A millennium update on pediatric diarrheal illness in the developing world

A Millennium Update on Pediatric Diarrheal Illness in the Developing World Miguel O’Ryan, MD,* Valeria Prado, MD,* and Larry K. Pickering, MD, FAAP† More than one billion diarrhea episodes occur every year among children younger than 5 years of age in socioeconomically developing countries causing 2 to 2.5 million deaths. More than twenty viral, bacterial, and parasitic enteropathogens are currently associated with acute diarrhea. Rotavirus and diarrheagenic Escherichia coli are the most common pathogens responsible for acute diarrhea episodes in children; Shigella spp., Salmonella spp, Campylobacter jejuni/coli, Vibrio cholerae, Aeromonas spp, and Plesiomonas spp. occur more commonly in poorer areas and infections caused by protozoa and helminthes occur mainly in areas where environmental sanitation is significantly deteriorated. Initial clinical assessment of a child with diarrhea should focus on obtaining an accurate evaluation of hydration and nutritional status. Assessment of stool characteristics (e.g., liquid non-bloody stools vs. dysenteric or bloody stools) is a key feature in determining potential pathogens causing an acute diarrhea episode. Diagnostic guidelines are discussed in the article. The major therapeutic intervention for all individuals with diarrhea consists of fluid and electrolyte therapy. When antimicrobial therapy is appropriate, selection of a specific agent should be made based upon susceptibility patterns of the pathogen or information on local susceptibility patterns. Current guidelines for administering appropriate antimicrobial treatment are provided in the article. Preventive measures include careful personal hygiene, especially promotion of hand washing. Immunizations currently or soon to be available for Salmonella serotype Typhi, cholera prevention, and rotavirus are discussed. Semin Pediatr Infect Dis 16:125-136 © 2005 Elsevier Inc. All rights reserved.

I

n the new millennium, diarrheal disease continues to be a significant cause of morbidity and mortality worldwide. Information available from the 1980s to date suggests that the overall frequency of childhood diarrhea has remained relatively constant, but with a steady decline of diarrheaassociated deaths.1 Estimates suggest that during the 1990s, nearly 1.4 billion diarrhea episodes occurred every year among children younger than 5 years of age in socioeconomically developing countries, of which 123.6 million episodes required outpatient medical care and 9 million episodes required hospitalization. Approximately 2 to 2.5 million diarrhea-associated deaths were estimated annually in this age group, concentrated in the most impoverished areas of the world.2,3 The highest age-mortality rate (8.5 per 1000/yr) occurred in children younger than 1 year of age.3 These esti*Microbiology and Mycology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile. †National Immunization Program, Centers for Disease Control and Prevention, Atlanta, Georgia. Address reprint requests to: Miguel L O’Ryan, Associate Director, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile. E-mail: [email protected]

1045-1870/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.spid.2005.12.008

mates are somewhat lower than the more than 3 million deaths from diarrhea reported 10 years before, indicating that significant advances have had a positive impact on diarrhea-associated outcomes.1 Children living in socioeconomically underdeveloped areas will have more overall diarrhea episodes, severe episodes with dehydration, and a higher death rate compared with children living in more economically developed areas. These events are a consequence of numerous conditions common to poverty, including deficiencies in infrastructure (decreased accessibility to noncontaminated water and appropriate sewage disposal), crowding and exposure to farm animals (free roaming chickens and pigs), lower standards in food handling and hygiene, decreased accessibility to medical care, and low educational level. Malnutrition, a well-recognized risk factor for death from diarrhea, occurs more commonly in less economically developed countries.4-7 The concept “developing country” is an oversimplification that tends to include a broad range of countries that have important socioeconomic, cultural, and medical-care related differences among them. For example, the Gross Domestic Product (GDP) per capita/yr of “developing” regions ranges 125

M. O’Ryan, V. Prado, and L.K. Pickering

126 from 7.374 international dollars for Latin America to 4.327 in Asia and 1.797 in sub-Saharan Africa.8 The risk of developing gastrointestinal tract infections and severe disease in the poorer countries will be significantly higher compared with middle-income countries within the economically developing world. Even more, within the same continent and country there are cities where the standards are similar to those of more developed countries. These differences need to be accounted for when seeking specific information on which to make recommendations. For example, a pediatrician in the United States asked to recommend diarrhea prevention strategies for a family moving to Santiago, Chile will make different recommendations than for a family moving to Dhaka, Bangladesh. General information can be obtained at specific web sites (www.cdc.gov/travel), but information obtained should be supplemented with country-specific information when possible. The need for the best local knowledge available to support recommendations is critical. Unfortunately, accurate information on the impact of diarrheal disease in most areas within the developing world is either not available or outdated, or the collection methods used do not permit comparisons. Taking into account these limitations, in general, a child in the developing world will have more diarrhea episodes than will a child living in middle- or high-income countries. The range in the number of diarrhea episodes per child/yr is wide and will vary depending on the risk factors indicated above. An 18-month-old child living in a small shanty town hut in Bangladesh or the Amazon area of Brazil, with poor sanitation and no access to sewage systems, receiving water from a well or river, lacking adequate nutrition, and sharing a bed with two or three siblings likely will have eight or more diarrhea episodes during his or her first year of life. The same 18-month-old child living in a rural area of Chile in a house of wood, with access to clean water and relatively adequate disposal of sewage, including stools, and receiving food that potentially could be contaminated but that most probably will be cooked will have two to three episodes of diarrhea per year.9,10 Breast-feeding plays a key role in prevention of diarrheal disease in infants.11,12 Breastfed infants, especially infants younger than 3 months of age, suffer fewer episodes of diarrhea than do infants who are not breastfed.13 Partial breastfeeding confers protection that is intermediate between that gained by infants who are exclusively breastfed and that of infants who are exclusively bottle-fed. Other measures such as vitamin A and zinc supplementation have been shown to have a positive impact in decreasing morbidity and mortality associated with Shigella infections in Bangladesh.14 The relative contribution of different pathogens accounting for diarrhea episodes will vary depending on the specific area of residence. Children living in areas with poor sanitation are at higher risk for fecal-oral transmission, and food and water contamination will result in a higher risk of acquiring infection caused by enteric bacteria and parasites. In contrast, in areas of better sanitary conditions, bacteria are a less common cause of diarrhea in children, with most cases being caused by enteric viruses.15-17 Severe outcomes (hospitalization and death) associated with acute diarrhea show a diver-

gent pattern in areas with different levels of economic development. Unfortunately but not unexpectedly, 85 percent of diarrheal deaths occur in the less privileged countries of the world. In these low-income countries, diarrhea accounts for as many as 21 percent of all deaths in children younger than 5 years of age.2,3 These figures are striking when compared with the more economically developed world, where diarrhea is associated with fewer than 1 percent of deaths in children.2 The leading cause of diarrhea-associated hospitalizations and death is dehydration. The risk of having severe dehydration increases if episodes are more frequent or are more severe and if the possibility of appropriately managing dehydration, including accessibility to oral rehydration solutions and to emergency departments and hospitals, is not readily available. In addition, the educational level of parents is critical in preventing and recognizing severe illness. In this context, children living in areas where specific pathogens tend to cause severe diarrhea-vomiting episodes (eg, cholera) and where accessing oral or IV rehydration is difficult will be at the highest risk for the development of severe dehydration. The possibility of dying will be highly concentrated in these settings within the poorest areas of the world, mainly underdeveloped areas of Asia, sub-Saharan Africa, India, and Latin America. Hospitalization rates for acute diarrhea will not parallel necessarily the trend observed for mortality rates. Hospitalization in many poor countries represents an opportunity that is not readily available. Conversely, in more developed countries, hospitalization often represents a safety measure that frequently is overused. Recent estimates suggest that hospitalization rates for acute diarrhea are higher in middle- and high-income countries than in poorer countries.2

Relevant Pathogens Causing Diarrhea More than 20 viral, bacterial, and parasitic enteropathogens are associated with acute diarrhea. Enteropathogens most frequently reported are shown in Table 1. Case-control studies required to determine the true pathogenic role of different microorganisms are scarce in the economically developing world. Available information is based mostly on descriptive studies that group children younger than 5 years of age and that do not define clearly the severity of disease nor diarrhea characteristics (watery versus dysenteric stools). Prevalence of specific pathogens is dependent on these variables and, thus, proposing age-adjusted prevalence rates for specific pathogens is difficult. Certain generalizations can be made and are discussed in the following section.

Enteric Viruses Four enteric viruses cause diarrhea in humans: rotavirus, astrovirus, human caliciviruses (divided into 2 genera, norovirus and sapovirus), and enteric adenoviruses. Independent of economic development, rotavirus is the most common cause of severe, acute nondysenteric diarrhea in most areas of the world where it has been studied. Rotavirus causes from 25 to 70 percent of cases in children of gastroenteritis severe

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Table 1 Enteropathogens Frequently Associated With Acute Diarrhea in Children Microorganisms Viruses Rotavirus Human calicivirus Norovirus Sapovirus Astrovirus Enteric adenovirus Bacteria Diarrheagenic E. coli EPEC* ETEC STEC EAEC EIEC Shigella spp.

Salmonella enteritidis Campylobacter spp. Vibrio cholerae Parasites Giardia lamblia Entamoeba histolytica

Cryptosporidium parvum Cyclospora cayetanensis Isospora belli

Highlights Most common cause of diarrhea in children <24 months of age Causes outbreaks and sporadic cases of gastroenteritis Outbreaks occur in closed populations; common source outbreaks associated with ingestion of contaminated food and water Less common; causes sporadic diarrhea episodes in children. Infection usually occurs in children <4 years of age. Diarrhea associated mainly with serotypes 40 and 41, most often in children.

Acute endemic and epidemic diarrhea in infants, occasionally associated with persistent diarrhea Infantile diarrhea in economically developing countries and travelers diarrhea in all ages Bloody diarrhea and hemolytic uremic syndrome in children <5 years of age, hemorrhagic colitis and thrombotic purpura following diarrhea in adults Acute and persistent diarrhea in infants Similar to disease caused by Shigella, spp Common cause of watery diarrhea and dysentery in children 12-48 months of age; S. flexneri is more common than S. sonnei in developing areas; significant antimicrobial resistance worldwide Zoonotic; common cause of foodborne outbreaks Zoonotic; mainly due to contact with poultry Severe watery diarrhea; O1 is endemic in South Asia and Africa, and O139 is epidemic in Asia Cause of diarrhea in all ages worldwide; asymptomatic shedding is common Prevalent in economically developing countries; less common in children; E. dispar is not pathogenic Associated with large waterborne outbreaks; person-to-person transmission occurs commonly Outbreaks associated with food and water; direct person-to-person transmission has not been documented Infection more common in tropical and subtropical areas and in areas of poor sanitation

*EPEC, enteropathogenic Escherichia coli; ETEC, enterotoxigenic E. coli; STEC, Shigatoxin-producing E. coli; EIEC, enteroinvasive E. coli; EAEC, enteroaggregative E. coli.

enough to require hospitalization.2,18-20 Rotavirus occurs most commonly in children younger than 2 years of age and uncommonly after they reach 5 years of age. In areas with low economic development, infection occurs more commonly in infants younger than 12 months of age compared with more industrialized areas, where infection occurs more commonly in children 12 to 24 months of age.21 Virtually all children are infected by the time they reach 3 years of age. Astrovirus, human caliciviruses, and enteric adenovirus together represent as many as 20 to 30 percent of cases of diarrhea in areas where bacterial infections are found less commonly. In areas with less economic development, these viruses also infect children, but their relative contribution to the total number of cases is diluted in lieu of the higher rate of bacterial infections. Enteric adenoviruses belonging to serotypes 40 and 41 have been associated with persistent diarrhea, generally in children younger than 4 years of age.20 Noroviruses have a worldwide distribution, are genetically and antigenetically diverse, and cause both sporadic disease and common-source outbreaks.17,20,22 Eight antigenic types

of astrovirus cause diarrhea in young children.23 All enteric viruses can cause asymptomatic infection.

Bacterial Pathogens Diarrheagenic Escherichia coli include the following clinically relevant pathotypes: enteropathogenic (EPEC), enterotoxigenic (ETEC), shigatoxin-producing (STEC), enteroaggregative (EAEC), and enteroinvasive (EIEC). As a group, diarrheagenic E. coli are the most common bacteria detected in studies from economically developing countries, causing 30 to 40 percent of acute diarrhea episodes in children.21,24-30 EAEC, EPEC and ETEC cause endemic watery diarrhea and have been reported most frequently in children younger than 2 years of age.21,31 ETEC is a common cause of traveler’s diarrhea in economically developing countries. EIEC causes diarrhea generally with fever and blood indistinctive from Shigella infections in all ages. STEC has been reported as a common cause of bloody diarrhea from some developing countries (mainly Chile and Argentina), but these findings have not been universal. Geographic location and methods

128 used for establishing the diagnosis have an important influence on incidence and prevalence.32 For instance, in the United States, E. coli O157:H7 is the STEC most frequently reported, whereas in Argentina and Chile other non-O157 STEC strains cause most cases of bloody diarrhea and hemolytic uremic syndrome (HUS).32,33 STEC has been established as the main etiologic agent of HUS.32 EAEC has been associated with persistent diarrhea.9 Enteric infections associated with Shigella spp., Salmonella spp., Campylobacter jejuni/coli, and other bacteria (Vibrio cholerae, Aeromonas spp, Plesiomonas spp.) occur more commonly in areas where development and hygiene are inadequate.21 In these areas, children commonly shed these organisms in the absence of diarrhea, confounding their pathogenic role in acute diarrhea episodes.9,21-23,28,34 Severity of Shigella infections can increase significantly in malnourished children, causing severe complications such as toxic megacolon, intestinal perforation, and HUS associated with S. dysenteriae type 1 infections. C. jejuni/coli is associated with consumption of poultry and the presence of poultry in the households; prevalence is variable among different areas, with most cases occurring in children younger than 24 months of age. Campylobacter also can be shed asymptomatically.35-37 The principal reservoirs of nontyphoidal Salmonella organisms are animals, including poultry, livestock, reptiles, and pets. The major vehicles of transmission are foods of animal origin, including eggs, dairy products, and poultry, and are most significant in areas where potentially contaminated food products (mainly derived from poultry) are processed in large scale. Foodborne outbreaks caused by nontyphoid Salmonella strains affect children and adults worldwide.38 Differences in seasonal prevalence of specific pathogens and epidemic curves need to be considered before proposing probable microorganisms causing acute diarrhea in a child. In general, rotavirus predominates during colder months, although infection tends to occur year-round in tropical areas and in some temperate climates. Bacterial infections predominate during warmer months. Salmonella enteritidis and C. jejuni/coli infections can be epidemic in a given area during a defined time period.37 V. cholerae needs to be considered among the possible causes in children living in endemic areas (currently, south Asia and Africa). V. cholerae O1, V. cholerae O139, and S. dysenteriae 1 can cause epidemics and pandemics in areas of extreme poverty and/or in areas with massive population migrations associated with natural disasters or long-lasting wars.39 Mixed infections can represent as many as 15 to 20 percent of diarrhea episodes. The possibilities of coinfections occurring reflect the most common organisms circulating within a community. Mixed infections are not necessarily more severe compared with infections caused by a sole pathogen.9,21,24,26,27-29

Parasites Infections caused by protozoa and helminths occur mainly in areas where potable water is not readily available and/or

M. O’Ryan, V. Prado, and L.K. Pickering where environmental sanitation is significantly deteriorated, as occurs in markedly deprived areas of the economically developing world. These infections decrease significantly in areas that have solved these basic sanitary deficiencies. Entamoeba histolytica can cause acute nonbloody and bloody diarrhea, necrotizing enterocolitis, ameboma, and liver abscess and needs to be differentiated from morphologically identical nonpathogenic strains such as Entamoeba dispar and Entamoeba moshkovskii.40 These species are excreted as cysts and trophozoits in stools of infected people, and infection is initiated most commonly by ingesting fecally contaminated water or food containing E. histolytica cysts. Giardia lamblia is a binucleate flagellated protozoan parasite with trophozoite and cyst stages. Giardia is spread by the fecal-oral route through ingestion of cysts, and infection is limited to the small intestine and biliary tract. Outbreaks in childcare centers have reflected person-to-person spread and have demonstrated high infectivity.41-43 Foodborne and waterborne transmission also occur. Infection often is asymptomatic or mildly symptomatic. Symptoms in giardiasis are related to the age of the patient, with diarrhea, vomiting, anorexia, and failure to thrive occurring typically in the youngest children. Infection rates in the economically developing world are high, as exemplified by a study in slum areas of Peru, where seroprevalence reaches 40 percent by the time infants reach the age of 6 months.44 Cryptosporidium parvum is a spore-forming coccidian protozoon. Other spore-forming protozoa that cause diarrhea are Isospora belli, Cyclospora cayetanensis, and Microsporidium spp.45,46 Cryptosporidium spp. are ubiquitous and, because Cryptosporidium infects a wide variety of animal species, infected individuals often have a history of animal contact.47 Person-to-person spread, particularly in household contacts and child-care centers, is well-documented and shows that the organism is highly infectious.48-50 Waterborne outbreaks of cryptosporidiosis occur and can reach massive proportions.51 The clinical manifestations of illness in immunocompetent persons include watery diarrhea, abdominal pain, myalgia, fever, and weight loss.47,49,50,52,53 Infants infected early in life may develop chronic diarrhea and malnutrition.54 Cyclosporiasis occurs worldwide but is endemic in some countries such as Peru and Haiti. Sporulation outside the host produces infectious organisms; therefore, direct person-toperson transmission does not occur. Outbreaks have been associated with contaminated food and water. Clinical signs and symptoms include watery diarrhea, which usually is selflimited.55 Isosporiasis occurs more commonly in tropical and subtropical climates and in areas of poor sanitary conditions. Infection occurs by the fecal-oral route and has been linked to contaminated food and water. Oocysts are passed unsporulated and require exposure to oxygen and temperature lower than 37° C before becoming infective.56 Watery diarrhea is the most common symptom. Two microsporidia species are important causes of chronic diarrhea in immunocompromised people, especially people infected with human immunodeficiency virus (HIV).57

Pediatric diarrheal illness in the developing world

Clinical Considerations and Diagnosis Diarrhea is a manifestation of intestinal dysfunction that results in increased stool output resulting in loss of water, electrolytes, and/or nutrients. The most commonly used definition of diarrhea is three or more loose stools during a 24-hour period, but physicians should consider the normal regular evacuation pattern of the affected individual before defining if he/she has diarrhea. In breastfed infants, for example, normal stool patterns include passages of six to eight liquid stools per day. Fever, vomiting, abdominal cramps, and dehydration of different magnitudes can accompany diarrhea. High fever and intense vomiting can be present in viral and bacterial infections and are not pathognomonic of a given pathogen. Acute diarrhea accompanied with urgency to defecate and tenesmus suggests an inflammatory/invasive process of the colon as described below. Most cases of acute diarrhea will resolve within 7 days. Persistent diarrhea lasting longer than 14 days has been associated with several infectious and noninfectious causes, including EAEC, Yersinia enterocolitica, enteric adenovirus, Isospora belli, Cyclospora cayetanensis, G. lamblia, Microsporidium, C. parvum, transitory lactose intolerance, and moderate to severe malnutrition.20,58-61 As indicated previously, the risk of acquiring infection with several enteric pathogens increases in areas where potable water is not readily available. Initial clinical assessment of a child with diarrhea should focus on obtaining an accurate evaluation of hydration and nutritional status. The first is critical for management because morbidity and mortality are associated predominantly with dehydration. Guidelines for evaluation and quantification of dehydration can be found elsewhere.62,63 Malnutrition is a risk factor for a poorer outcome, and physicians should ensure that appropriate actions are taken to avoid nutritional deterioration that occurs during the acute diarrheal episode (maintain oral protein/calorie intake). Limiting intake of milk currently is not recommended for the great majority of children with acute diarrhea; this measure should be considered only if lactose malabsorption causing persistent diarrhea is suspected. Assessment of characteristics of the stool is a key feature in determining potential pathogens causing an acute diarrhea episode. Liquid nonbloody stools are associated predominantly with a secretory/small intestinal dysfunction process, whereas dysenteric (blood and pus) or bloody stools generally are associated with an inflammatory/invasive process of the colon. Mucous can be present in both situations and should be differentiated from pus. Table 2 lists the pathogens most likely to be detected in children with moderate to severe acute endemic diarrhea living in developing areas. The ability to obtain an etiological diagnosis in a child with diarrhea is highly dependent on the quality of the stool sample, the experience and skill of the microbiologist, and resources available for stool evaluation. Appropriate management of the stool sample requires collection of a recently passed sample directly from the diaper or an appropriately

129 Table 2 Most Commonly Reported Microorganisms Associated With Acute Endemic Diarrhea in Economically Developing Areas by Age Groups and Diarrhea Characteristic* All Episodes <2 year

2–5 years

Watery/mucous <2 year

2–5 years

Dysenteric/bloody <2 year

2–5 years

Microorganisms Rotavirus EPEC, ETEC Astrovirus, Caliciviruses, Enteric Adenovirus Shigella flexneri, Shigella dysenteriae type 1† Campylobacter jejuni‡ STEC, EAEC ETEC S. flexneri, S. dysenteriae type 1† Rotavirus Non-typhi Salmonella† Giardia lamblia Rotavirus EPEC, ETEC Astrovirus, Caliciviruses, Enteric adenovirus ETEC S. flexneri/S. dysenteriae type 1 Rotavirus

S. flexneri, S. dysenteriae type 1† STEC C. jejuni‡ S. flexneri/S. dysenteriae type 1† STEC Non-typhi Salmonella† Entamoeba histolytica§

*List generated by consensus of authors based on literature review and personal experience. The list order of the pathogens represents a gross approximation from higher to lower probability. †In areas where infection is endemic. ‡Associated with presence of animals (poultry) in the household. §Mainly in areas where hygiene is markedly deficient.

obtained rectal tube or swab sample. Areas of stools with pus, blood, or mucous are optimal for sampling. All samples should be inoculated immediately or placed into transport media and immediately transported to the laboratory. Once in the laboratory, the number and types of selective media used and the number of suspicious colonies studied will impact the ability to identify an enteric pathogen in stools. A universal consensus guideline for stool evaluation is not available, and different laboratories have established their own guidelines.64,65 Culture techniques used in microbiology laboratories should be able to identify Shigella, Salmonella, Yersinia, and Campylobacter. Because selective media for Campylobacter are expensive, identifying this microorganism may be difficult in economically developing countries.66 Identifying other enteropathogens requires additional testing not always available in diagnostic microbiology laboratories. Enteric viruses such as rotavirus, enteric adenovirus, astrovirus, and the parasite G. lamblia can be detected by commercially available techniques with acceptable sensitivity and specificity.18,67 Detection of E. coli pathotypes and calicivi-

M. O’Ryan, V. Prado, and L.K. Pickering

130 ruses are available in selected research or reference laboratories.15,68,69 Studies suggest that detection of low inoculumviable microorganisms such as Shigella spp. or differentiation of E. histolytica from E. dispar can be improved significantly by using genetic amplification techniques such as real-time polymerase chain reaction (PCR), but the clinical and epidemiological relevance and applicability of detection based on gene amplification in culture-negative individuals will require further clarification.70,71 The possibility of incorporating new molecular techniques for routine diagnostic testing in most economically developing countries will require appropriate cost-benefit analyses of these new techniques. Most episodes of diarrhea, independent of etiology, are mild, self-limited, and not affected by specific antimicrobial treatment. In addition, the numbers of different pathogens that can cause acute diarrhea are significant, and diagnostic testing is difficult to perform and expensive. This concern is especially important in economically developing countries where resources are limited. In addition, in most laboratories, stool culture results are reported 48 to 72 hours after collection of the sample, a time period during which patients with acute diarrhea may have been treated and most of whom will have improved significantly with or without specific treatment. Considering the limitations of enteropathogen detection, our current recommendation for physicians managing children with acute diarrhea is to focus diagnostic efforts on children in whom the likelihood of obtaining a pathogen will be reasonable and will make a difference for the child or his/her potential contacts. Neonates and immunocompromised patients with diarrhea should be studied because they have a higher risk for acquiring invasive or unusual pathogens. Individuals involved in foodborne or waterborne outbreaks and, when possible, children in childcare centers should be studied for epidemiological and preventive reasons. Children with persistent diarrhea also should be studied, although the yield may be low. Children with moderate to severe bloody diarrhea, especially children requiring hospitalization, should be studied to detect Shigella, STEC, Salmonella, Campylobacter, and E. histolytica in areas where these infections are prevalent. Appropriate case-control studies performed on a regular basis in different areas represent the best strategy to define the most probable microorganisms causing disease. These studies are an invaluable aid in empiric management of children with diarrhea residing in these areas. Stool assays for rapid identification of episodes likely to be caused by an invasive organism have been proposed. Stool leukocytes, lactoferrin, and occult blood have been the most common fecal screening tests evaluated.72-75 In general, children with diarrhea who have one or more of these elements in stools will have a higher probability of harboring an invasive pathogen, but the clinical usefulness of these nonspecific tests is limited. A metanalysis concluded that these tests perform moderately well in suggesting invasive pathogens such as Shigella, Salmonella, EIEC, and Campylobacter in economically developed countries but poorly in developing countries.72 Considering that current guidelines support treat-

ment of moderate to severe invasive diarrhea caused by Shigella spp. and not STEC, that the additional benefit of microscopic over macroscopic/clinical findings in severe cases is unclear, and that fecal screening tests do not help in discriminating between these pathogens, we consider these tests to be of limited benefit for most children in the economically developing world. To assist in the macroscopic evaluation of a stool specimen, screening tests could be considered in a febrile child with severe watery diarrhea if Shigella is suspected. A positive test could favor administering antimicrobial treatment while awaiting culture results. In a febrile child with grossly bloody diarrhea, these tests will not provide benefit and will increase management costs of the episode unnecessarily.

Treatment The major therapeutic intervention for all infants, children, adolescents, and adults with diarrhea consists of fluid and electrolyte therapy.76 Antimicrobial therapy is not indicated for most patients with diarrhea because most enteric infections are self-limited or are caused by agents for which antimicrobial therapy is not available or effective. In addition, concerns inherent with antimicrobial therapy include safety and tolerability of antimicrobial agents, particularly in immunocompromised people, the young and the elderly; potential enhancement of virulence factors; prolongation of the carrier state; and development of resistance.77,78 Antimicrobial agents are given to patients with diarrhea caused by select bacterial and protozoal pathogens (Table 3). The purpose of this therapy is to reduce signs, symptoms, and duration of disease; prevent morbidity and mortality; eradicate fecal shedding of the causative organism; and eliminate transmission. Benefits and limitations of antimicrobial therapy should be considered when approaching a patient with gastroenteritis. When antimicrobial therapy is appropriate, selection of a specific agent should be made based on susceptibility patterns of the pathogen or information on local susceptibility patterns obtained from active surveillance studies if the first is not available. Because resistance among enteric organisms can spread rapidly, constant monitoring of susceptibility patterns is important for selecting appropriate agents for therapy when indicated.

Bacterial Resistance Enteric bacterial pathogens are becoming increasingly resistant to antimicrobial agents for many reasons, including inappropriate and excessive use of antimicrobial agents in humans79 and inclusion of various classes of antimicrobial agents as growth promoters in feeds of livestock.80-82 Recent use of an antimicrobial agent in a human, particularly within the previous 4 weeks, is a documented risk factor for development of infection or colonization with resistant bacterial pathogens.79 In many countries of the world, an increase in antimicrobial resistance patterns has occurred among the major bacterial enteric pathogens, including Shigella spp, E. coli patho-

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Table 3 Antimicrobial Therapy for Enteric Pathogens Organism

Drug of Choice

Campylobacter Spp.

Azithromycin or erythromycin

Clostridium difficile Nontyphi Salmonella

Metronidazole Cefotaxime Ceftriaxone Fluoroquinolone Fluoroquinolone Azithromycin

Shigella

Vibrio cholerae

Doxycycline if >8 years of age TMP/SMX

E. histolytica

Metronidazole followed by Iodoquinol

G. lamblia

Metronidazole

Cryptosporidium parvum Isospora belli Cyclospora cavetanensis

Nitazoxanide TMP/SMX TMP/SMX

Alternative Drugs Fluoroquinolone Tetracycline Gentamicin Oral vancomycin Ampicillin TMP/SMX Chloramphenicol Nalidixic acid TMP/SMX Ceftriaxone Fluoroquinolone Chloramphenicol Furazolidone Tinidazole Secnidazole Ornidazole Tinadazole Quinacrine Furazolidone Paramomycin (pregnant women) Paramomycin ⴙ azythromicin

types associated with diarrhea, C. jejuni/coli, and Salmonella spp. These resistance patterns frequently have shown a progressive increase over the course of time and have demonstrated resistance to several classes of antimicrobial agents.

ommended therapy of people infected with Shigella includes fluoroquinolones, azithromycin, and extended-spectrum cephalosporins. To optimize therapy, one should know local susceptibility patterns.

Shigella Species

C. jejuni and C. coli

Shigella strains have become progressively resistant to multiple antimicrobial agents since the introduction of sulfonamides, and multiresistance is a global problem. Resistance of S. flexneri and S. sonnei, the most frequent causes of shigellosis, has developed to tetracycline, chloramphenicol, streptomycin, ampicillin, kanamycin, and TMP-SMX less than 10 years after each was licensed for use in humans. Data from the National Antimicrobial Resistance Monitoring System (NARMS) in the United States show that in 2001 resistance of Shigella isolates (70% of which were S. sonnei) to ampicillin was approximately 80 percent and to TMP-SMX was 47 percent.83 None of the isolates was resistant to ceftriaxone, imipenem, or gentamicin, and only one isolate (0.3%) was resistant to ciprofloxacin. Susceptibility testing against azithromycin was not performed. Similar resistance patterns have been reported from England and Wales,84 Canada,85 and Germany.86 In economically developing countries, current data from Chile indicate that most Shigella spp. are resistant to ampicillin, TMP/SMX, tetracycline, and chloramphenicol and are susceptible to ciprofloxacin and extended spectrum cephalosporins.87,88 Reports from Bangladesh, where shigellosis is highly endemic, show a similar resistance pattern.89 Outbreaks caused by multiresistant S. dysenteriae type 1, including strains resistant to ciprofloxacin, has been reported.90,91 Neither ampicillin nor TMP-SMX should be considered appropriate empiric therapy for shigellosis. Rec-

More than 16 species of Campylobacter have been identified, but not all of them infect humans. Most episodes of Campylobacter-associated diarrhea are caused by C. jejuni/coli strains. Azithromycin, erythromycin, or fluoroquinolones are the agents of choice for therapy of gastroenteritis caused by C. jejuni/coli. Erythromycin resistance in most economically developed and developing countries generally is stable at less than 5 percent,92-94 including strains isolated from children.95,96 However, in some countries, higher resistance rates to erythromycin have been reported.77,95,97 Strains that demonstrate high-level resistance to erythromycin also manifest resistance to azithromycin and clarithromycin.97 Resistance to fluoroquinolones in human strains has ranged from 3 to 96 percent. Data from NARMS in the United States show that in 2001, 18 percent of C. jejuni/coli isolates were resistant to ciprofloxacin.83 In studies from countries throughout the world, including Austria, Canada, Germany, Finland, Norway, and the Netherlands, resistance has increased from 9 to 30 percent.77 A high frequency of crossresistance has been reported among the fluoroquinolones.77,98-100 In several countries, the increase in fluoroquinolone resistance coincided with initiation of administration of a fluoroquinolone compound to animal food or use in veterinary animals.83,84,100 These studies highlight the importance of being familiar with local or regional resistance patterns when making decisions about therapy.

M. O’Ryan, V. Prado, and L.K. Pickering

132 Table 4 Vaccines Currently or Soon-to-Be Available to Prevent Enteric Infections Organism

Vibrio cholerae Salmonella serotype typhi Rotavirus

Vaccine

Type

CVD-103HgR B-WC Ty21A ViCPS Monovalent Pentavalent

Live attenuated Inactivated Live attenuated Polysaccharide Live attenuated Live attenuated

Salmonella Species The type of syndrome produced by nontyphoidal Salmonella strains dictates the selection and duration of antimicrobial therapy. Problems with use of antimicrobial agents among persons who are nontyphoidal Salmonella carriers or in patients who have mild gastroenteritis are lack of clinical effectiveness,101 conversion of intestinal carriage to systemic disease with bacteremia,102 production of bacteriologic and symptomatic relapse,101,102 development or selection of resistant strains, and prolonged periods of fecal excretion.102 In NARMS data from the United States, the 16 most common serotypes accounted for 80 percent of isolates that were serotyped. The two serotypes most commonly identified, Typhimurium (23%) and Enteritidis (20%), showed differences in resistance to five or more antimicrobial agents, 35 percent and 1 percent, respectively. Only 2 percent of isolates were resistant to TMP-SMX, 2 percent to ceftriaxone, and 0.2 percent to ciprofloxacin. Worldwide antimicrobial resistance to Salmonella strains is a common finding,103-106 but specific serotypes responsible for causing infection and the degree of resistance of specific serotypes differ by geographic location. Data collected from seven cities in Argentina reported resistance rates of 35 percent, 14 percent, and 42 percent against ampicillin, chloramphenicol, and TMP/SMX, respectively.107

Shiga Toxin-Producing E. coli (STEC) The STEC most commonly isolated in the United States is E. coli 0157:H7. Other STEC types, such as O26:H11, O45, O55:H7, O55:H10, O111:H8, O111:H30, O111:H34, O113, O121, and O145, are found more commonly in other countries.33 Antimicrobial resistance patterns of various animal and human STEC strains have been reported, with resistance noted to ampicillin, sulfamethoxazole, tetracycline, streptomycin, and TMP-SMX.108 Resistance is associated with country of origin or source of the isolates tested. In the 2001 NARMS data, of 277 E. coli 0157:H7 isolates tested, 9 percent were resistant to one or more antimicrobial agents, 5 percent were multidrug-resistant, 5 percent were resistant to sulfamethoxazole, 5 percent to tetracycline, 2 percent to ampicillin, and 2 percent to streptomycin; none was resistant to ceftriaxone, ciprofloxacin, amikacin, or imipenem.83 Data from Chile for O157 and non-O157 STEC isolates obtained from clinical and food origins showed that strains were 100 percent susceptible to ampicillin, TMP/SMX, ciprofloxacin, chloramphenicol, tetracycline, aminoglycosides, and extended spectrum cephalosporins.109

Route of Administration Oral Oral Oral Intramuscular Oral Oral

Age >2 years all ages >6 years >2 years 2,4 months 2,4,6 months

Antimicrobial therapy of children infected with STEC is not recommended because of the potential for bacteriophage induction with enhanced cytotoxin production, leading to development of HUS by certain classes of antimicrobial agents.110-112 A meta-analysis showed no benefit or increased risk for sequelae from therapy of children with STEC intestinal infection.113

Effect of Resistance on Clinical Manifestations and Treatment Options Clinical manifestations of enteric infections include signs and symptoms involving the gastrointestinal tract, dissemination of organisms to sites outside the gastrointestinal tract, neurologic manifestations, and immune-mediated sequelae. People infected with enteric pathogens that are resistant to frequently used antimicrobial agents may manifest as either clinical or bacteriologic treatment failures114-117 and may have an extended duration of excretion of viable organisms.114,118

Prevention The most important aspect in control of diarrheal disease is hygiene, both general and personal. General issues deal with clean water, clean food, and appropriate sanitation facilities. Despite the high-quality water and food supplies available in the United States and other socioeconomically developed areas of the world, outbreaks of foodborne and waterborne disease continue to occur, generally due to improper handling and storage of food.119 Personal measures include careful personal hygiene, especially handwashing, and limited use of antacids, antimotility drugs, and antimicrobial agents. Promotion of handwashing has proven to be a highly effective measure in decreasing the incidence of diarrhea among people living in high-risk areas, such as settlements in Pakistan.120 Appropriate diaper-changing facilities and techniques should be available and implemented in childcare facilities. Breastfeeding in all areas of the world should be promoted, implemented, and supported. The number of immunizations available to prevent enteric infections is scarce but expected to increase in the future with development of new technologies including delivery mechanisms (Table 4).121 Vaccines against Salmonella serotype Typhi are the only vaccines against enteric diseases commercially available in the United States (Table 4). Currently, two vaccines are licensed for cholera prevention. The oral live

Pediatric diarrheal illness in the developing world genetically attenuated CVD 103HgR (Orochol®, Berna Biotech, Bern, Switzerland) has demonstrated 100 percent protection against severe cholera, but protection is not longlasting (14% of individuals living in endemic areas were protected 4 years after vaccination). This vaccine is indicated for individuals older than 2 years of age traveling to a choleraendemic area.122 The inactivated whole cell vaccine with B subunit has proven to be safe and effective up to 3 years after vaccination in Bangladesh. Two doses conferred 70 percent protection in adults but only 25 percent in children.123 Live genetically attenuated vaccines for Shigella are in different stages of development. These vaccines are serotype-specific, meaning that multivalent vaccines will be required to protect against the most prevalent serotypes worldwide (eg, Shigella dysenterie type 1, S. sonnei, and S. flexneri 2a, 3a, and 6).124 Vaccines to prevent rotavirus (RV) have been shown to be effective,125 but the association of the rhesus RV vaccine with intussusception resulted in withdrawal of this vaccine from the U.S. market in October 1999, following licensure in August of 1998. This vaccine has not been licensed in any other country of the world. A vaccine of lamb origin has been used in China for years, but its safety and efficacy profile are unknown. Phase III studies evaluating two new vaccines to prevent infection with RV are nearing completion or have been finalized. The efficacy of these vaccines against severe RV gastroenteritis surpasses 80 percent and against any RV gastroenteritis, regardless of severity, is approximately 70 percent. One vaccine is a G1 human attenuated monovalent vaccine that has been tested in Latin America and Finland. The other vaccine is a G1, G2, G3, G4, and P1A[8] bovinehuman reassortant pentavalent vaccine tested in the United States, Europe, and in a few Latin American countries. The monovalent RV vaccine has been licensed in Mexico for infants and should be available in early 2005 (Vaccine Enteric Disease Meeting, Jamaica 2004). There are no licensed vaccines against parasitic enteric infection. Vaccines against other enteric pathogens and improved vaccines against pathogens for which immunizations are available are undergoing study.121 Nonspecific agents that may interfere with microbial adherence or with the virulence mechanisms of toxins are being developed and evaluated, as are compounds that will serve as competitors for binding of organisms or toxins to receptors in the intestine. The use of glycoconjugates and probiotics in prevention and treatment of diarrheal disease may be beneficial and is undergoing investigation.126 Breastfeeding provides young infants with significant protection against morbidity and mortality due to diarrheal disease.127-129 In part, breastfeeding protects against diarrhea through decreased exposure of breastfed infants to organisms present on or in contaminated bottles, food, or water. In addition, immunologic components in human milk protect infants against disease after exposure to an infectious agent.

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