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Infectious Diarrhea
According to the World Health Organization (WHO), diarrheal disease is the second leading cause of death in children younger than 5 years of age worldwide. It is also the leading cause of malnutrition in children younger than 5 years of age. Globally, diarrhea alone kills more than 2000 children daily, more than the daily death rate from other deadly diseases such as human immunodeficiency virus (HIV), malaria, and measles combined. In the United States, it has been estimated that approximately 369 childhood deaths occur annually from diarrheal illness.
Knowledge of diarrheal disease has increased remarkably during the past few decades, increasing our understanding of pathogenic organisms and mechanisms. Although this has led to improvements in therapy and significant reductions in mortality, diarrheal disease remains a devastating childhood condition in many countries. For example, most attributable cases of moderate-to-severe childhood diarrhea in Africa and Asia are caused by four pathogens: rotavirus, Cryptosporidium spp., enterotoxigenic Escherichia coli producing heat-stable toxin (ST), and Shigella spp. This chapter discusses the major viral and bacterial agents of infectious diarrhea, including epidemiology, pathogenesis, clinical manifestations, diagnosis, and therapy.
Multiplex Molecular Testing, an Introduction
Before we begin the discussion of the various entities of infectious diarrhea, it is important to review recent advances in the detection and identification of gastrointestinal pathogens. Historically, care providers have used various platforms in an attempt to identify the etiology of diarrhea. These include stool samples sent for culture, ova and parasite examination, tissue biopsy with subsequent microscopic examination, immunoassays, rectal swabs, etc. More recently the idea of sending a single specimen to collectively test for various pathogens has become more prevalent. To make this possible, multiplex PCR analysis was developed. Proponents of this clinical tool emphasize the following advantages: (1) high sensitivity and specificity; (2) faster turnaround time; (3) detection of coinfections; (4) avoidance of unnecessary infection control precautions through reliance on the high negative predictive value of multiplex PCR; and (5) enhancement of patient care. Furthermore, several studies have demonstrated the potential cost savings using multiplex PCR testing when compared with traditional fragmented methods.
Molecular testing is available in two categories, syndromic panels and class panels. Syndromic panels target a group of the most common pathogens (viral, bacterial, parasitic) responsible for specific symptoms such as diarrhea. Class panels target for a group of pathogens that fall into a class such as a viral panel, parasite panel, or bacterial panel. Currently there are several multiplex PCR–based, laboratory-developed tests available for use in the United States. One example is the gastrointestinal pathogen panel (GPP) developed by the Milwaukee Health Department. This syndromic panel screens for 19 pathogens including 9 bacteria, 3 parasites, and 4 viruses. Validation studies of this panel demonstrated a 94.5% comparative performance and 99% sensitivity when compared with conventional testing.
The utilization of multiplex PCR panels is becoming more common in both the inpatient and outpatient setting. Several studies have been published demonstrating its potential in population health and illustrating differences with respect to conventional methods. Unfortunately, a major limitation of this methodology is the shotgun approach to many pathogens. For common pathogens it is very useful. For rare pathogens (i.e., those with low and very low prevalence rates), even when the sensitivity and specificity of the test is high, the false-positive rate will greatly exceed the true positive rate.
Viral Gastroenteritis
Diarrheal disease caused by viral agents occurs far more frequently than does similar disease of bacterial origin. Rotavirus, norovirus, adenovirus, and a number of other viruses have been identified as a major cause of nonbacterial gastroenteritis in children and adults. This discussion focuses on these established pathogens, in addition to a brief summary of several newer viral enteropathogens.
Rotavirus
Rotavirus was first identified as a specific viral pathogen in duodenal cells of children with diarrhea by Bishop and associates in 1973 and has played a major role globally in morbidity and mortality from diarrheal illness. Rotavirus remains the leading cause of watery diarrhea in children and comprises 29% of all deaths globally from diarrheal illness in children younger than 5 years of age. Although the majority of deaths occur in low- and middle-income countries, the impact of this virus on high-income nations is not insignificant. For example, among children younger than 5 years old in the United States, rotavirus-associated gastroenteritis accounts for approximately 53% of hospitalizations, 59% of emergency department visits, and 47% of outpatient clinic visits during the usual rotavirus season. It is likely that this impact is less with the increasing impact of rotavirus vaccination. Compared with other causes of gastroenteritis, rotavirus has the potential to cause severe symptoms. Before the initiation of the rotavirus vaccination program in 2006, nearly every child in the United States was infected with rotavirus by age 5 years.
Virology
Rotaviruses are nonenveloped RNA viruses that belong to the family Reoviridae. They are approximately 100 nm in diameter and are composed of three separate shells (capsids) that surround and encase the viral genome consisting of 11 double strands of RNA. This structure gives the virus its characteristic appearance of a wide-rimmed wheel with spokes radiating from the hub, from which its name was derived ( rota is Latin for “wheel”).
Rotaviruses are classified into various serotypes based on the antigenic differences of two outer layer structural proteins coded for by the RNA viral genome, VP4 and VP7. These structural proteins are the target for natural antibodies and have been the targeted approach to vaccine development. VP4 is designated as the P antigenic protein because it is cleaved by the protease trypsin at the intestinal level. VP7 is designated as the G antigenic protein because it is a glycosylated structure. There are at least 60 different G/P strains with different serotype combinations. However, four serotypes—G1, G2, G3, and G4—are the predominant cause of gastroenteritis worldwide. , Among these serotypes there are substantial geographic differences. For example, G1P[8] is the major strain responsible for more than 70% of infections in North America, Australia, and the United Kingdom but is only found in 25% to 50% of infections in South America and Africa.
Epidemiology
Although rotavirus infection occurs in developing countries as well as industrialized countries, the seasonality is varied. In temperate climates, incidence peaks more commonly during the winter months. Tropical climates demonstrate a less specific seasonality. Transmission is primarily from person to person, through contact with feces or contaminated fomites, and highly contagious.
Although the virus may affect all age groups, it most commonly produces disease in children between 6 and 24 months of age. Infants younger than 3 months of age can become infected with rotavirus but may not manifest symptoms due to the presence of transplacental maternal antibodies in the first few months of life. Before vaccination, most children were infected at least once by the age of 3 to 5 years and developed rotavirus antibodies by the age of 2 years, which helps to explain the observed decreased incidence of rotavirus infection later in childhood. Children residing in low-income countries contract infection at a younger age (median age 6 to 9 months) compared with those children living in higher-income countries (median age 2 to 5 years).
Clinical Manifestations
The clinical presentation of rotavirus infections varies widely from mild loose stools to severe diarrhea accompanied by vomiting, which can lead in some instances to dehydration and shock, electrolyte disturbances, and even death. For most infections, an abrupt onset of watery and explosive diarrhea follows an incubation period that ranges from 1 to 3 days. The duration of illness is most commonly 3 to 7 days but can be as long as 2 to 3 weeks. Fever and vomiting usually resolve after 24 to 48 hours. In the neonatal population, abdominal distension with mucoid, bloody stools may occur, even though rotavirus is not thought to infect the colon. An association between rotavirus infection and necrotizing enterocolitis has also been observed.
A typical, less severe form of infection with mild diarrhea and lack of systemic symptoms is common among children who are immunocompromised. However, children and adults with congenital immunodeficiency or who have received bone marrow or solid organ transplantation often have a more severe and sometimes fatal rotavirus-induced gastroenteritis. , The severity of rotavirus disease among children infected with HIV is thought to be similar to that among children without HIV infection.
Shedding of virus into the intestinal lumen begins with infection and is usually present prior to clinical manifestations of the illness. Peak shedding occurs on day 3 of infection and typically begins to resolve after 7 days. However, shedding has been documented to last for several weeks even in immunocompetent hosts. , Prolonged shedding (>3 weeks) is common in immunocompromised individuals. It is important to be aware that the more severe the illness, the more prolonged the shedding of viral particles. A comparison of the characteristics of rotavirus infections with those of other enteric viruses is presented in Table 38.1 .
TABLE 38.1
Viral Enteric Pathogens
O’Ryan M. The ever-changing landscape of rotavirus serotypes. Pediatr Infect Dis J . 2009;28(3 Suppl):S60–62; Ousingsawat J, Mirza M, Tian Y, et al. Rotavirus toxin NSP4 induces diarrhea by activation of TMEM16A and inhibition of Na+ absorption. Pflugers Arch . 2011;461(5):579–589; Siah SP, Merif J, Kaur K, et al. Improved detection of gastrointestinal pathogens using generalised sample processing and amplification panels. Pathology . 2014;46(1):53–59; Thiagarajah JR, Ko EA, Tradtrantip L, et al. Discovery and development of antisecretory drugs for treating diarrheal diseases. Clin Gastroenterol Hepatol . 2014;12(2):204–209; Ahmadi E, Alizadeh-Navaei R, Rezai MS. Efficacy of probiotic use in acute rotavirus diarrhea in children: a systematic review and meta-analysis. Caspian J Intern Med . 2015;6(4):187–195.
| Virus | Predominant Age Group Affected | Seasonality | Duration of Symptoms |
|---|---|---|---|
| Rotavirus | 6–24 months | ↑ in winter months | 3–7 days |
| Norovirus/caliciviruses | <5 years, adults | ↑ in winter months | 24–60 h |
| Enteric adenovirus | <2 years | All year round | Up to 14 days |
| Astrovirus | 1–3 years | Unknown | 1–4 days |
Pathophysiology
Rotavirus primarily invades mature villus intestinal epithelial cells of the small intestine. After invasion and replication, there is epithelial cell death and sloughing. Histologically, this is manifested as blunting of the intestinal villi and crypt hypertrophy in response to the loss of villus cells. The lytic infection of highly differentiated absorptive enterocytes and the sparing of undifferentiated crypt cells results in both a loss of absorptive capacity with “unopposed” crypt cell secretion (causing secretory diarrhea) and loss of brush border hydrolase activity (causing osmotic diarrhea). Hence the picture of rotavirus infection is that of a mixed secretory/osmotic diarrhea.
Another mechanism for rotavirus diarrhea also has been demonstrated. The rotavirus nonstructural glycoprotein NSP4 has been shown to act as an enterotoxin by inducing a secretory diarrhea in mice through activation of a chloride channel, TMEM16A, and inhibition of sodium absorption through interactions with the sodium channel, ENaC, and the sodium/glucose transporter, SGLT1.
Diagnosis
Currently, there are many different diagnostic techniques available for the detection of rotavirus infection. However, molecular techniques are faster and have demonstrated better sensitivity and specificity, making them more widely used at this time. Enzyme immunoassays (EIAs) are the most commonly used method currently for rotavirus detection and use reactive antibodies directed towards epitopes of VP6, a protein found among all rotavirus strains. Various EIA kits are available for routine laboratory use. Multiplex PCR panels or Luminex-based assays with universal sample preparation may allow streamlined, rapid diagnosis of rotavirus and other common viral, bacterial, and parasitic gastrointestinal pathogens.
Treatment
Currently, supportive care with oral or intravenous rehydration is the mainstay of therapy. Although novel antisecretory therapies have been reported, no antiviral agents effective against rotavirus have yet been developed. However, probiotic therapy has been demonstrated to reduce duration of diarrheal disease in pediatrics. Specifically, treatment with Lactobacillus rhamnosus GG, Lactobacillus reuteri , and Bifidobacterium lactis were shown to reduce duration and severity of illness and perhaps shorten viral shedding. Additional studies have demonstrated that use of probiotics as a single species (Lactobacillus acidophilus, Saccharomyces boulardii) or polyspecies ( L. acidophilus, L. rhamnosus, Bifidobacterium longum, and S. boulardii ) decreased duration of diarrhea by 30%, as well as duration of fever and vomiting, in children ranging in age from 1 to 23 months. Antiemetics may reduce the need for intravenous rehydration because of vomiting and the number of hospital admissions. However, the main antiemetic, ondansetron, has a warning for potentially severe side effects, and data on cost effectiveness for the routine use of ondansetron treatment for acute gastroenteritis are lacking.
Prevention
In infants, natural rotavirus infection does not confer absolute immunity against reinfection. However, it does protect against severity of disease with a subsequent reinfection. Immunity can also be conferred following vaccination with oral live vaccines. The first licensed rotavirus vaccine in the United States was the RotaShield Wyeth-Lederle Vaccine in 1998. Although vaccine efficacy against severe rotavirus-induced gastroenteritis approached 90%, the vaccine was withdrawn from the market secondary to an increased rate of intussusception. Two different rotavirus vaccine products were subsequently developed and are currently licensed and have been widely used in infants in the United States since 2006.
RotaTeq is an oral, live pentavalent (G1, G2, G3, G4, and P[8]) human-bovine reassortant vaccine. It is administered orally as a three-dose series beginning as early as 6 weeks of age and dosed in 4-week intervals. The maximum age for the last dose in the series is 8 months. In several large randomized placebo-controlled trials, RotaTeq was found to be 98% effective against severe rotavirus gastroenteritis during the first full rotavirus season following vaccination. Efficacy against rotavirus in subsequent seasons was 74%.
Rotarix is a live, oral monovalent (G1P1A) vaccine that has been licensed in the United States since 2008. The vaccine is to be administered orally in a two-dose series at ages 2 and 4 months with the same minimum and maximum age ranges and intervals as RotaTeq. Studies have revealed the efficacy to be 84% against severe rotavirus gastroenteritis, with an 85% reduction in hospitalizations.
Early success from the vaccines has been documented. The National Respiratory and Enteric Virus Surveillance System (NREVSS) and the New Vaccine Surveillance Network (NVSN) indicated that the onset and peak of the 2008 rotavirus season were delayed by 15 and 8 weeks, respectively, as compared with the six previous consecutive seasons. Further data indicate that the number of tests positive for rotavirus during the 2008 season decreased by more than two-thirds as compared with the seven preceding rotavirus seasons. The overall impact of these vaccines has been evaluated both in the United States and globally. To date, more than 80 countries have implemented the rotavirus vaccine into their immunization programs. Hospitalization for acute gastroenteritis has been reduced by 38% globally among children less than 5 years of age. In addition, visits to the emergency department and hospitalizations have been reduced by almost 90% in some studies. Although the protection from rotavirus infection in developing countries is not as good, due to the higher burden of disease, the absolute benefit is higher in these settings.
Small Round Structured Viruses
Caliciviruses
“Winter vomiting disease” was thought to be caused by nonbacterial gastroenteritis for decades, before an etiologic agent was identified from an outbreak, in 1968, in Norwalk, Ohio. In this outbreak, only some of the patients had diarrhea. The predominant clinical manifestation was vomiting and nausea. Virus particles were visualized by immunoelectron microscopy on fecal material derived from the Norwalk outbreak. This represented the first definitive association between a specific virus (Norwalk virus) and acute gastroenteritis. Subsequently a number of similar etiologic agents were identified. Before the cloning of the prototype Norwalk virus genome, these viruses, which were a group of morphologically diverse, positive-stranded RNA viruses that caused acute gastroenteritis, were identified as Norwalk-like agents. These organisms were also named for the communities in which they were first isolated (e.g., Montgomery County, Hawaii, Snow Mountain, Taunton, Otofuke, and Sapporo viruses). Based on PCR, the sequence structure of these viruses has enabled their classification as human caliciviruses (HuCV). HuCV s as in HuCVs are now recognized as a leading cause of diarrhea worldwide among persons of all ages.
HuCV are classified into five genera, Norovirus, Sapovirus, Lagovirus, Vesivirus, and Nebovirus . Norovirus and Sapovirus comprise human viruses, and the other genera involve animal viruses. Despite the potential for future understanding of the contribution of individual HuCV to outbreaks of nonbacterial gastroenteritis, Norovirus still remains the prototypic agent of HuCV.
Norovirus
Epidemiology
Norovirus is a single-stranded RNA, nonenveloped virus belonging to the Caliciviridae family and is the leading cause of foodborne disease outbreaks worldwide, with an estimated 23 million cases alone in the United States annually. Noroviruses are the most common cause of medically attended gastroenteritis in the United States subsequent to the introduction of rotavirus vaccine. They are also the most common cause of foodborne disease outbreaks in the United States. In a large epidemiology study, Norovirus was detected in 21% of young children seeking medical attention for acute gastroenteritis in 2009 and 2010. Noroviruses are the second most common cause of severe pediatric gastroenteritis worldwide in children younger than 5 years old and are responsible for 12% of hospitalizations in this age group for severe gastroenteritis. There are six known genotypes based on the capsid (VP1) gene. Genogroup I (GI) and II (GII) are most commonly associated with human infections. The original Norwalk virus is a GI virus. GII viruses are most often implicated in outbreaks worldwide. The majority of patients exposed to norovirus do become symptomatic, with children exhibiting more symptoms than adults. In the United States, nearly half (47%) of all medically attended norovirus infections occurred in children who were 6 to 23 months of age. The mean age of children with acute gastroenteritis who had positive test results for norovirus was 17 months (median 14 months). , Asymptomatic infection also occurs in children, with detection rates between 8% and 30% in some studies. Natural immunity following norovirus infection is common but is felt to be limited only to strains similar to the original infection, leaving the host susceptible to different strains of norovirus. Natural immunity is not indefinite, usually lasting for several years.
Transmission of norovirus is most often fecal-oral but also occurs vomit-oral and person to person. Person-to-person transmission is believed to be the most common mode of spread in outbreaks, especially settings where larger groups of people are in close proximity (i.e., cruise ships, hospital settings, and airplanes). Foodborne transmission also occurs and is felt to be most often due to contamination of food products prepared by infected food handlers. Norovirus is also capable of existing on contaminated surfaces, demonstrating stability in freezing and hot conditions and thereby facilitating ease of transmission in this manner. , Several characteristics of norovirus facilitate its spread in epidemics: (1) low infectious dose (between 10 1 and 10 3 organisms), (2) prolonged viral shedding, (3) stability of the virus in relatively high concentrations of chlorine and a wide range of temperatures, and (4) repeated infections occurring with reexposure.
Pathophysiology
There are several proposed pathways for the mechanism of norovirus infection. Norovirus may infect epithelial cells directly through binding with histo-blood group antigen (HBGA) present on the surface of intestinal epithelial cells. Other proposed pathways involve the infection of monocytes in a microfold (M) cell–dependent manner or through the transportation across the epithelium via interactions with commensal bacteria and lymphoid cells. Histologically, norovirus does alter the intestinal mucosa, which leads to enterocyte apoptosis, flattened villi, crypt hypertrophy, disruption of the epithelial barrier function, and mucosal inflammation. Inflammation is characterized by infiltration of neutrophils into the lamina propria, which disrupts the absorptive surface of the intestine, leading to clinical symptoms.
Clinical Manifestations
Following an incubation of 24 to 48 hours, the clinical manifestations of disease produced by norovirus include nausea, vomiting, and cramping abdominal pain (see Table 38.1 ). Norovirus is not an invasive disease; dysentery is rare, and diarrhea is usually watery and is observed to be a less consistent feature of this illness. In the original outbreak, only 44% of patients experienced diarrhea, whereas 84% had vomiting. However, other studies have found that diarrhea occurs in most children and experimentally infected adult volunteers who become ill from this virus. Fever occurs in approximately one-third of affected patients, but respiratory symptoms are not typically a part of this illness. Infection is self-limited, with a duration of 24 to 60 hours. However, shedding can occur for up to 8 weeks in postinfected, asymptomatic individuals. In neonates and premature infants the symptoms are variable, ranging from the typical symptoms to abdominal distension, apnea, and sepsis-like appearance. Symptoms can be more pronounced and severe in children, the elderly, and the immunocompromised to include renal failure, disseminated intravascular coagulation, and chronic diarrhea.
Diagnosis and Treatment
Norovirus can be detected in fecal samples following virus inoculation for a period of approximately 4 to 8 weeks. Peak viral titers are most commonly found in fecal samples collected after resolution of symptoms. The most widely used diagnostic tool for norovirus detection is stool EIA directed towards GI and GII antigens in stool specimens. Sensitivity ranges from 36% to 80%, whereas specificity ranges from 47% to 100%. , PCR assays have also been developed and display a better sensitivity and specificity in the diagnosis and detection of noroviruses in clinical and environmental specimens, such as water and food. All current methods to diagnose norovirus have limitations of sensitivity and specificity for nonoutbreak use. PCR is the preferred method of detection in epidemiologic studies and outbreaks, whereas molecular methods are preferred for the detection of viral etiologies of acute gastroenteritis. Although molecular methods will significantly increase the detection of the causative agent, many positive samples containing low viral loads are also found in patients with complaints other than intestinal symptoms.
The treatment for norovirus is largely supportive and aimed at preventing dehydration. Although rare, severe dehydration can occur, necessitating hospitalization for fluid management. A number of candidate vaccines are currently being evaluated. A randomized double-blind placebo-controlled trial showed a statistically significant decline in degree of infectivity and infection rates for Norwalk virus GI following administration of an intranasal virus-like particle-based vaccine.
Enteric Adenovirus
The enteric adenoviruses are among the more recently recognized viral pathogens that cause acute gastroenteritis. Adenoviruses are a large group of viruses long recognized for their role in the pathogenesis of respiratory, urinary tract, and gastrointestinal infections. There are 52 human adenovirus serotypes, and these are classified into six subgenera (A through F) based on variations in biology and genetics. The subgenus F is most commonly associated with viral gastroenteritis, with AdV-40 and AdV-41 being the most common serotypes.
Infection with enteric adenoviruses is most common in children younger than 2 years of age and occurs throughout the year, with only slight seasonal variation. Enteric adenovirus is spread by the fecal-oral route. Transmission of the disease to family contacts is unusual.
Watery diarrhea is the most commonly reported symptom of enteric adenoviral infection. In contrast to diarrhea from other viral enteritides, diarrhea from enteric adenovirus typically persists for a prolonged period, sometimes as long as 14 days. Vomiting and low-grade fever frequently occur but are usually mild and of a much shorter duration than is the diarrhea. Mild dehydration is also often seen and can sometimes lead to hospitalization.
Enzyme-linked immunosorbent assay (ELISA) and PCR techniques are currently used successfully in the diagnosis of enteric adenovirus, and multiplex PCR-based assays that are in development for a broad range of stool pathogens commonly include adenovirus. Treatment is mainly supportive, and oral rehydration solutions are useful in cases of dehydration.
Astrovirus
Human astroviruses are small single-stranded RNA viruses that also belong to the Astroviridae family. Astrovirus is worldwide in distribution and plays a major role in infectious diarrhea among all age groups. Most individuals (90%) will have developed antibodies towards astrovirus by age 9 years, underscoring its prevalence. Infection with astrovirus is most often asymptomatic. However, watery diarrhea is the most common manifestation and usually short lived, lasting 2 to 4 days. Spread of the virus may occur via the fecal-oral route from person-to-person contact or through contaminated food or water.
Other Viruses
A variety of other viruses are being studied to determine what role, if any, they may play in the pathogenesis of human enteric infections. With the exception of those viruses discussed previously in detail, insufficient data are available to ascertain clinical and epidemiologic differences, if any, among the various small round viruses. In a surveillance study of children with acute gastroenteritis in the United States, sapovirus, parechovirus, bocavirus, and aichivirus were detected in the stool specimens of 5.4%, 4.8%, 1.4%, and 0.2% of patients and 4.2%, 4.4%, 2.4%, and 0% of healthy controls, respectively.
Human bocavirus is a parvovirus and belongs to the family Parvoviridae. Bocavirus has primarily been recognized as a contributor to respiratory illness and historically was felt to be an incidental finding in stool samples. However, recent investigations now confirm that bocavirus, namely genotype HBoV2, is associated with 6.9% of acute gastroenteritis cases among children younger than 5 years of age.
Coronavirus is an enveloped RNA virus well recognized for causing respiratory disease in humans. Two serogroups exist, HCoV-229E and HCoV-NL63. Infections occur throughout the year, with a stronger presence in the winter months. Diarrheal disease with this organism is uncommon and usually is accompanied by respiratory symptoms. HCoV-HKU1, a member of the HCOV-NL63 serogroup, has been identified most often in stool samples among pediatric patients.
Cytomegalovirus is a double-stranded DNA virus that is well studied as a cause for colitis as well as inflammatory bowel disease in immunocompromised hosts. Illness in immunocompetent subjects has not historically been documented. However, cases of gastroenteritis secondary to cytomegalovirus among adults as well as pediatric immunocompetent subjects are becoming more recognized. Affected subjects present with diarrhea that can be bloody, in addition to fever. ,
Bacterial Gastroenteritis
Host-Defense Factors
For an infecting bacterial agent to cause diarrhea, it must first overcome the following gastrointestinal tract defenses: (1) gastric acidity, (2) intestinal motility, (3) mucous secretion, (4) normal intestinal microflora, and (5) specific mucosal and systemic immune mechanisms. Gastric acidity is the first barrier encountered by infecting organisms. Many studies have demonstrated the bactericidal properties of gastric juice at pH less than 4. In patients with achlorhydria or decreased gastric acid secretion, the gastric pH is higher, and this bactericidal effect is diminished. Gastric acidity serves to decrease the number of viable bacteria that proceed to the small intestine.
Organisms surviving the gastric acidity barrier are trapped within the mucous layer of the small intestine, facilitating their movement through the intestine by peristalsis. If motility in the intestine is abnormal or absent, organisms are more readily able to initiate the infectious process. Some organisms can elaborate toxic substances that impair intestinal motility.
In addition to its role in conjunction with intestinal motility, mucus also serves to provide a nonspecific barrier to bacterial proliferation and mucosal colonization. This barrier has been shown to be effective in preventing toxins from exerting their effects. Exfoliated mucosal cells trapped in the mucous layer may trap invading microorganisms. Mucus also contains carbohydrate analogues of surface receptors, which may prevent invading organisms from binding to actual receptors.
The normal endogenous microflora of the gut serves as its next line of defense. Anaerobes, which are a large component of the normal flora, elaborate short-chain fatty acids and lactic acid, which are toxic to many potential pathogens. In breast-fed infants, this line of defense is enhanced by the presence of anaerobic lactobacilli, which produce fermentative products that act as toxins to foreign bacteria. Further evidence in support of the importance of endogenous microflora is the increase in susceptibility to infection after one’s normal flora has been reduced by antibiotic administration, as is seen with Clostridium difficile infection (CDI).
The most complex element in the host-defense armamentarium involves the mucosal and systemic immune systems. Both serum and secretory antibodies may exert their protective effects at the intestinal level, even though the serum components are produced outside the gut. An immune response may be specific to a particular infective agent or generalized to a common group of bacterial antigens.
Mechanisms of Bacterial Disease Production
Bacteria have developed a variety of virulence factors ( Table 38.2 ) to overcome host-defense mechanisms: (1) invasion of the mucosa, followed by intraepithelial cell multiplication or invasion of the lamina propria; (2) production of cytotoxins , which disrupt cell function via direct alteration of the mucosal surface; (3) production of enterotoxins , polypeptides that alter cellular salt and water balance yet leave cell morphology undisturbed; and (4) adherence to the mucosal surface with resultant flattening of the microvilli and disruption of normal cell functioning. Each of the bacterial virulence mechanisms acts on specific regions of the intestine. Enterotoxins are primarily effective in the small bowel but can affect the colon. The effects of cytotoxins and direct epithelial cell invasion occur predominantly in the colon. Enteroadhesive mechanisms appear to function in both the small intestine and colon.
TABLE 38.2
Bacterial Pathogens Grouped by Pathogenic Mechanism
Modified from Cohen MB. Etiology and mechanisms of acute infectious diarrhea in infants in the United States. J Pediatr . 1991;118:S34–43, with permission.
| Invasive | Cytotoxic | Toxigenic | Adherent |
|---|---|---|---|
| Shigella | Shigella | Shigella | Enteropathogenic Escherichia coli |
| Salmonella | Enteropathogenic E. coli | Enterotoxigenic E. coli | Shiga toxin–producing E. coli |
| Yersinia enterocolitica | Shiga toxin–producing E. coli | Y. enterocolitica | Enteroaggregative E. coli |
| Campylobacter jejuni | Clostridium difficile | Aeromonas | Diffusely adherent E. coli |
| Vibrio parahaemolyticus | Vibrio cholerae and non-O1 vibrios |
Salmonella
Members of the species Salmonella are currently recognized as the most common cause of bacterial diarrhea among children in the United States. Surveillance data from the Centers for Disease Control and Prevention (CDC) show that in 2015 the incidence of Salmonella was 15.89 per 100,000. Infection caused by Salmonella may result in several different clinical syndromes, including (1) acute gastroenteritis; (2) focal, nonintestinal infections; (3) bacteremia; (4) asymptomatic carrier state; and (5) enteric fever (including typhoid fever). Each of these entities may be caused by any of the commonly recognized species of Salmonella .
Microbiology
Salmonella is a motile, gram-negative bacillus of the family Enterobacteriaceae. It can be identified on selective media because it does not ferment lactose. Three distinct species of Salmonella are recognized: Salmonella enteritidis, Salmonella choleraesuis, and Salmonella typhi. S. enteritidis is further subdivided into approximately 1700 serotypes. Each serotype is referred to by its genus and serotype names (e.g., Salmonella typhimurium ) rather than the formally correct S. enteritidis , serotype typhimurium. S. choleraesuis and S. typhi are known to have only one serotype each. The most common serotypes in infants are Typhimurium, Newport, Javiana, Enteritidis, and Heidelberg.
Epidemiology
Salmonella is estimated to cause 1.2 million gastrointestinal infections each year in the United States. In addition, the CDC estimates that approximately 23,000 hospitalizations and 450 deaths are attributed annually to Salmonella . The incidence of infection is highest among children younger than 5 years, followed by children 5 to 9 years of age. Nontyphoidal Salmonella is usually spread via contaminated water supplies or foods, with meat, fresh produce, fowl, eggs, and raw milk frequently implicated.
Outbreaks of Salmonella have occurred with a variety of food products, including cereal, eggs, coconut, salad, pork, and peppers. Processed foods that may contain contaminants (e.g., whey powder) and eggs are also vehicles for transmission. Although any food source may become contaminated through contact with an infected food handler, the farm animals themselves are often infected. Pets, notably cats, turtles, lizards, snakes, and chicks, may also harbor Salmonella . Turtles in particular continue to be a source of salmonella infections in the United States despite a ban on the sale of turtles with shell lengths less than 4 inches long issued by the U.S. Food and Drug Administration (FDA) in 1975. Person-to-person spread of infection also occurs and is especially common in cases involving infants. A population-based case-control study was done in infants younger than 1 year of age and identified the following risk factors: (1) travel outside the United States; (2) attending daycare with a child with diarrhea; (3) riding in a shopping cart next to meat or poultry; and (4) exposure to reptiles. Breastfeeding was found to be protective.
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