken antibiotics. Even when cultures are positive, the delay in laboratory identification limits their cost-effectiveness for managing individual patients. The information is always epidemiologically and clinically important; however, during epidemics, culturing every patient is unnecessary when the causative organism is known. Antimicrobial resistance data are essential to guide initial antibiotic choices.

New rapid tests to detect inflammatory mediators or white or red blood cells in stool offer the promise of distinguishing between secretory and inflammatory disease and optimizing case management (Huicho and others 1996). High background levels, probably from frequent infections, limits the use of such tests in developing countries, where they would be most useful (Gill and others 2003).

Simple microscopy for protozoa or helminths can be quick and effective when the proper sample is obtained and a well-trained technician is available to examine a fresh specimen, but these prerequisites are often not available in developing countries. Newer immunological and nucleic acid–based tests to detect pathogen-specific factors hold great promise for all diarrhea agents, but they are too expensive or require specialized instrumentation and trained technicians. For the foreseeable future, then, syndromic diagnosis will be the norm.

Syndromic Diagnosis

Three major diarrhea syndromes exist. They are acute watery diarrhea, which results in varying degrees of dehydration; persistent diarrhea, which lasts 14 days or longer, manifested by malabsorption, nutrient losses, and wasting; and bloody diarrhea, which is a sign of the intestinal damage caused by inflammation. The three are physiologically different and require specific management. Syndromic diagnosis provides important clues to optimal management and is both programmatically and epidemiologically relevant.

Acute watery diarrhea can be rapidly dehydrating, with stool losses of 250 milliliters per kilogram per day or more, a quantity that quickly exceeds total plasma and interstitial fluid volumes and is incompatible with life unless fluid therapy can keep up with losses. Such dramatic dehydration is usually due to rotavirus, enterotoxigenic E. coli, or V. cholerae (the cause of cholera), and it is most dangerous in the very young.

Persistent diarrhea is typically associated with malnutrition, either preceding or resulting from the illness itself (Ochoa, Salazar-Lindo, and Cleary 2004). Even though persistent diarrhea accounts for a small percentage of the total number of diarrhea episodes, it is associated with a disproportionately increased risk of death. In India, persistent diarrhea accounted for 5 percent of episodes but 14 percent of deaths, and a mortality rate three times higher than briefer episodes (Bhan and others 1989). In Pakistan, persistent diarrhea accounted for 8 to 18 percent of episodes but 54 percent of deaths (Khan and others 1993). In Bangladesh, persistent diarrhea associated with malnutrition was responsible for nearly half of diarrhea deaths, and the relative risk for death among infants with persistent diarrhea and severe malnutrition was 17 times greater than for those with mild malnutrition (Fauveau and others 1992). Persistent diarrhea occurs more often during an episode of bloody diarrhea than an episode of watery diarrhea, and the mortality rate when bloody diarrhea progresses to persistent diarrhea is 10 times greater than for bloody diarrhea without persistent diarrhea. HIV infection is another risk factor for persistent diarrhea in both adults and children (Keusch and others 1992). Management focuses on overcoming the nutritional alterations initiated by persistent diarrhea.

Bloody diarrhea, defined as diarrhea with visible or microscopic blood in the stool, is associated with intestinal damage and nutritional deterioration,often with secondary sepsis.Some dehydration—rarely severe—is common, as is fever. Clinicians often use the term bloody diarrhea interchangeably with dysentery; however,dysentery is a syndrome consisting of the frequent passage of characteristic, small-volume, bloody mucoid stools; abdominal cramps; and tenesmus, a severe pain that accompanies straining to pass stool. Those features show the severity of the inflammation. Agents that cause bloody diarrhea or dysentery can also provoke a form of diarrhea that clinically is not bloody diarrhea, although mucosal damage and inflammation are present, and fecal blood and white blood cells are usually detectable by microscopy. The release of host-derived cytokines causes fever, altering host metabolism and leading to the breakdown of body stores of protein, carbohydrate, and fat and the loss of nitrogen and other nutrients. Those losses must be replenished during convalescence, which takes much longer than the illness does to develop. For these reasons, bloody diarrhea calls for management strategies that are markedly different than those for watery or persistent diarrhea. New bouts of infection that occur before complete restoration of nutrient stores can initiate a downward spiral of nutritional status terminating in fatal protein-energy malnutrition (Keusch 2003).

Diarrhea, Environment, and Poverty

Diarrheal disease affects rich and poor, old and young, and those in developed and developing countries alike, yet a strong relationship exists between poverty, an unhygienic environment, and the number and severity of diarrheal episodes—especially for children under five.

Poverty is associated with poor housing, crowding, dirt floors, lack of access to sufficient clean water or to sanitary disposal of fecal waste, cohabitation with domestic animals that may carry human pathogens, and a lack of refrigerated storage for food—all of which increase the frequency of diarrhea. Poverty also restricts the ability to provide age-appropriate, nutritionally balanced diets or to modify diets when diarrhea develops so as to mitigate and repair nutrient losses. The impact is exacerbated by the lack of adequate, available, and affordable medical care. Thus, the young suffer from an apparently never-ending sequence of infections, rarely receive appropriate preventive care, and too often encounter the health care system when they are already severely ill.

Although the presence of blood in the stool is a recognized danger signal, prompting more urgent care seeking, even these patients either are not treated early or receive poor medical care. Ironically, the poor spend considerable amounts on inappropriate care and useless drugs purchased from local shops and untrained practitioners. If antibiotics are properly prescribed, poverty often limits the purchase of a full course of treatment or leads to cessation of treatment as soon as symptoms improve, even though the infection has not been cured.

Public Health Significance of Diarrheal Illnesses

Continuing surveillance and longitudinal studies allow tracking of current levels and trends in diarrhea incidence and mortality and provide the basis for future projections and for evaluations of different control strategies.

Morbidity

Comparisons over time of the global burden of diarrheal diseases have revealed secular trends and demonstrated the impact of public health interventions (Bern and others 1992; Kosek, Bern, and Guerrant 2003; Snyder and Merson 1982). The long-term consequences of diarrhea are only now being systematically assessed and are not reflected in earlier studies.

Reviews in 1992 (Bern and others) and 2003 (Kosek, Bern, and Guerrant) are similar in many ways—for example, assessing morbidity at least twice weekly—but differ significantly in the use of different sources for data on children under five and in the inclusion of studies differing in design and data collection protocols (and only the later study includes data from China). Remarkably, the estimated median incidence of diarrheal disease in children under five in developing countries has not changed much since the early 1990s (figure 19.1): 3.2 episodes per child per year in 2003 (Parashar and others 2003) compared with 3.5 episodes per child per year in 1993 (Jamison and others 1993). However, many fewer surveys were available for the most recent review (31 in 20 countries) compared with the 1993 consensus (276 in 60 countries), reflecting diminished support for the systematic collection of incidence data. Incidence rates in Sub-Saharan Africa and Latin America are clearly greater than in Asia or the Western Pacific, while subject to greater data limitations from individual countries. Incidence continues to show a peak in infants age 6 to 11 months, dropping steadily thereafter.

Figure 19.1

Median Age-specific Incidences for Diarrheal Episodes per Child per Year from Three Reviews of Prospective Studies in Developing Areas, 1955–2000

The seemingly lower estimates of diarrheal incidence before 1980 (Snyder and Merson 1982) are likely due to methodological differences. These estimates are not precise or directly comparable; the trends are most relevant. The persistently high rates of diarrhea throughout the 1990s despite intensive efforts at control, particularly among children age 6 to 24 months, is of particular concern. Early childhood diarrhea during periods of critical postnatal development may have long-term effects on linear growth and on physical and cognitive functions.

Data on the incidence of shigellosis, the principal cause of bloody diarrhea in developing countries, are even more limited. Kotloff and others' (1999) review of studies on Shigella infection estimates that more than 113 million episodes occur every year in children under five in developing countries, or 0.2 episodes of bloody diarrhea per year caused by Shigella species.

Mortality

Bern and others (1992); Kosek, Bern, and Guerrant (2003); and Snyder and Merson (1982) also estimate diarrheal mortality using data from longitudinal studies with active surveillance in place (figure 19.2). The estimate before 1980 was 4.6 million deaths per year. This estimate dropped to 3.3 million per year between 1980 and 1990 and to 2.6 million per year between 1990 and 2000. Two other studies (Parashar and others 2003; Boschi-Pinto and Tomaskovic forthcoming) report even lower figures for 1990–2000: 2.1 million and 1.6 million deaths per year, respectively. Methodological variations (inclusion of studies with different designs and data collection methods and inclusion of data from China, different sources for estimating the number of children under five, and different strategies for calculating mortality for this age group) may account for some of the striking differences. However, the end of the 20th century witnessed significant reductions in diarrheal deaths in children under five.

Figure 19.2

Estimates of Diarrhea Mortality, 1975–2000

This steady decline in diarrheal mortality, despite the lack of significant changes in incidence, is most likely due to modern case management (introduced since the 1980s) and to the improved nutrition of infants and children. Major recommendations include the following:

• counseling mothers to begin suitable home-prepared rehydration fluids immediately on the onset of diarrhea
• treating mild to moderate dehydration early with oral rehydration solution (ORS), reserving intravenous electrolytes for severe dehydration
• continuing breastfeeding and complementary foods during diarrhea and increasing intake afterward
• limiting antibiotic use to cases of bloody diarrhea or dysentery and avoiding antidiarrheal and antimotility drugs
• advising mothers to increase fluids and continue feeding during future episodes.

Victora and others' (2000) review provides evidence that this strategy, and especially oral rehydration therapy (ORT), has influenced the outcome of dehydrating diarrhea. Data from 99 national surveys carried out in the mid 1990s and compiled by the United Nations Children's Fund (UNICEF) increasingly show that diarrhea patients are appropriately managed in most parts of the world,with overall use rates of ORS or recommended home fluids reaching 49 percent. Country case studies in Brazil, the Arab Republic of Egypt, Mexico, and the Philippines showed a dramatic reduction of diarrhea mortality as ORT use rates increased from close to zero in the early 1980s to 35 percent in Brazil, 50 percent in Egypt, 81 percent in Mexico, and 33 percent in the Philippines in the early 1990s. Hospital admissions for diarrhea also plummeted (Victora and others 2000). As mortality attributable to acute dehydration decreased, the proportionate mortality associated with persistent diarrhea increased. Data from Brazil and Egypt suggest that even relatively low ORT use rates can positively affect mortality,because ORT use tends to be much higher for severe illness (Victora and others 2000).

Worldwide mortality caused by Shigella infection is estimated to be 600,000 deaths per year among children under five, or a quarter to a third of all diarrhea-related mortality in this age group (Kotloff and others 1999). Because mortality caused by bloody diarrhea is not tracked separately, it is difficult to assess the impact of standard case management recommendations, and disease-specific trends cannot be tracked. In the past few years, however, data from the International Centre for Diarrheal Disease Research, in Bangladesh, have shown a marked decrease in the rate of hospitalization caused by Shigella, especially S. dysenteriae type 1, the most severe form of shigellosis. Some investigators have suggested that this decrease may be because Shigella infections are now in the low part of a 10-year cycle (Legros 2004). The observed change could also be explained by better case management with more efficacious antimicrobials. More comprehensive, syndrome-specific surveillance data will be required if rational control priorities are to be set, because the options for dehydrating and bloody diarrheal diseases differ substantially.

Despite national data that indicate a significant decline in mortality (Baltazar, Nadera, and Victora 2002; Miller and Hirschhorn 1995), diarrheal diseases remain among the five top preventable killers of children under five in developing countries and among the top two in many.

Preventive Strategies

Strategies for controlling diarrheal diseases have remained substantially unchanged since the 1993 edition of this volume (Martinez, Phillips, and Feachem 1993). The World Health Organization (WHO 2004) recently reevaluated these interventions to determine the extent to which they have been effectively implemented and their effect.

Case Management

Two recent advances in managing diarrheal disease—(a) newly formulated ORS containing lower concentrations of glucose and salts and (b) zinc supplementation—used in combination with promotion of exclusive breastfeeding, general nutritional support, and selective and appropriate use of antibiotics, can further reduce the number of diarrheal deaths among children. Families and communities are key to achieving case management goals by making these recommendations routine practice in homes and health facilities.

Cost-Effectiveness of Interventions

Cost-effectiveness ratios of diarrheal disease interventions were calculated by World Bank region in terms of disability-adjusted life years (DALYs) averted for a model population of 1 million, following the standardized guidelines of the Disease Control Priorities Project for economic analyses (see chapter 15). Europe and Central Asia were excluded because data were lacking owing to the low prevalence of disease. Input variables included (a) region-specific diarrhea morbidity rates adapted from Kosek, Bern, and Guerrant (2003); (b) region-specific underlying mortality rates and age structures provided by the Disease Control Priorities Project; (c) median intervention effectiveness rates (that is, percentage of diarrheal morbidity reduction and percentage of diarrheal mortality reduction); and (d) median per capita intervention costs gathered from the literature and from personal communications (table 19.1).

Table 19.1

Cost and Effectiveness Values Used to Calculate Cost-Effectiveness Ratios for Select Interventions for Diarrhea for Children under Age Five.

Because approximately 90 percent of all cases in the developing world occur in children under five, the analysis focused on this age group alone. Uniform intervention effectiveness rates were assumed for all regions because region-specific information was not available. Regional variations in cost-effectiveness were due to regional variations in the prevalence of diarrheal disease, in the diarrhea-attributable morbidity and mortality, and in the intervention cost, where region-specific information was available.

Disability-adjusted life years are averted through the avoidance of cotemporaneous disability and mortality attributable to diarrhea. We did not consider long-term developmental and cognitive effects of childhood diarrhea or the external benefits of interventions unrelated to diarrhea (for instance, benefits of measles immunization unrelated to diarrhea or other health benefits of improved public water and sanitation). Therefore, our estimates err on the conservative side.

We explored two general categories of interventions: early interventions that take place within the first year of life—breastfeeding promotion and immunizations for rotavirus (with the prototype Rhesus reassortant tetravalent vaccine), cholera (with live oral vaccine), and measles—and other interventions that treat an entire cohort of children under five simultaneously (improved water and sanitation). For early interventions, cost-effectiveness ratios were calculated by considering the cost of treating all newborns in a single year and the benefits (DALYs averted) from those treatments that occur over the first five years of life. These benefits include avoided mortality that allows individuals to live to the expected life expectancy for the region. Other interventions included ORT and improved water and sanitation infrastructure. Because a single year of these interventions yields only cotemporaneous benefits—because effectively treated individuals do not necessarily live to life expectancy given that they are likely to be reinfected the next year—we calculated cost-effectiveness of a five-year intervention. Analysis of a five-year intervention enabled us to consider the case in which an entire cohort of children age zero to four avoids early childhood diarrheal mortality because of the intervention and receives the benefit of living to life expectancy.

Disability and deaths averted for those benefiting from improved water and sanitation were calculated from only the fraction of the model populations currently without access. For each region, the proportion of rural and urban children age zero to four currently without access to improved water and sanitation was calculated using region-specific information from World Bank Development Indicators (World Bank 2002) for 2000. Infrastructure improvements for rural and urban populations were considered separately because of differences in infrastructure type and cost, although the same effectiveness rates were used for both.

The per child treatment costs and effectiveness rates used are presented in table 19.1. Cost per treatment of ORT varied widely depending on the type and method of ORT implemented. Oral rehydration therapy can be as inexpensive as US$0.02 per child treated—the cost of a home remedy with sugar and salt. However, treatment can become substantially more expensive if commercially manufactured ORS is used or if there are substantial personnel or infrastructure costs (Martinez, Phillips, and Feachem 1993). Finally, our analysis considered only long-run marginal costs (which vary with the number of individuals treated) and did not include fixed costs of initiating a program where none currently exists.

Figure 19.3 shows the cost-effectiveness of all interventions over the first five years of life. Two interventions administered during the first year of life—breastfeeding promotion (US$930 per DALY) and measles immunization (US$981 per DALY)—were the most cost-effective. ORT (US$1,062 per DALY) and water and sanitation in rural areas (US$1,974 per DALY) were the next most cost-effective, but only if they were implemented continuously for five years, thereby allowing an entire cohort of effectively treated children age zero to four to survive past the age at which they are most at risk for diarrheal infection, disability, and mortality. Rotavirus immunization (US$2,478 per DALY), cholera immunization (US$2,945 per DALY), and water and sanitation in urban areas (US$6,396 per DALY) were the least cost-effective.

Figure 19.3

Cost-Effectiveness: Intervention at Birth through Age 5 with Benefits That Occur over Five Years (age 0–4)

Among the early interventions, breastfeeding promotion was less effective than other interventions but also less expensive than rotavirus and measles vaccination (table 19.1). Cholera vaccination was less expensive than breastfeeding promotion, but it was also many times less effective because of the significantly higher prevalence of diarrhea that is not related to cholera—making cholera vaccination the least cost-effective of the early interventions considered. Oral rehydration therapy and water and sanitation interventions were more effective than breastfeeding and vaccination interventions in reducing morbidity and mortality caused by diarrhea, but they were also more expensive. However, our analysis for water and sanitation did not consider the benefits of this intervention other than those related to health, and the high cost-effectiveness ratio is more a limitation of our methodology than of the intervention itself.

The high cost-effectiveness ratio for ORT is attributable to the high variation in reported treatment costs, which may inflate the median cost used in this analysis (table 19.2). Given the range of reported treatment costs (table 19.1), the cost-effectiveness ratio of ORT could be as low as US$4 per DALY or as high as US$2,124 per DALY in low- and middle-income countries. High variation in reported treatment costs results in high variation in cost-effectiveness for the other regions as well. There remains little doubt, however, about the effect of widespread use of ORT on diarrhea morbidity and mortality and about the associated direct and indirect cost savings for treatment and hospitalization.

Table 19.2

Cost-Effectiveness Ratios of Oral Rehydration Therapy Interventions Based on Minimum, Median, and Maximum per Capita Costs (2001 US$/DALY).

Research Agenda

Good evidence now supports the view that promoting ORT in conjunction with other key interventions, preventive as well as curative, has had a large role in the marked reduction in deaths of children caused by diarrhea (Victora and others 2000). Preventive strategies—such as breastfeeding, improving complementary feeding and using micronutrient supplementation or fortification, and increasing coverage with the full set of Expanded Programme on Immunization vaccines (especially measles vaccine)—are all useful and effective (GAVI 2005). Failure to separately track the full impact of bloody diarrhea—especially Shigella infection—on morbidity and mortality or to effectively implement good clinical management (including guidelines for and control over the use of antibiotics) has contributed to the continuing burden of bloody diarrhea and dysentery worldwide and the alarming increase in antibiotic resistance. The challenges for the next decade will be to increase or ensure universal appropriate implementation of these interventions in developing countries and to avoid a situation in which they compete for funding and staff time. Delivery of good-quality services is essential, and much remains to be learned through research before this requirement can be met.

Other interventions, such as vaccines against rotavirus, Shigella, or cholera, are either not yet available or not ready for universal administration. Progress toward the development of these vaccines, with the highest priority for the first two, is encouraging, but further investments in research and development will be required before large-scale implementation of these interventions can be considered. The cost of these vaccines will remain a major constraint for poor people, who cannot pay for the costs of development and ensure reasonable profits for industry. However, increased public investment in fundamental and applied research, vaccine purchase schemes, and development of low-cost, high-quality manufacturing capacity in developing countries may change the prevailing dynamics. By creating public-private partnerships for vaccine development, organized as targeted product development programs, the public sector, private foundations, and industry are taking steps toward these goals.

Because of the fecal-oral transmission of enteric pathogens, improving the supply of safe water and the ability to safely dispose of fecal waste are the best ways to reduce the burden of morbidity and mortality. However, major investments and critical improvements in water and sanitary waste disposal on the necessary scale are unlikely to occur in the next decade or two. Local low-tech solutions can be useful, and enhanced efforts to find ways to improve water cleanliness at the point of use and to build simple latrines that will be used consistently are needed (chapter 41). However, in the face of HIV and the attention being given to tuberculosis and malaria, coordinated efforts to build safe water and sanitation capacity at the local level, one village at a time, that are sufficient to significantly influence the burden of illness are unlikely—even though many more infants and children die each year of preventable and treatable diarrhea than of HIV/AIDS.

The cycle of research, followed by implementation, followed by research has enabled the development of improved tools to manage diarrheal diseases—tools that have the potential to further drive down diarrhea mortality. The challenge is to achieve high coverage and good practice with ORT and correct diarrhea case management, including antimicrobial and nutrition interventions. Interventions to integrate health care through programmatic initiatives such as the Integrated Management of Childhood Illness program, critically evaluated elsewhere in this book (chapter 63), could be essential to ensure this high coverage. Some concern remains that in low-resource settings such targeted vertical programs may be abandoned, to the detriment of the goals for disease burden reduction that they were established to achieve.

The challenge posed by the case management of bloody diarrhea is a different matter. Until a vaccine is available, the keystone for managing bloody diarrhea will continue to be the early use of effective antimicrobial agents. That is made difficult by increasing drug resistance, aided by the widespread indiscriminate and inappropriate use of antimicrobials, and the increasingly difficult task of finding a safe, inexpensive, and effective oral agent and then ensuring that the drug is given in a clinically optimal manner. From a technical perspective, the development of a vaccine against Shigella infections is still in its infancy and in need of greater investment. For both watery and bloody diarrhea, the challenge of developing drugs to normalize the pathophysiology caused by the infection remains a scientific challenge and a distant hope.

Conclusions

Existing interventions to prevent or treat diarrheal diseases have proven their efficacy in reducing mortality, but a major challenge for the next 10 years will be to scale up these interventions to achieve universal utilization coverage. The United Nations Millennium Development Goal to reduce the mortality rate among children under five by two-thirds by 2015 will be easier to attain if the scale-up goals are reached. New products and tools could significantly improve the efficacy of these interventions—for example, rapid specific diagnostics, new treatment strategies based on reversing the pathophysiology of the infection, simple and effective ways to produce clean water and control human waste, and vaccines to prevent illness. However, these products and tools will not become widely available in time to influence the achievement of the Millennium Development Goals. Continued investment in diarrheal disease research across the spectrum of basic, social and behavioral, and applied investigations is, therefore, essential, including expanded behavioral research to understand how parents assess risk and how actionable health messages can be presented in different cultures and settings.

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