Diarrhea Acquired in Institutional Centers: Childcare Centers

Gastrointestinal infections acquired in institutional settings are normally caused by highly contagious pathogens transmitted either by person-to-person contact, fomites, or ingestion of contaminated food. A typical setting for the pediatric population is daycare centers. Rotavirus, norovirus, astrovirus, Giardia , and Cryptosporidium are the most common pathogens reported. However, a number of other pathogens have been implicated, including Shigella , enteric adenovirus, hepatitis A, sapovirus, Escherichia coli O157:H7, and Salmonella. Rigorous hygiene practices, exclusion or cohorting of sick children from daycare, and judicious use of antimicrobial agents are all effective strategies for infection control. Criteria for child exclusion from daycare attendance and duration of exclusion have been published.

Antimicrobial-Associated Diarrhea

Intestinal microbiota play a major role in gastrointestinal function and immune system homeostasis. Antimicrobial agents induce significant modification of enteric flora both in terms of diversity and bacterial biomass. Such modification, which can persist long after the inciting agent has been discontinued, can result in altered gastrointestinal function and increased susceptibility to opportunistic pathogens such as Clostridium difficile or Candida albicans. Diarrhea is a common side effect of antibiotics, occurring in 11% to 40% of the children treated with antimicrobial agents. C. difficile is the most common bacterial agent associated with severe antimicrobial-associated diarrhea. The spectrum of disease ranges from a mild self-resolving illness to pseudomembranous colitis, toxic megacolon, and possibly death. Type and dose of antibiotic and host characteristics affect the severity of clinical manifestations.

The epidemiology of C. difficile has changed dramatically in recent years; C. difficile is increasingly recognized as an important pathogen among children. Rates and severity of C. difficile infections have been increasing among adults and to a lesser extent in children, in part owing to the emergence of a hypervirulent strain called BI/NAP1/027. This strain produces higher amounts of toxins A and B and a third toxin called binary toxin, and it is associated with more severe disease. In the United States, C. difficile was responsible for almost half a million infections and was associated with approximately 29,000 deaths in 2011.

Prior use of antibiotics is the single most important risk factor for C. difficile disease. Nearly all the antibiotics have been implicated, but penicillins, cephalosporins, clindamycin, and fluoroquinolones are the most frequently involved. Additional risk factors for C. difficile infection in children include gastrostomy or jejunostomy tubes, use of proton pump inhibitors, altered intestinal mobility, and prolonged hospitalization. Certain underlying diseases, such as immunodeficiency, malignancy, cystic fibrosis, and inflammatory bowel disease also predispose to C. difficile infection. Risk factors for recurrent C. difficile infection in children include malignancy, recent surgery, and the number of antibiotic exposures. Guidelines for diagnosis and treatment of C. difficile infection have been published by the Infectious Diseases Society of America (IDSA), Society for Health Care Epidemiology of America (SHEA), and the American Academy of Pediatrics.

Diarrhea in Immunosuppressed Host

Enteric infections are often a major problem in people with primary and secondary immunologic disorders. The spectrum of disease and the types of involved pathogens can vary with the type of underlying deficit and the degree of immunosuppression. Patients with defects in cellular immunity (e.g., solid organ or bone marrow recipients, patients on chemotherapy for malignancies, children infected by human immunodeficiency virus [HIV] or born with congenital disorders) are mainly susceptible to pathogens with partial or predominant intracellular localization. Among common enteric pathogens, Salmonella and Listeria infections can result in disseminated, life-threatening diseases. Viral infections by routine enteric pathogens such as rotavirus or norovirus can become chronic and debilitating. Opportunistic agents such as cytomegalovirus can cause severe colitis in patients with advanced immune suppression, whereas cryptosporidiosis and microsporidiosis have been associated with persistent diarrhea.

HIV-infected children represent a major group of immunosuppressed hosts, especially in some developing countries. Gastrointestinal dysfunction is common in these patients and can be related to a number of causes: concomitant infections, HIV enteropathy, malignancy, or highly active antiretroviral therapy (HAART) medicines. In addition to the conventional enteric pathogens, opportunistic agents can cause significant disease in patients with advanced disease. In addition to protozoal infections like microsporidiosis and cryptosporidiosis, Mycobacterium avium complex is a common cause of persistent diarrhea and mainly affects the small intestine. Cytomegalovirus can cause diffuse and severe ileocolitis and dysentery-like illness. C. difficile can play a role, especially in children previously treated with antibiotics. Salmonella infection is associated with a high risk of septicemia and should be treated aggressively. A description of enteropathogens causing infections in HIV-infected patients is provided in Table 44.1 .

The advent of antiretroviral treatment has dramatically changed the epidemiology of opportunistic infections in HIV-infected children. HAART can result in complete clinical, microbiologic, and histologic responses in patients with AIDS infected with Cryptosporidium parvum and Enterocytozoon bieneusi and in patients with HIV enteropathy.

Severe defects in humoral immunity, such as X-linked agammaglobulinemia or common variable immunodeficiency, are often associated with persistent diarrhea and malabsorption syndrome; rotavirus and Giardia lamblia can be etiologic factors. Enteric infections caused by Campylobacter jejuni and Salmonella spp. are more frequent and can be more severe and prolonged than in immunocompetent individuals.

Traveler’s Diarrhea

Traveler’s diarrhea is the most common illness reported by individuals traveling from high-income countries to middle- and low-income areas: occurrence as high as 40% to 60% is reported. The most important determinant of risk is travel destination: high-risk areas include most of Asia, Africa, Middle East, and Central and South America.

Half of travelers experience diarrhea within the first few weeks after arrival. A variety of intestinal pathogens can be responsible for traveler’s diarrhea. Bacteria account for 80% to 90% of the cases: enterotoxigenic E. coli (ETEC) is the most common pathogen, followed by Campylobacter, Shigella , Salmonella, and enteroaggregative E. coli (EAEC). Parasites account for 10% of the cases: Giardia lamblia and Cryptosporidium are the most common pathogens; Cyclospora, Entamoeba, and Dientamoeba are occasionally encountered. Viruses represent 5% to 10% of cases: rotavirus, norovirus, and calicivirus are the most frequently reported. However, based on the GeoSentinel Surveillance Network, the main pathogens isolated from international travelers with gastroenteritis are parasites (65%), followed by bacteria (31%) and viruses (3%).

Clinical illness varies, reflecting the diversity of causative agents. Typically illness presents as loose stools over a 24-hour period, accompanied by fever, nausea, vomiting, and abdominal cramping. Tenesmus and bloody diarrhea are less common. An incubation period of 6 to 48 hours normally suggests a bacterial or viral etiology, whereas parasites tend to have longer incubation periods and rarely present in the first week after travel; an exception is Cyclospora cayetanensis, which can present as an acute illness resembling bacterial pathogens. Traveler’s diarrhea is normally a mild, self-limited illness that can resolve spontaneously in 3 to 5 weeks; protozoal diarrhea, however, can persist for months if untreated.

Children who travel are at risk of developing the same well-known illnesses that affect adult travelers. The etiology, treatment, and actual risk of these illnesses are not as well defined as in adults. Treatment of traveler’s diarrhea in children consists of fluid replacement and antibiotics. Antidiarrheal agents are not recommended for young children, although they can be considered for older children and adults, provided there is no gross blood in the stool or fever higher than 38.5°C (101.3°F). Because access to good-quality health care can be problematic in certain regions, travelers should be advised to take with them medications with expected activity against the prevalent bacteria. Antibiotic therapy has been shown to reduce duration of disease from several days to approximately 1 day. Recommended antibiotics for empiric treatment of traveler’s diarrhea in adults and children are fluoroquinolones, azithromycin, and rifaximin, which is an alternative for afebrile nondysenteric diarrhea.

Traveler’s diarrhea is mainly a food- or waterborne disease: poor hygiene practices of food handlers, inadequate food storage and refrigeration, and high levels of environment contamination by fecal flora due to poor sanitation infrastructure are risk factors for acquiring enteric infections in developing countries. Travelers should be advised on safe practices regarding food and beverage consumption. No effective vaccinations are currently available for traveler’s diarrhea. Similarly chemoprophylaxis with antibiotics is not recommended in healthy travelers. Prophylactic treatment can be taken into consideration for hosts at increased risk of acquiring severe diarrhea, including patients with immunodeficiencies, malignancies, or chronic intestinal illnesses.

Food- and Waterborne Diseases: Food Poisoning

Food- or waterborne diseases can result from ingestion of food or water contaminated with bacteria, viruses, parasites, or other types of chemical poisoning. They can present either as sporadic cases or as outbreaks; the latter are defined as clusters of two or more individuals experiencing a similar illness after ingesting common food or water. Food- and waterborne diseases represent major public health concerns and are subject to different degrees of surveillance across countries. In the United States, several surveillance systems coordinated by the Centers for Disease Control and Prevention (CDC) are in place to monitor food- and waterborne disease occurrence, track sources of contaminated food, identify emerging pathogens, and provide administrative guidance.

The Foodborne Disease Active Surveillance Network (FoodNet), coordinated by the CDC, conducts population-based, active surveillance investigation of foodborne disease in the United States. The surveillance includes laboratory-confirmed infections for nine common pathogens ( Campylobacter spp., Listeria spp., Salmonella spp., Shigella spp., Shiga toxin–producing E. coli [STEC], Vibrio spp., Yersinia spp., Cryptosporidium spp., and Cyclospora spp.). Although some other important pathogens known to be transmitted by food are not actively tracked by the system, the control measures triggered by FoodNet inputs will likely have an impact on all foodborne infection. The National Notifiable Disease Surveillance System (NNDSS) is a passive surveillance database. Reportable foodborne diseases include botulism, listeriosis, salmonellosis, STEC infections, hemolytic-uremic syndrome (HUS), and vibriosis. A complete list of other CDC surveillance systems is available at the CDC website ( http://cdc.gov/foodborneburden/surveillance-systems.html ).

In 2014, FoodNet reported 19,542 infections, 4445 hospitalizations, and 71 deaths in the United States. The most common isolated pathogens were Salmonella , Campylobacter, and Shigella . The incidence of STEC O157 and Salmonella enterica serotype Typhimurium infections declined in 2014 compared with 2006–2008, and the incidence of infection with Campylobacter , Vibrio , and Salmonella serotypes Infantis and Javiana was higher. Compared with 2011–2013, the incidence of STEC O157 and Salmonella Typhimurium infections was lower, and the incidence of STEC non-O157 and Salmonella serotype Infantis infections was higher in 2014. Population at extremes of age were the most affected, with highest incidence for Salmonella, Campylobacter, Shigella, STEC O157 and non-O157, and Cryptosporidium being reported among children younger than 5 years, whereas individuals older than 65 years had the highest rates for infection with Salmonella and Campylobacter. Case-fatality rate is higher for Listeria, Vibrio, Yersinia, and STEC O157. The highest number of deaths was reported among the elderly ( http://www.cdc.gov/foodnet/trends/tables-2014.html ). Data from modeling based on different surveillance systems estimates around 9.4 million foodborne illnesses, with viral infections accounting for 59% of the cases, bacterial infections 39%, and parasites 2%. Norovirus, nontyphoidal Salmonella, Clostridium perfringens, and Campylobacter were estimated to be the pathogens most commonly involved. Norovirus, nontyphoidal Salmonella, Campylobacter, and Toxoplasma were responsible for the most hospitalizations. Salmonella, Toxoplasma, and Listeria accounted for the majority of documented deaths. When modeling included foodborne illnesses caused by unspecified pathogens—either microbes or toxins for which there are no surveillance systems in place or pathogens yet to be discovered—the number of expected foodborne diseases rose to 48 million per year, leading to 128,000 hospitalizations and 3000 deaths annually.

The WHO has recently estimated the number of foodborne illnesses globally at 2 billion cases, over 1 million deaths, and 78 million disability-adjusted life years (DALYs) in 2010; 29% of cases were transmitted by contaminated food. Norovirus was the leading cause of foodborne illness, causing 125 million cases, while Campylobacter caused 96 million foodborne illnesses.

Clinical manifestations of foodborne disease can affect the gastrointestinal tract and the central nervous system or cause systemic symptoms with little or no intestinal tract involvement. Incubation period and type of consumed food are helpful tools for establishing a presumptive diagnosis (see Box 44.1 ).

Rotaviruses

Worldwide, rotavirus is the leading cause of severe gastroenteritis in children. Rotavirus is responsible for the deaths of nearly 450,000 children younger than 5 years each year, mainly in developing countries. Rotavirus gastroenteritis affects more than 90% of children by the time they are 3 years old and may cause moderate to severe vomiting that precedes diarrhea. It accounts for 10% to 50% of the cases of diarrhea in children, is the most common cause of diarrhea in children during winter months in colder climates, and accounts for 35% to 50% of young children hospitalized for acute diarrhea. However, these rates have decreased in many countries after vaccine introduction. Stools usually are watery or soft, and the presence of blood or leukocytes is rare. Asymptomatic rotavirus infections occur frequently, and reinfection appears to be a common event. The mechanism of spread is fecal-oral. Shedding of virus most frequently occurs from a few days before to 10 days after the onset of illness. Natural rotavirus infection efficiently protects against severe disease associated with reinfection. Two virus surface proteins with antigenic properties, VP4 and VP7, are found in various conformations and are the basis for a binary serologic classification scheme that defines the G/P type of the virus. Five genotypes (G1 to G4 and G9) accounted for 88% of all strains, although extensive geographic and temporal differences exist. Rotavirus vaccines have reduced the health burden of rotavirus gastroenteritis in both developed and developing countries (see “ Prevention ” section).

Noroviruses

Noroviruses are in the family Caliciviridae and have been identified as the second most common viral cause of severe gastroenteritis in children younger than 5 years in developing and developed countries, preceded only by rotavirus. Norovirus is considered the most common cause of outbreaks of nonbacterial gastroenteritis worldwide. It accounts for 12% of severe gastroenteritis cases among children younger than 5 years of age. It is estimated that each year norovirus causes 64,000 episodes of diarrhea requiring hospitalization, 900,000 clinic visits among children in industrialized countries, and up to 200,000 deaths of children younger than 5 years in developing countries. Young children (<5 years) have the highest incidence of norovirus diarrhea; 6.5% higher than the population older than 5 years. Approximately 70% of pediatric norovirus cases occur between 6 and 23 months of age, with less than 15% occurring before 6 months. The mean incubation period for norovirus is 24 to 48 hours. The primary routes of transmission are fecal-oral, including consumption of fecally contaminated food or water; direct person-to-person contact, especially in schools, childcare centers, restaurants, summer camps, hospitals, nursing homes, and cruise ships ; and through contaminated objects or environments. A low inoculum dose is required for infection. Clinical manifestations include acute onset of vomiting, nonbloody diarrhea, or both lasting 12 to 60 hours. The identification of human histo-blood group antigens as norovirus receptors opens a new approach for evaluation of susceptibility and therapy of norovirus infection. Noroviruses are genetically and antigenically diverse. Five genogroups (G) and several subgenogroups have been assigned. Strains of three genogroups GI, GII, and GIV are found in humans; GII is the most prevalent worldwide. Candidate vaccines are presently in clinical development (see “ Prevention ” section).

Astroviruses

Astrovirus gastroenteritis occurs worldwide and has been associated with outbreaks of mild gastroenteritis in schools, daycare centers, pediatric wards, and nursing homes. Illness is restricted primarily to children younger than the age of 2 years, elderly people, and immunocompromised individuals. Astrovirus infections can be asymptomatic and associated with other enteric viruses. Eighty percent or more of adults have antibodies against the virus. The incubation period is 2 to 4 days. Symptoms include fever and malaise, followed by watery diarrhea that may last approximately 3 days; vomiting is an uncommon symptom. Classic human astroviruses contain eight serotypes and account for 2% to 9% of all acute nonbacterial gastroenteritis in children worldwide. The virus can be detected by electron microscopy, enzyme immunoassays, or reverse transcriptase–PCR (RT-PCR).

Enteric Adenoviruses

Human adenoviruses of subgroups A to F have been identified as etiologic agents in a wide range of human diseases, including conjunctivitis, upper respiratory tract infections, and pneumonia. A subgroup of fastidious adenoviruses (group F) with a distinct set of antigenic determinants and specific tissue culture growth characteristics has been shown to be associated with acute gastroenteritis and is referred to as enteric adenovirus. Serotypes 40 and 41 (group F) are responsible for approximately 5% to 10% of cases of endemic pediatric diarrhea worldwide, with higher prevalence in children younger than 24 months. Nonenteric adenoviruses, specially adenovirus 31, can also be found in children with diarrhea. The clinical manifestations include watery diarrhea accompanied by vomiting, low-grade fever, and mild dehydration. Antibody prevalence to enteric adenovirus increases from 20% during the first 6 months of life to 50% or greater by the third or fourth year of life. Seasonal shifts in the predominance of types 40 and 41 may occur. Outbreaks of enteric adenovirus diarrhea have been described in childcare centers, where asymptomatic excretion is a common occurrence.

Shigella

Shigella is the principal cause of clinical dysentery and an important cause of morbidity and mortality among children in impoverished regions of the developing world. In the United States, shigellosis is the third most frequent FoodNet pathogen in sentinel states but appears to be decreasing in incidence. There are four serogroups of Shigella, containing 46 serotypes: S. dysenteriae, S. flexneri, S. boydii, and S. sonnei. In developing countries S. flexneri is the predominant species, whereas S. sonnei predominates in industrialized regions; however, in recent years there has been an important shift in the etiology of bacillary dysentery, with Shigella sonnei expansion across industrializing regions in Asia, Latin America, and the Middle East. Infection by Shigella spp. rarely occurs in the first few months of life but is a common occurrence in children between the ages of 6 months and 10 years. Children exclusively breastfed have significantly lower risk of moderate and severe diarrhea due to Shigella compared to non-breastfed children. In highly endemic areas, peak infection rates occur in the second year of life. Children infected with Shigella can have asymptomatic excretion, watery diarrhea, or dysentery. HUS may occur after infection with Shiga toxin 1 (Stx1)-producing strains (primarily S. dysenteriae serotype 1). The postinfectious complications include reactive arthritis and postinfectious irritable bowel syndrome. Shigellosis results from the exposure to low inoculums of the bacteria; in addition to person-to-person spread, shigellae can be transmitted through contaminated foods, sexual contact, and water used for drinking or recreational purposes. Mild symptoms are self-limiting, but in more severe cases antibiotics are recommended for cure and preventing relapse. The progressive development of antibiotic resistance in Shigella isolates is a worldwide problem.

Salmonella

Salmonella infections are associated with several clinical syndromes: asymptomatic carriage, acute gastroenteritis, bacteremia, enteric fever, and dissemination with localized suppuration, such as abscess, osteomyelitis, or meningitis. Based on the current classification, the genus Salmonella contains only two species, S. bongori and S. enterica, but there are more than 2500 serovars of S. enterica. S. enterica serovar typhi (S. typhi) and nontyphoidal salmonellae (NTS) are important causes of infection and disease in children. Typhoid fever is particularly common in South and Southeast Asia and is estimated to cause more than half a million deaths each year. NTS are a major cause of foodborne infections including gastroenteritis worldwide. HIV-infected persons and malaria-infected children are at increased risk for invasive NTS. Salmonella gastroenteritis occurs most commonly in the first 5 years of life, decreases in frequency during childhood, and remains relatively constant throughout the adult years. In the United States, in the past decade, the Salmonella isolates most frequently reported have been S. enterica serotype Typhimurium and S. enterica serotype Enteritidis. Although most episodes of Salmonella infection are foodborne, reptiles, including turtles, snakes, lizards, and iguanas, carry certain serotypes of Salmonella in their intestinal tracts and have been associated with episodes of salmonellosis. Numerous outbreaks of disease caused by Salmonella after ingestion of contaminated food products, including eggs, milk, ice cream, peanut butter, and fresh produce, have been reported (see “ Foodborne Disease ” section).

Campylobacter

Campylobacter spp. are recognized as among the most important causes of acute diarrheal disease in humans throughout the world, including in the United States. The organism is a microaerophilic, curved gram-negative rod, carried in the intestine of many wild and domestic animals, particularly avian species including poultry. Healthy animals may be intestinal carriers. Water can be a direct source of human infection, although food contamination from food-producing animals is a more significant problem. The main risk factors for Campylobacter infection are international travel, consumption of undercooked chicken, environmental exposure, and direct contact with farm animals. Most C. jejuni diarrheal illness in the United States is foodborne. Currently, 26 Campylobacter spp. and subspecies are recognized; C. jejuni and C. coli are the two predominant species ; however, many clinical microbiology laboratories do not differentiate between them. People infected with C. jejuni may develop diarrhea, cramping abdominal pain, chills, and fever. Gross rectal bleeding may occur, and mucus and fecal leukocytes may be present, resembling the illness produced by Shigella. Campylobacter fetus, recognized as a cause of fever, bacteremia, and meningitis in immunocompromised hosts and of abortion rarely causes diarrhea. Campylobacter has been associated with periodontitis, inflammatory bowel disease, and several extraintestinal manifestations including reactive arthritis, Guillain-Barré syndrome, and Miller Fisher syndrome. There is growing recognition of an association between Campylobacter infection and malnutrition.

Diarrheagenic Escherichia coli

E. coli associated with diarrhea is referred to as diarrheagenic E. coli. There are six well-described categories of diarrheagenic E. coli classified based on clinical, microbiologic, and epidemiologic characteristics. Current classification is based mainly on the identification of specific virulence genes associated with each pathotype ( Table 44.6 ). In children, diarrheagenic E. coli as a group are responsible for 30% to 40% of all diarrhea cases worldwide.

Vibrio cholerae

Cholera is an acute, severe diarrheal disease caused by Vibrio cholerae that affects millions of people each year. Without prompt rehydration, death can occur within hours of the onset of symptoms. Cholera affects people of all ages, but children are involved disproportionately. Strains of V. cholerae are classified according to somatic or O groups. V. cholerae strains are separated further into two main serotypes (Ogawa and Inaba) and two biotypes (classic and El Tor). V. cholerae responsible for epidemic cholera belong to serogroups O1 and, in recent decades, O139. It is estimated that V. cholerae causes 1 to 4 million cases of diarrhea and more than 100,000 deaths annually. During the past several decades, despite advances in water sanitation technology and antibiotic treatment, the seventh cholera pandemic has spread. The cholera burden has grown strikingly during the past 4 years and has spread to countries previously spared by this disease. The current spread has proved especially violent, as illustrated by the recent deadly epidemics in East Africa and Haiti. Cholera emerged in Haiti in 2010, with more than 650,000 cases and over 8000 deaths, as of March 2013. Cholera is rare in the United States. Most clinical isolates of V. cholerae O1 in the United States are associated with foreign travel and with ingestion of undercooked seafood, and many are resistant to antimicrobial agents. Crabs harvested from the U.S. Gulf Coast are a common source of cholera. After Hurricane Katrina in 2005, crabs were the source of illness for certain cases of cholera. Most Vibrio infections after the hurricane were V. vulnificus, V. parahaemolyticus, and nontoxigenic V. cholerae. V. cholerae O75 has caused cholera in the U.S. Gulf Coast states. Since epidemic cholera began in Haiti in 2010, a total of 23 cholera cases caused by toxigenic V. cholerae O1 have been confirmed in the United States.

V. cholerae O1 adheres to and multiplies on small intestinal mucosa. Diarrhea occurs after elaboration of several toxins, the most important of which is cholera toxin (CT) composed of one A and five B subunits. The B subunits bind the toxin to the terminal galactose of G _M1 ganglioside receptors present on intestinal mucosal cells. Inside the epithelial cell, the A subunit activates adenylate cyclase, initiating continuous cyclic adenosine monophosphate production. This results in chloride and fluid secretion into the small intestine lumen. Strains of V. cholerae belonging to serotypes other than O1 and O139 are much less significant pathogens, although they can cause mild and occasionally profuse, watery diarrhea. Other Vibrio spp., including V. fluvialis, V. mimicus, V. hollisae, and V. furnissii, have been shown occasionally to cause gastrointestinal tract disease.

Vibrio parahaemolyticus

V. parahaemolyticus inhabits warm estuarine waters worldwide. The organism has been found in water, shellfish, fish, and plankton and has caused outbreaks of gastroenteritis after ingestion of contaminated seafood. Although widely distributed in coastal waters, V. parahaemolyticus is an uncommon cause of diarrhea where consumption of raw seafood is common, usually in summer. Clinical manifestations of infection with V. parahaemolyticus are gastroenteritis in 59% of cases and include abdominal cramps, nausea, and, less frequently, vomiting, headache, low-grade fever, and chills; wound infections, including hemorrhagic cellulitis in 34% and septicemia in 5%. A dysentery-like syndrome has been described in India and Bangladesh. Preexisting liver disease predisposes infected patients to development of septicemia and death. Three serotypes (O3:K6, O4:K68, and O1:K untypable) are extremely virulent and pathogenic to humans. Surveillance data from the United States indicate that the incidence of vibriosis increased from 1996 to 2010 overall and for each of the three most commonly reported species: V. parahaemolyticus, V. vulnificus, and V. alginolyticus.

Yersinia enterocolitica

Yersinia enterocolitica is a gram-negative bacillus that appears to be a common cause of gastroenteritis among children in Europe and Canada but is a relatively uncommon cause of enteritis in the United States. Yersiniosis incidence is higher among African-American children and Hispanic people. The ingestion of contaminated milk or food such as chitterlings has been implicated as the mode of transmission in reported outbreaks. The clinical manifestations vary according to the age of the person involved. Illness in children younger than 5 years usually is self-limited gastroenteritis. Stools may contain blood and mucus or be watery. Associated symptoms consist of fever, vomiting, and abdominal pain. Older children may present with abdominal pain associated with mesenteric adenitis that mimics acute appendicitis. Adults develop diarrhea and abdominal pain less frequently than do children but may present with polyarthritis, arthralgia or erythema nodosum. Patients with β-thalassemia and iron overload are at an increased risk for development of severe yersiniosis.

Aeromonas hydrophila

Aeromonas spp. are gram-negative bacteria found in soil and fresh and brackish water worldwide. Aeromonas spp. are recognized as colonizers and pathogens of cold-blooded animals, including fish, reptiles, and amphibians. Aeromonas spp. have been associated with a wide spectrum of human disease, most frequently gastroenteritis, soft tissue infection, and bacteremia, especially in immunocompromised hosts. There are many species of Aeromonas associated with human diseases; however, A. hydrophila, A. veroni, and A. caviae are the major species associated with gastroenteritis. Because many clinical laboratories cannot perform precise identification, most species isolated are reported as A. hydrophila. The role of A. hydrophila in human diarrhea remains controversial; however, new evidence supports its pathogenic role. Aeromonas -associated diarrhea occurs worldwide, but the exact prevalence of this infection on a global scale is unknown. The GEMS study found Aeromonas in a significant proportion of children with moderate to severe diarrhea in some but not all countries. Children with watery diarrhea associated with Aeromonas are significantly more likely to have organisms that possess genes for both heat-labile and heat-stable enterotoxins than do control children. Aeromonas has been linked to cholera-like and dysentery-like illnesses.

Plesiomonas shigelloides

P. shigelloides is a gram-negative bacillus that has been associated with opportunistic infections in immunocompromised hosts and with sporadic cases of diarrhea in immunocompetent hosts in a variety of countries. In some case-control studies, the organism has been found to be associated with diarrhea, whereas in others it has not. The organism has been isolated from surface water and the intestines of freshwater fish and many animals, including dogs and cats. Plesiomonas occurs commonly in tropical and subtropical areas from which most stool isolates have been reported. Coinfection with other pathogens is associated with diarrhea. Patients with P. shigelloides infection describe self-limited diarrhea, occasionally characterized by blood and mucus. The organism has failed to produce illness when fed to volunteers, and its role as an enteric pathogen remains uncertain.

Clostridium difficile

C. difficile is the most common bacterial agent associated with severe antimicrobial-associated diarrhea. Enterotoxin A and cytotoxin B account for most of its virulence. C. difficile infection is less common in children than adults, but the incidence of C. difficile infection in children is increasing. Asymptomatic colonization is very common in neonates and young children; reported rates range from 0% to 50% in neonates and up to 70% in infants. Frequency of colonization gradually decreases with age: after 4 years of age, rates are less than 5%, similar to those of healthy adults. Colonization generally persists for a few months, though it can persist for up to 12 months or longer. Elevated colonization rates have been described among hospitalized children and children with malignancy or inflammatory bowel disease. Despite the high frequency of colonization by C. difficile, infants rarely develop symptomatic disease. In older children, C. difficile disease was traditionally considered a hospital-acquired infection but community-acquired infection has been increasingly described. Children with community-associated infection tend to be healthier and have lower rates of exposure to antibiotics and acid suppressants than children with health care–associated disease. Gastrointestinal feeding devices (i.e., gastrostomy or jejunostomy tubes), proton pump inhibitors, and, to a lesser extent, histamine-2 receptor antagonists, have been associated with an increased risk of C. difficile infection in children.

Clostridium perfringens

C. perfringens types A, C, and D produce an enterotoxin that is implicated in the pathogenesis of a short-duration food poisoning syndrome. Most foodborne outbreaks are caused by type A strains and are associated with meat and poultry products. Within 14 hours after ingesting contaminated food, patients experience watery diarrhea and abdominal pain with minimal nausea, vomiting, or fever; illness resolves in less than 24 hours. C. perfringens type C also is associated with a rare destructive intestinal disease called enteritis necroticans or pigbel, characterized by vomiting, abdominal pain, bloody diarrhea, and small bowel necrosis, with peritonitis, shock, and death. These strains produce three toxins (α-toxin, β-toxin, and an enterotoxin) of potential pathogenetic significance. Enteritis necroticans occurs after ingestion of undercooked pork.

Staphylococcus aureus

S. aureus produces a wide variety of toxins including staphylococcal enterotoxins and staphylococcal-like proteins. Staphylococcal enterotoxins are a major cause of food poisoning, which typically occurs after ingestion of processed meat or dairy products, which have been contaminated with S. aureus due to improper handling and subsequent storage at elevated temperatures. Symptoms include nausea and vomiting, with or without diarrhea. The illness is usually self-limiting, and only occasionally is it severe enough to warrant hospitalization. The severity of the illness depends on the amount of food ingested, the amount of toxin in the ingested food, and the general health of the host. Staphylococcal enterotoxin type A has been responsible for more than half of the reported outbreaks of staphylococcal food poisoning in the United States.

Bacillus cereus

B. cereus is an aerobic, spore-forming, gram-positive bacillus that is widely distributed environmentally; it causes an emetic or a diarrheal food-associated illness primarily in the industrialized world. B. cereus is associated mainly with food poisoning but can also cause potentially fatal nongastrointestinal infections. B. cereus should be suspected as the cause of gastrointestinal tract illness if appropriate symptoms are present and if incriminated food, particularly fried rice, has been ingested. Two distinct forms of gastrointestinal tract illness can be produced by this organism: (1) the emetic disease, a food intoxication caused by cereulide, a small ring-form peptide; the emetic toxin produces a syndrome that resembles illness produced by staphylococcal enterotoxin, with nausea, vomiting, and abdominal cramps that begin within 1 to 6 hours of ingestion; and (2) a diarrheal syndrome caused by vegetative cells, ingested as viable cells or spores, that produce protein enterotoxins in the small intestine. These enterotoxins produce profuse watery diarrhea and abdominal pain that begin within 6 to 24 hours, with minimal or no vomiting. Some strains produce both toxins, whereas others produce only one toxin. Symptoms caused by either toxin usually resolve in less than 24 hours, and fever rarely occurs. Spores of B. cereus are resistant to heat and therefore may withstand a brief period of cooking or boiling.

Listeria monocytogenes

L. monocytogenes is the causative agent of listeriosis, a potentially fatal opportunistic foodborne infection. Listeria spp. are isolated from a diversity of environmental sources, including soil, water, foods, and the feces of humans and animals. The foods most frequently contaminated include soft cheeses and dairy products; pâtés and sausages; smoked fish; and industrially produced, refrigerated, ready-to-eat products that are eaten without cooking or reheating. L. monocytogenes can cause gastroenteritis in otherwise healthy individuals and more severe invasive disease in immunocompromised patients. Listeria infection in pregnancy may cause fetal loss or a preterm delivery, and the neonate is prone to neonatal sepsis and death. Common symptoms include fever, watery diarrhea, nausea, headache, cramps, and myalgia.

Entamoeba histolytica

Entamoeba histolytica is the causative agent of amebiasis, a disease that is a major source of morbidity and mortality in the developing world. The genus Entamoeba contains many species, six of which can reside in the human intestinal lumen. E. histolytica is the only species definitely pathogenic. New approaches to identifying E. histolytica are based on detection of E. histolytica –specific antigen and DNA in stool and other clinical specimens. Clinical patterns that occur in patients with amebiasis consist of intestinal amebiasis with the gradual onset of colicky abdominal pain and frequent bowel movements, tenesmus, and little or no constitutional disturbance; amebic dysentery, characterized by profuse diarrhea containing blood and mucus and the presence of constitutional signs, such as fever, dehydration, and electrolyte alterations; hepatic amebiasis, which usually presents as abscess formation without gastrointestinal tract symptoms; and asymptomatic colonization. In infants in developing countries most infections are asymptomatic; diarrhea is associated with both the amount of parasite and the composition of the microbiota. Patients may experience tender hepatomegaly, jaundice, weight loss, fever, and anorexia. The frequency of liver abscess in patients with amebiasis is between 1% and 5%. The complications of intestinal amebiasis include perforation, ameboma, stricture, hemorrhage secondary to erosion into a blood vessel, intussusception, ischiorectal abscess, fistulas, and rectal prolapse.

Giardia intestinalis

G. intestinalis (synonyms: G. lamblia and G. duodenalis ) is a flagellated protozoan parasite that reproduces in the small intestine, causing giardiasis. Giardia is one of the most common intestinal parasites in the world; it contributes to diarrhea and nutritional deficiencies in children in developing regions. In the United States it is the most common intestinal parasite identified by public health laboratories. Giardia infection is transmitted by the fecal-oral route and occurs after ingestion of Giardia cysts in fecally contaminated food or water or through person-to-person transmission. The low infectious dose of 10 cysts places people in close contact, including children in daycare, at risk of acquiring infection. Children appear to be more susceptible to Giardia than adults. Specific conditions that predispose to giardiasis are hypogammaglobulinemia, secretory immunoglobulin A (IgA) deficiency, peptic ulcer disease, biliary tract disease, and pancreatitis. The parasite may exist in two forms: cyst and trophozoite. The trophozoites usually are seen in duodenal aspirates and loose stools, whereas cysts can be found in formed stools and can remain viable and infectious in water for longer than 3 months. Diagnostic assays using antigen detection are available. Giardia infection can be asymptomatic or present as an acute illness with a sudden onset of explosive, watery, foul-smelling stools and flatulence, abdominal distention, nausea, and anorexia, with the absence of blood and mucus or as chronic diarrhea and malabsorption, with exacerbations and remissions of flatulence, abdominal distention, and abdominal pain often lasting for months. A recent systematic review showed that G. lamblia was not associated with acute diarrhea in children in developing countries. Giardia infections can result in chronic gastrointestinal disorders such as postinfectious irritable bowel syndrome, and symptoms may manifest at extraintestinal sites even though the parasite does not disseminate beyond the gastrointestinal tract.

Cryptosporidium

Cryptosporidium is an intestinal coccidian protozoan parasite that causes diarrheal diseases in humans worldwide. Children and immunosuppressed individuals, especially those with HIV infection or AIDS, are disproportionately affected. In developing countries there is a high prevalence of cryptosporidiosis in young children, particularly among those who are malnourished or HIV infected, with high rates of hospitalization and mortality. The GEMS study identified Cryptosporidium as one of the four major contributors to moderate to severe diarrheal diseases during the first 2 years of life at all sites. Fecal-oral transmission of Cryptosporidium oocysts occurs from person to person, through ingestion of contaminated drinking water or recreational water, through consumption of contaminated food, or by contact with infected animals (cattle and sheep). Unlike bacterial pathogens, Cryptosporidium is resistant to chlorine disinfection and can survive for days in treated recreational water, including swimming pools and recreational water parks. Children aged 4 years and younger appear to be at a particularly high risk for acquiring this organism. Cryptosporidium has been implicated as a cause of diarrhea in travelers, outbreaks, and of epidemics in hospitals, daycare centers, and other institutional settings worldwide. Cryptosporidiosis can be manifested with a wide spectrum of symptoms, including asymptomatic excretion, acute diarrhea, chronic diarrhea, epidemic diarrhea, severe life-threatening watery diarrhea, and biliary tract disease. Stools do not contain blood or leukocytes. Vomiting, flatulence, abdominal pain, and low-grade fever routinely accompany diarrhea. Symptoms usually subside in an average of 9 days. Patients may have cholera-like illness, transient diarrhea, relapsing episodes, or a protracted clinical course with unremitting, profuse diarrhea lasting for months accompanied by profound malabsorption and weight loss. In immunocompetent individuals, infection with this parasite may be asymptomatic or cause a self-limiting diarrheal illness. However, in immunocompromised patients such as those with HIV infection or AIDS, Cryptosporidium spp. may cause severe, chronic, and possibly fatal diarrhea and wasting. Identification of the organisms and symptoms is more frequent when the CD4 count is less than 200 cells/µL. Antiretroviral therapy is protective against disease.

Isospora belli

Isospora gained importance with the advent of AIDS and, before HAART, was shown to be an important cause of severe and prolonged gastroenteritis. Infection can occur in adults and children and has been reported in infants with severe diarrhea. This organism also has been implicated as a cause of traveler’s diarrhea. Transmission is fecal-oral, through ingestion of oocysts contaminating food, water, or environmental surfaces. The clinical spectrum of disease caused by Isospora is indistinguishable from that described for Cryptosporidium. The spectrum includes asymptomatic infection, acute diarrhea in children in developing countries, and chronic diarrhea or severe, protracted, life-threatening diarrhea in patients with AIDS. Fever, malaise, abdominal pain, and headache have been reported. Stools are watery and do not contain blood or leukocytes. Malabsorption, steatorrhea, severe weight loss, and chronic diarrhea lasting months to years are the most likely occurrences in immunocompromised hosts.

Cyclospora

Cyclospora cayetanensis, a coccidian protozoon, is transmitted by the fecal-oral route. Direct person-to-person transmission is unlikely to occur because excreted oocysts require days to weeks under favorable environmental conditions to sporulate and to become infectious. An animal reservoir has not been described. Outbreaks of diarrhea caused by consumption of water and fresh fruits contaminated with Cyclospora have been described, and travelers to developing countries are at increased risk for development of diarrhea caused by Cyclospora. In the United States approximately half of the cases are associated with international travel, known outbreaks, or both. Most of the reported cases have occurred during the spring and summer. The mean incubation period appears to be 7 days. Clinical manifestations include asymptomatic excretion, acute watery diarrhea, and diarrhea that may be protracted for days to weeks with frequent, watery stools, which may remit and relapse. The clinical presentation is somewhat different in areas of endemicity, where asymptomatic infections are more frequent. Nevertheless, younger children have more severe clinical symptoms. In endemic settings, infections tend to be milder as children get older because the duration of the infection is shorter and the severity of disease decreases. As in young children, the elderly may also present with a more severe illness.

Microsporidia

Microsporidia have emerged as causes of opportunistic infections associated with diarrhea and wasting in AIDS patients. Among non–HIV-infected but immune-suppressed individuals, microsporidia have infected organ transplant recipients, diabetics, children, the elderly, and patients with malignant disease. In otherwise healthy immune-competent HIV-seronegative populations, self-limiting diarrhea occurred in travelers and as a result of a foodborne outbreaks. Greater awareness and implementation of better diagnostic methods are demonstrating that microsporidia contribute to a wide range of clinical syndromes in HIV-infected and non–HIV-infected people. The nontaxonomic term human Microsporidia can refer to any of the order of Microsporidia known to cause disease in humans: Enterocytozoon spp. , Encephalitozoon spp. , Pleistophora spp., and Nosema spp. Of these Enterocytozoon bieneusi and Encephalitozoon intestinalis are the most important in gastrointestinal tract disease of humans. Both species have been detected in intestinal biopsy specimens of patients with AIDS, with a clinical picture of prolonged diarrhea and weight loss. The clinical spectrum appears to depend on the immune status of the host. The primary location of all intestinal spore-forming protozoal infection is the small intestine, but colonic infection has been reported with E. bieneusi. Infection of the biliary tract with E. bieneusi and E. intestinalis in patients with AIDS can cause sclerosing cholangitis and acalculous cholecystitis. E. intestinalis can infect lamina propria macrophages, fibroblasts, and endothelial cells and can disseminate to other organs, including liver, respiratory tract, and kidney. Extraintestinal infection develops after infection with other species of the order of Microsporidia occurs.

Strongyloides stercoralis

S. stercoralis is a nematode that infects humans through the intestinal tract or through skin if either comes in contact with soil that contains larvae. About one-third of people with strongyloidiasis are asymptomatic, and the remainder may have skin, pulmonary, or, more frequently, gastrointestinal tract involvement. People at risk include residents and travelers to endemic areas ; natives and residents of the Appalachian region in the United States; institutionalized patients; and people treated with corticosteroids, cimetidine, and antacids. Epigastric abdominal pain occurs and is associated with diarrhea that contains mucus and blood. Some patients may complain of nausea, vomiting, and weight loss with evidence of malabsorption. Eosinophilia and an urticarial rash are prominent features of infection. Diagnosis of Strongyloides is often delayed, owing to patients presenting with nonspecific gastrointestinal complaints, a low parasite load, and irregular larval output. Novel diagnostic methods are expected to improve epidemiologic studies and control efforts for prevention and treatment of strongyloidiasis. The hyperinfection syndrome caused by Strongyloides stercoralis has a high mortality rate (15–87%). Risk factors include new immunosuppressive therapies, human T-lymphotropic virus (HTLV)-1 infection, cadaveric transplantation, immune reconstitution syndrome, hematologic malignancies (especially lymphoma), tuberculosis, malnutrition secondary to chronic Strongyloides diarrhea, international travel, and immigration.

Fecal Leukocytes

Microscopic examination of stool specimens for evidence of fecal leukocytes provides information about the cause of diarrhea and helps determine the anatomic location and presence of mucosal inflammation. Fecal leukocytes are produced in response to bacteria that diffusely invade the colonic mucosa and indicate that the patient has colitis. No inflammatory bacterial enteritis exists in which results of the fecal leukocyte examination are uniformly positive. Thus results of examination are more helpful when they are positive than when negative. When results are positive (>50–100 leukocytes per high-power field), the patient probably has an invasive or cytotoxin-producing organism, such as Shigella spp., Salmonella spp., Campylobacter spp., invasive E. coli, STEC, C. difficile, or Y. enterocolitica, although ulcerative colitis and Crohn disease also are associated with fecal leukocytes.

Diarrheagenic E. coli is associated with a mild inflammatory response during symptomatic infection in children. Fecal leukocytes generally are not present in stools from patients with diarrhea secondary to viruses, enterotoxin-producing bacteria, or parasites. The leukocytes seen in cytotoxin-associated and invasive bacterial diarrhea syndromes are polymorphonuclear. If the fecal leukocyte examination shows evidence of inflammatory enteritis, further laboratory evaluation is indicated. Fecal lactoferrin and fecal calprotectin are newly available markers associated with intestinal inflammation. Fecal lactoferrin is a much more sensitive indicator of inflammatory diarrhea than the fecal leukocyte or occult blood test, but it may not be useful in differentiating inflammatory from noninflammatory diarrhea in diarrhea-endemic countries. Stool lactoferrin may be falsely positive in breastfed infants. Fecal calprotectin can also be used to screen for bacterial diarrhea and to differentiate between bacterial and viral pathogens in children with gastroenteritis and in children with inflammatory bowel diseases.

Ova and Parasites

Normally examination of stools for ova and parasites is unnecessary unless the patient has a history of recent travel to high-risk areas, stool cultures are negative for other enteropathogens, the patient is involved in an outbreak of parasitic diarrhea, diarrhea persists for longer than 1 week, or the patient is immunosuppressed. Both trophozoites and cysts of G. lamblia and larvae of Strongyloides spp. can be identified on direct smears of stool specimens. However, the sensitivity of stool examination for most parasites can be improved by use of a concentration technique and by placement of stools in vials containing a stool preservative. Trichrome and iron hematoxylin both are useful as permanent stains for Giardia spp. Pooling of preserved fecal samples is an efficient and economical procedure for detecting ova and parasites. Rational use of the stool ova and parasite examination relies on communication between the clinician and laboratory personnel. For patients in whom giardiasis, cryptosporidiosis, isosporiasis, or strongyloidiasis is considered and in whom stool cultures are negative, aspiration or biopsy of the duodenum or upper jejunum may be indicated. Because these organisms live in the upper intestine, this procedure is more reliable than is examination of stool specimens. E. histolytica can be diagnosed by microscopic examination of fresh stool specimens or bowel wall scrapings for cysts or trophozoites. A concentration technique may be helpful in demonstrating amebic cysts. Examination of several stool samples by an experienced technician may be necessary because excretion of cysts often is intermittent and interpretation is difficult. Confusion in differentiating amebic cysts from fecal leukocytes may occur. Microscopy can be used only as presumptive evidence of E. histolytica because the nonpathogen E. dispar is morphologically identical.

Special Stains for Coccidia

Diagnosis of Cryptosporidium, Isospora, Cyclospora, and the Microsporidia is based on morphologic appearance and staining of stool or histologic examination of tissue sections. Among the most widely used stains to visualize these coccidia are standard acid-fast or modified acid-fast stains, which are based on the use of reagents that enhance the penetration of fuchsin into the organism without the need for heating (modified Kinyoun acid-fast stain). In a modified acid-fast stain, Cryptosporidium oocysts, which are 4 to 6 µm with four crescentic sporozoites, stain red and can be differentiated readily from yeasts that stain green. In a study of seven microscopy-based Cryptosporidium oocyst detection methods, false-positive results were detected by acid-fast and auramine-rhodamine stains but not by monoclonal antibody–based methods. Oocysts of I. belli often are visualized by wet-mount preparations because of their size, which is 20 to 30 µm with four sporozoites in two sporocysts. Cyclospora oocysts are 8 to 10 µm in diameter and are nonrefractile spherical organisms containing two sporozoites in two sporocysts that are seen easily on wet mount preparations and are variably acid fast. Microsporidia are difficult to differentiate from bacteria and debris because of the small size of the spores, which measure 1 to 2 µm. For detection, formalin-fixed stool or duodenal fluid can be stained with a calcofluor stain, a modified trichrome stain, or a fluorescent stain. Gram, acid-fast, periodic acid–Schiff, and Giemsa stains also have been used to stain the organism. Small bowel biopsy may be more sensitive than is stool examination for establishing the diagnosis of intestinal microsporidiosis. Spores are gram positive, and parts of the internal structure are positive for acid-fast or periodic acid–Schiff stains.