# Digestive System Infections

## Bacterial Infections of the Gastrointestinal Tract

### Learning Objectives

By the end of this section, you will be able to:
1. Identify the most common bacteria that can cause infections of the GI tract
2. Compare the major characteristics of specific bacterial diseases affecting the GI tract
A wide range of gastrointestinal diseases are caused by bacterial contamination of food. Recall that foodborne disease can arise from either infection or intoxication. In both cases, bacterial toxins are typically responsible for producing disease signs and symptoms. The distinction lies in where the toxins are produced. In an infection, the microbial agent is ingested, colonizes the gut, and then produces toxins that damage host cells. In an intoxication, bacteria produce toxins in the food before it is ingested. In either case, the toxins cause damage to the cells lining the gastrointestinal tract, typically the colon. This leads to the common signs and symptoms of diarrhea or watery stool and abdominal cramps, or the more severe dysentery. Symptoms of foodborne diseases also often include nausea and vomiting, which are mechanisms the body uses to expel the toxic materials.
Most bacterial gastrointestinal illness is short-lived and self-limiting; however, loss of fluids due to severe diarrheal illness can lead to dehydration that can, in some cases, be fatal without proper treatment. Oral rehydration therapy with electrolyte solutions is an essential aspect of treatment for most patients with GI disease, especially in children and infants.

### Staphylococcal Food Poisoning

Staphylococcal food poisoning is one form of food intoxication. When  grows in food, it may produce enterotoxins that, when ingested, can cause symptoms such as nausea, diarrhea, cramping, and vomiting within one to six hours. In some severe cases, it may cause headache, dehydration, and changes in blood pressure and heart rate. Signs and symptoms resolve within 24 to 48 hours. S. aureus is often associated with a variety of raw or undercooked and cooked foods including meat (e.g., canned meat, ham, and sausages) and dairy products (e.g., cheeses, milk, and butter). It is also commonly found on hands and can be transmitted to prepared foods through poor hygiene, including poor handwashing and the use of contaminated food preparation surfaces, such as cutting boards. The greatest risk is for food left at a temperature below 60 °C (140 °F), which allows the bacteria to grow. Cooked foods should generally be reheated to at least 60 °C (140 °F) for safety and most raw meats should be cooked to even higher internal temperatures ().
There are at least 21 Staphylococcal enterotoxins and Staphylococcal enterotoxin-like toxins that can cause food intoxication. The enterotoxins are proteins that are resistant to low pH, allowing them to pass through the stomach. They are heat stable and are not destroyed by boiling at 100 °C. Even though the bacterium itself may be killed, the enterotoxins alone can cause vomiting and diarrhea, although the mechanisms are not fully understood. At least some of the symptoms may be caused by the enterotoxin functioning as a superantigen and provoking a strong immune response by activating T cell proliferation.
The rapid onset of signs and symptoms helps to diagnose this foodborne illness. Because the bacterium does not need to be present for the toxin to cause symptoms, diagnosis is confirmed by identifying the toxin in a food sample or in biological specimens (feces or vomitus) from the patient. Serological techniques, including ELISA, can also be used to identify the toxin in food samples.
The condition generally resolves relatively quickly, within 24 hours, without treatment. In some cases, supportive treatment in a hospital may be needed.

### Shigellosis (Bacillary Dysentery)

When gastrointestinal illness is associated with the rod-shaped, gram-negative bacterium , it is called bacillary dysentery, or shigellosis. Infections can be caused by S. dysenteriae, S. flexneri, S. boydii, and/or S. sonnei that colonize the GI tract. Shigellosis can be spread from hand to mouth or through contaminated food and water. Most commonly, it is transmitted through the fecal-oral route.
Shigella bacteria invade intestinal epithelial cells. When taken into a phagosome, they can escape and then live within the cytoplasm of the cell or move to adjacent cells. As the organisms multiply, the epithelium and structures with M cells of the Peyer’s patches in the intestine may become ulcerated and cause loss of fluid. Stomach cramps, fever, and watery diarrhea that may also contain pus, mucus, and/or blood often develop. More severe cases may result in ulceration of the mucosa, dehydration, and rectal bleeding. Additionally, patients may later develop hemolytic uremic syndrome (HUS), a serious condition in which damaged blood cells build up in the kidneys and may cause kidney failure, or reactive arthritis, a condition in which arthritis develops in multiple joints following infection. Patients may also develop chronic post-infection irritable bowel syndrome (IBS).
S. dysenteriae type 1 is able to produce Shiga toxin, which targets the endothelial cells of small blood vessels in the small and large intestine by binding to a glycosphingolipid. Once inside the endothelial cells, the toxin targets the large ribosomal subunit, thus affecting protein synthesis of these cells. Hemorrhaging and lesions in the colon can result. The toxin can target the kidney’s glomerulus, the blood vessels where filtration of blood in the kidney begins, thus resulting in HUS.
Stool samples, which should be processed promptly, are analyzed using serological or molecular techniques. One common method is to perform immunoassays for S. dysenteriae. (Other methods that can be used to identify Shigella include API test strips, Enterotube systems, or PCR testing. The presence of white blood cells and blood in fecal samples occurs in about 70% of patientsJaya Sureshbabu. “Shigella Infection Workup.”  (). Severe cases may require antibiotics such as ciprofloxacin and azithromycin, but these must be carefully prescribed because resistance is increasingly common.

### Salmonellosis

 gastroenteritis, also called salmonellosis, is caused by the rod-shaped, gram-negative bacterium Salmonella. Two species, S. enterica and S. bongori, cause disease in humans, but S. enterica is the most common. The most common serotypes of S. enterica are Enteritidis and Typhi. We will discuss typhoid fever caused by serotypes Typhi and Paratyphi A separately. Here, we will focus on salmonellosis caused by other serotypes.
Salmonella is a part of the normal intestinal microbiota of many individuals. However, salmonellosis is caused by exogenous agents, and infection can occur depending on the serotype, size of the inoculum, and overall health of the host. Infection is caused by ingestion of contaminated food, handling of eggshells, or exposure to certain animals. Salmonella is part of poultry’s microbiota, so exposure to raw eggs and raw poultry can increase the risk of infection. Handwashing and cooking foods thoroughly greatly reduce the risk of transmission. Salmonella bacteria can survive freezing for extended periods but cannot survive high temperatures.
Once the bacteria are ingested, they multiply within the intestines and penetrate the epithelial mucosal cells via M cells where they continue to grow (). They trigger inflammatory processes and the hypersecretion of fluids. Once inside the body, they can persist inside the phagosomes of macrophages. Salmonella can cross the epithelial cell membrane and enter the bloodstream and lymphatic system. Some strains of Salmonella also produce an enterotoxin that can cause an intoxication.
Infected individuals develop fever, nausea, abdominal cramps, vomiting, headache, and diarrhea. These signs and symptoms generally last a few days to a week. According to the Centers for Disease Control and Prevention (CDC), there are 1,000,000 cases annually, with 380 deaths each year.Centers for Disease Control and Prevention.  However, because the disease is usually self-limiting, many cases are not reported to doctors and the overall incidence may be underreported. Diagnosis involves culture followed by serotyping and DNA fingerprinting if needed. Positive results are reported to the CDC. When an unusual serotype is detected, samples are sent to the CDC for further analysis. Serotyping is important for determining treatment. Oral rehydration therapy is commonly used. Antibiotics are only recommended for serious cases. When antibiotics are needed, as in immunocompromised patients, fluoroquinolones, third-generation cephalosporins, and ampicillin are recommended. Antibiotic resistance is a serious concern.

### Typhoid Fever

Certain serotypes of S. enterica, primarily serotype Typhi (S. typhi) but also Paratyphi, cause a more severe type of salmonellosis called typhoid fever. This serious illness, which has an untreated mortality rate of 10%, causes high fever, body aches, headache, nausea, lethargy, and a possible rash.
Some individuals carry S. typhi without presenting signs or symptoms (known as asymptomatic carriers) and continually shed them through their feces. These carriers often have the bacteria in the gallbladder or intestinal epithelium. Individuals consuming food or water contaminated with these feces can become infected.
S. typhi penetrate the intestinal mucosa, grow within the macrophages, and are transported through the body, most notably to the liver and gallbladder. Eventually, the macrophages lyse, releasing S. typhi into the bloodstream and lymphatic system. Mortality can result from ulceration and perforation of the intestine. A wide range of complications, such as pneumonia and jaundice, can occur with disseminated disease.
S. typhi have  (SPIs) that contain the genes for many of their virulence factors. Two examples of important typhoid toxins are the Vi antigen, which encodes for capsule production, and chimeric A2B5 toxin, which causes many of the signs and symptoms of the acute phase of typhoid fever.
Clinical examination and culture are used to make the diagnosis. The bacteria can be cultured from feces, urine, blood, or bone marrow. Serology, including ELISA, is used to identify the most pathogenic strains, but confirmation with DNA testing or culture is needed. A PCR test can also be used, but is not widely available.
The recommended antibiotic treatment involves fluoroquinolones, ceftriaxone, and azithromycin. Individuals must be extremely careful to avoid infecting others during treatment. Typhoid fever can be prevented through vaccination for individuals traveling to parts of the world where it is common.

### E. coli Infections

The gram-negative rod  is a common member of the normal microbiota of the colon. Although the vast majority of E. coli strains are helpful commensal bacteria, some can be pathogenic and may cause dangerous diarrheal disease. The pathogenic strains have additional virulence factors such as type 1 fimbriae that promote colonization of the colon or may produce toxins (see Virulence Factors of Bacterial and Viral Pathogens). These virulence factors are acquired through horizontal gene transfer.
Extraintestinal disease can result if the bacteria spread from the gastrointestinal tract. Although these bacteria can be spread from person to person, they are often acquired through contaminated food or water. There are six recognized pathogenic groups of E. coli, but we will focus here on the four that are most commonly transmitted through food and water.
Enterotoxigenic , also known as traveler’s diarrhea, causes diarrheal illness and is common in less developed countries. In Mexico, ETEC infection is called Montezuma’s Revenge. Following ingestion of contaminated food or water, infected individuals develop a watery diarrhea, abdominal cramps, malaise (a feeling of being unwell), and a low fever. ETEC produces a heat-stable enterotoxin similar to cholera toxin, and adhesins called colonization factors that help the bacteria to attach to the intestinal wall. Some strains of ETEC also produce heat-labile toxins. The disease is usually relatively mild and self-limiting. Diagnosis involves culturing and PCR. If needed, antibiotic treatment with fluoroquinolones, doxycycline, rifaximin, and trimethoprim-sulfamethoxazole (TMP/SMZ) may shorten infection duration. However, antibiotic resistance is a problem.
Enteroinvasive  is very similar to shigellosis, including its pathogenesis of intracellular invasion into intestinal epithelial tissue. This bacterium carries a large plasmid that is involved in epithelial cell penetration. The illness is usually self-limiting, with symptoms including watery diarrhea, chills, cramps, malaise, fever, and dysentery. Culturing and PCR testing can be used for diagnosis. Antibiotic treatment is not recommended, so supportive therapy is used if needed.
Enteropathogenic  can cause a potentially fatal diarrhea, especially in infants and those in less developed countries. Fever, vomiting, and diarrhea can lead to severe dehydration. These E. coli inject a protein (Tir) that attaches to the surface of the intestinal epithelial cells and triggers rearrangement of host cell actin from microvilli to pedestals. Tir also happens to be the receptor for Intimin, a surface protein produced by EPEC, thereby allowing E. coli to “sit” on the pedestal. The genes necessary for this pedestal formation are encoded on the locus for enterocyte effacement (LEE) pathogenicity island. As with ETEC, diagnosis involves culturing and PCR. Treatment is similar to that for ETEC.
The most dangerous strains are enterohemorrhagic , which are the strains capable of causing epidemics. In particular, the strain O157:H7 has been responsible for several recent outbreaks. Recall that the O and H refer to surface antigens that contribute to pathogenicity and trigger a host immune response (“O” refers to the O-side chain of the lipopolysaccharide and the “H” refers to the flagella). Similar to EPEC, EHEC also forms pedestals. EHEC also produces a Shiga-like toxin. Because the genome of this bacterium has been sequenced, it is known that the Shiga toxin genes were most likely acquired through transduction (horizontal gene transfer). The Shiga toxin genes originated from  dysenteriae. Prophage from a bacteriophage that previously infected Shigella integrated into the chromosome of E. coli. The Shiga-like toxin is often called verotoxin.
EHEC can cause disease ranging from relatively mild to life-threatening. Symptoms include bloody diarrhea with severe cramping, but no fever. Although it is often self-limiting, it can lead to hemorrhagic colitis and profuse bleeding. One possible complication is HUS. Diagnosis involves culture, often using MacConkey with sorbitol agar to differentiate between E. coli O157:H7, which does not ferment sorbitol, and other less virulent strains of E. coli that can ferment sorbitol.
Serological typing or PCR testing also can be used, as well as genetic testing for Shiga toxin. To distinguish EPEC from EHEC, because they both form pedestals on intestinal epithelial cells, it is necessary to test for genes encoding for both the Shiga-like toxin and for the LEE. Both EPEC and EHEC have LEE, but EPEC lacks the gene for Shiga toxin. Antibiotic therapy is not recommended and may worsen HUS because of the toxins released when the bacteria are killed, so supportive therapies must be used.  summarizes the characteristics of the four most common pathogenic groups.

### Cholera and Other Vibrios

The gastrointestinal disease cholera is a serious infection often associated with poor sanitation, especially following natural disasters, because it is spread through contaminated water and food that has not been heated to temperatures high enough to kill the bacteria. It is caused by  serotype O1, a gram-negative, flagellated bacterium in the shape of a curved rod (vibrio). According to the CDC, cholera causes an estimated 3 to 5 million cases and 100,000 deaths each year.Centers for Disease Control and Prevention.
Because V. cholerae is killed by stomach acid, relatively large doses are needed for a few microbial cells to survive to reach the intestines and cause infection. The motile cells travel through the mucous layer of the intestines, where they attach to epithelial cells and release cholera enterotoxin. The toxin is an A-B toxin with activity through adenylate cyclase (see Virulence Factors of Bacterial and Viral Pathogens). Within the intestinal cell, cyclic AMP (cAMP) levels increase, which activates a chloride channel and results in the release of ions into the intestinal lumen. This increase in osmotic pressure in the lumen leads to water also entering the lumen. As the water and electrolytes leave the body, it causes rapid dehydration and electrolyte imbalance. Diarrhea is so profuse that it is often called “rice water stool,” and patients are placed on cots with a hole in them to monitor the fluid loss ().
Cholera is diagnosed by taking a stool sample and culturing for Vibrio. The bacteria are oxidase positive and show non-lactose fermentation on MacConkey agar. Gram-negative lactose fermenters will produce red colonies while non-fermenters will produce white/colorless colonies. Gram-positive bacteria will not grow on MacConkey. Lactose fermentation is commonly used for pathogen identification because the normal microbiota generally ferments lactose while pathogens do not. V. cholerae may also be cultured on thiosulfate citrate bile salts sucrose (TCBS) agar, a selective and differential media for Vibrio spp., which produce a distinct yellow colony.
Cholera may be self-limiting and treatment involves rehydration and electrolyte replenishment. Although antibiotics are not typically needed, they can be used for severe or disseminated disease. Tetracyclines are recommended, but doxycycline, erythromycin, orfloxacin, ciprofloxacin, and TMP/SMZ may be used. Recent evidence suggests that azithromycin is also a good first-line antibiotic. Good sanitation—including appropriate sewage treatment, clean supplies for cooking, and purified drinking water—is important to prevent infection ()
V. cholera is not the only  species that can cause disease. V. parahemolyticus is associated with consumption of contaminated seafood and causes gastrointestinal illness with signs and symptoms such as watery diarrhea, nausea, fever, chills, and abdominal cramps. The bacteria produce a heat-stable hemolysin, leading to dysentery and possible disseminated disease. It also sometimes causes wound infections. V. parahemolyticus is diagnosed using cultures from blood, stool, or a wound. As with V. cholera, selective medium (especially TCBS agar) works well. Tetracycline and ciprofloxacin can be used to treat severe cases, but antibiotics generally are not needed.
Vibrio vulnificus is found in warm seawater and, unlike V. cholerae, is not associated with poor sanitary conditions. The bacteria can be found in raw seafood, and ingestion causes gastrointestinal illness. It can also be acquired by individuals with open skin wounds who are exposed to water with high concentrations of the pathogen. In some cases, the infection spreads to the bloodstream and causes septicemia. Skin infection can lead to edema, ecchymosis (discoloration of skin due to bleeding), and abscesses. Patients with underlying disease have a high fatality rate of about 50%. It is of particular concern for individuals with chronic liver disease or who are otherwise immunodeficient because a healthy immune system can often prevent infection from developing. V. vulnificus is diagnosed by culturing for the pathogen from stool samples, blood samples, or skin abscesses. Adult patients are treated with doxycycline combined with a third generation cephalosporin or with fluoroquinolones, and children are treated with TMP/SMZ.
Two other vibrios,  and , are also associated with marine environments and raw seafood; they can also cause gastroenteritis. Like V. vulnificus, A. hydrophila is more often associated with infections in wounds, generally those acquired in water. In some cases, it can also cause septicemia. Other species of Aeromonas can cause illness. P. shigelloides is sometimes associated with more serious systemic infections if ingested in contaminated food or water. Culture can be used to diagnose A. hydrophila and P. shigelloides infections, for which antibiotic therapy is generally not needed. When necessary, tetracycline and ciprofloxacin, among other antibiotics, may be used for treatment of A. hydrophila, and fluoroquinolones and trimethoprim are the effective treatments for P. shigelloides.

### Campylobacter jejuni Gastroenteritis

 is a genus of gram-negative, spiral or curved bacteria. They may have one or two flagella. , a form of campylobacteriosis, is a widespread illness that is caused by Campylobacter jejuni. The primary route of transmission is through poultry that becomes contaminated during slaughter. Handling of the raw chicken in turn contaminates cooking surfaces, utensils, and other foods. Unpasteurized milk or contaminated water are also potential vehicles of transmission. In most cases, the illness is self-limiting and includes fever, diarrhea, cramps, vomiting, and sometimes dysentery. More serious signs and symptoms, such as bacteremia, meningitis, pancreatitis, cholecystitis, and hepatitis, sometimes occur. It has also been associated with autoimmune conditions such as Guillain-Barré syndrome, a neurological disease that occurs after some infections and results in temporary paralysis. HUS following infection can also occur. The virulence in many strains is the result of hemolysin production and the presence of Campylobacter cytolethal distending toxin (CDT), a powerful deoxyribonuclease (DNase) that irreversibly damages host cell DNA.
Diagnosis involves culture under special conditions, such as elevated temperature, low oxygen tension, and often medium supplemented with antimicrobial agents. These bacteria should be cultured on selective medium (such as Campy CV, charcoal selective medium, or cefaperazone charcoal deoxycholate agar) and incubated under microaerophilic conditions for at least 72 hours at 42 °C. Antibiotic treatment is not usually needed, but erythromycin or ciprofloxacin may be used.

### Peptic Ulcers

The gram-negative bacterium  is able to tolerate the acidic environment of the human stomach and has been shown to be a major cause of peptic ulcers, which are ulcers of the stomach or duodenum. The bacterium is also associated with increased risk of stomach cancer (). According to the CDC, approximately two-thirds of the population is infected with H. pylori, but less than 20% have a risk of developing ulcers or stomach cancer. H. pylori is found in approximately 80% of stomach ulcers and in over 90% of duodenal ulcers.Centers for Disease Control and Prevention. “
H. pylori colonizes epithelial cells in the stomach using pili for adhesion. These bacteria produce urease, which stimulates an immune response and creates ammonia that neutralizes stomach acids to provide a more hospitable microenvironment. The infection damages the cells of the stomach lining, including those that normally produce the protective mucus that serves as a barrier between the tissue and stomach acid. As a result, inflammation (gastritis) occurs and ulcers may slowly develop. Ulcer formation can also be caused by toxin activity. It has been reported that 50% of clinical isolates of H. pylori have detectable levels of exotoxin activity in vitro.T. L. Cover. “The Vacuolating Cytotoxin of  This toxin, VacA, induces vacuole formation in host cells. VacA has no primary sequence homology with other bacterial toxins, and in a mouse model, there is a correlation between the presence of the toxin gene, the activity of the toxin, and gastric epithelial tissue damage.
Signs and symptoms include nausea, lack of appetite, bloating, burping, and weight loss. Bleeding ulcers may produce dark stools. If no treatment is provided, the ulcers can become deeper, more tissues can be involved, and stomach perforation can occur. Because perforation allows digestive enzymes and acid to leak into the body, it is a very serious condition.
To diagnose H. pylori infection, multiple methods are available. In a breath test, the patient swallows radiolabeled urea. If H. pylori is present, the bacteria will produce urease to break down the urea. This reaction produces radiolabeled carbon dioxide that can be detected in the patient’s breath. Blood testing can also be used to detect antibodies to H. pylori. The bacteria themselves can be detected using either a stool test or a stomach wall biopsy.
Antibiotics can be used to treat the infection. However, unique to H. pylori, the recommendation from the US Food and Drug Administration is to use a triple therapy. The current protocols are 10 days of treatment with omeprazole, amoxicillin, and clarithromycin (OAC); 14 days of treatment with bismuth subsalicylate, metronidazole, and tetracycline (BMT); or 10 or 14 days of treatment with lansoprazole, amoxicillin, and clarithromycin (LAC). Omeprazole, bismuth subsalicylate, and lansoprazole are not antibiotics but are instead used to decrease acid levels because H. pylori prefers acidic environments.
Although treatment is often valuable, there are also risks to H. pylori eradication. Infection with H. pylori may actually protect against some cancers, such as esophageal adenocarcinoma and gastroesophageal reflux disease.Martin J. Blaser. “Disappearing Microbiota: Ivan F. N. Hung and Benjamin C. Y. Wong. “Assessing the Risks and Benefits of Treating

### Clostridium perfringens Gastroenteritis

 is a generally mild foodborne disease that is associated with undercooked meats and other foods. C. perfringens is a gram-positive, rod-shaped, endospore-forming anaerobic bacterium that is tolerant of high and low temperatures. At high temperatures, the bacteria can form endospores that will germinate rapidly in foods or within the intestine. Food poisoning by type A strains is common. This strain always produces an enterotoxin, sometimes also present in other strains, that causes the clinical symptoms of cramps and diarrhea. A more severe form of the illness, called pig-bel or enteritis necroticans, causes hemorrhaging, pain, vomiting, and bloating. Gangrene of the intestines may result. This form has a high mortality rate but is rare in the United States.
Diagnosis involves detecting the C. perfringens toxin in stool samples using either molecular biology techniques (PCR detection of the toxin gene) or immunology techniques (ELISA). The bacteria itself may also be detected in foods or in fecal samples. Treatment includes rehydration therapy, electrolyte replacement, and intravenous fluids. Antibiotics are not recommended because they can damage the balance of the microbiota in the gut, and there are concerns about antibiotic resistance. The illness can be prevented through proper handling and cooking of foods, including prompt refrigeration at sufficiently low temperatures and cooking food to a sufficiently high temperature.

### Clostridium difficile

 is a gram-positive rod that can be a commensal bacterium as part of the normal microbiota of healthy individuals. When the normal microbiota is disrupted by long-term antibiotic use, it can allow the overgrowth of this bacterium, resulting in antibiotic-associated diarrhea caused by . Antibiotic-associated diarrhea can also be considered a nosocomial disease. Patients at the greatest risk of C. difficile infection are those who are immunocompromised, have been in health-care settings for extended periods, are older, have recently taken antibiotics, have had gastrointestinal procedures done, or use proton pump inhibitors, which reduce stomach acidity and allow proliferation of C. difficile. Because this species can form endospores, it can survive for extended periods of time in the environment under harsh conditions and is a considerable concern in health-care settings.
This bacterium produces two toxins,  (TcdA) and  (TcdB). These toxins inactivate small GTP-binding proteins, resulting in actin condensation and cell rounding, followed by cell death. Infections begin with focal necrosis, then ulceration with exudate, and can progress to pseudomembranous colitis, which involves inflammation of the colon and the development of a pseudomembrane of fibrin containing dead epithelial cells and leukocytes (). Watery diarrhea, dehydration, fever, loss of appetite, and abdominal pain can result. Perforation of the colon can occur, leading to septicemia, shock, and death. C. difficile is also associated with necrotizing enterocolitis in premature babies and neutropenic enterocolitis associated with cancer therapies.
Diagnosis is made by considering the patient history (such as exposure to antibiotics), clinical presentation, imaging, endoscopy, lab tests, and other available data. Detecting the toxin in stool samples is used to confirm diagnosis. Although culture is preferred, it is rarely practical in clinical practice because the bacterium is an obligate anaerobe. Nucleic acid amplification tests, including PCR, are considered preferable to ELISA testing for molecular analysis.
The first step of conventional treatment is to stop antibiotic use, and then to provide supportive therapy with electrolyte replacement and fluids. Metronidazole is the preferred treatment if the  diagnosis has been confirmed. Vancomycin can also be used, but it should be reserved for patients for whom metronidazole was ineffective or who meet other criteria (e.g., under 10 years of age, pregnant, or allergic to metronidazole).
A newer approach to treatment, known as a fecal transplant, focuses on restoring the microbiota of the gut in order to combat the infection. In this procedure, a healthy individual donates a stool sample, which is mixed with saline and transplanted to the recipient via colonoscopy, endoscopy, sigmoidoscopy, or enema. It has been reported that this procedure has greater than 90% success in resolving C. difficile infections.Faith Rohlke and Neil Stollman. “Fecal Microbiota Transplantation in Relapsing

### Foodborne Illness Due to Bacillus cereus

, commonly found in soil, is a gram-positive endospore-forming bacterium that can sometimes cause foodborne illness. B. cereus endospores can survive cooking and produce enterotoxins in food after it has been heated; illnesses often occur after eating rice and other prepared foods left at room temperature for too long. The signs and symptoms appear within a few hours of ingestion and include nausea, pain, and abdominal cramps. B. cereus produces two toxins: one causing diarrhea, and the other causing vomiting. More severe signs and symptoms can sometimes develop.
Diagnosis can be accomplished by isolating bacteria from stool samples or vomitus and uneaten infected food. Treatment involves rehydration and supportive therapy. Antibiotics are not typically needed, as the illness is usually relatively mild and is due to toxin activity.

### Foodborne Illness Due to Yersinia

The genus  is best known for Yersinia pestis, a gram-negative rod that causes the plague. However, Y. enterocolitica and Y. pseudotuberculosis can cause gastroenteritis. The infection is generally transmitted through the fecal-oral route, with ingestion of food or water that has been contaminated by feces. Intoxication can also result because of the activity of its endotoxin and exotoxins (enterotoxin and cytotoxin necrotizing factor). The illness is normally relatively mild and self-limiting. However, severe diarrhea and dysentery can develop in infants. In adults, the infection can spread and cause complications such as reactive arthritis, thyroid disorders, endocarditis, glomerulonephritis, eye inflammation, and/or erythema nodosum. Bacteremia may develop in rare cases.
Diagnosis is generally made by detecting the bacteria in stool samples. Samples may also be obtained from other tissues or body fluids. Treatment is usually supportive, including rehydration, without antibiotics. If bacteremia or other systemic disease is present, then antibiotics such as fluoroquinolones, aminoglycosides, doxycycline, and trimethoprim-sulfamethoxazole may be used. Recovery can take up to two weeks.

### Key Concepts and Summary

1. Major causes of gastrointestinal illness include Salmonella spp., Staphylococcus spp., Helicobacter pylori, Clostridium perfringens, Clostridium difficile, Bacillus cereus, and Yersinia bacteria.
2. C. difficile is an important cause of hospital acquired infection.
3. Vibrio cholerae causes cholera, which can be a severe diarrheal illness.
4. Different strains of E. coli, including ETEC, EPEC, EIEC, and EHEC, cause different illnesses with varying degrees of severity.
5. H. pylori is associated with peptic ulcers.
6. Salmonella enterica serotypes can cause typhoid fever, a more severe illness than salmonellosis.
7. Rehydration and other supportive therapies are often used as general treatments.
8. Careful antibiotic use is required to reduce the risk of causing C. difficile infections and when treating antibiotic-resistant infections.

### Multiple Choice

### Fill in the Blank

### Critical Thinking


# Digestive System Infections

## Viral Infections of the Gastrointestinal Tract

### Learning Objectives

By the end of this section, you will be able to:
1. Identify the most common viruses that can cause infections of the GI tract
2. Compare the major characteristics of specific viral diseases affecting the GI tract and liver
In the developing world, acute viral gastroenteritis is devastating and a leading cause of death for children.Caleb K. King, Roger Glass, Joseph S. Bresee, Christopher Duggan. “Managing Acute Gastroenteritis Among Children: Oral Rehydration, Maintenance, and Nutritional Therapy.”  Worldwide, diarrhea is the second leading cause of mortality for children under age five, and 70% of childhood gastroenteritis is viral.Elizabeth Jane Elliott. “Acute Gastroenteritis in Children.”  As discussed, there are a number of bacteria responsible for diarrhea, but viruses can also cause diarrhea. E. coli and rotavirus are the most common causative agents in the developing world. In this section, we will discuss rotaviruses and other, less common viruses that can also cause gastrointestinal illnesses.

### Gastroenteritis Caused by Rotaviruses

Rotaviruses are double-stranded RNA viruses in the family Reoviridae. They are responsible for common diarrheal illness, although prevention through vaccination is becoming more common. The virus is primarily spread by the fecal-oral route ().
These viruses are widespread in children, especially in day-care centers. The CDC estimates that 95% of children in the United States have had at least one rotavirus infection by the time they reach age five.Centers for Disease Control and Prevention. “Rotavirus,”  Due to the memory of the body’s immune system, adults who come into contact with rotavirus will not contract the infection or, if they do, are asymptomatic. The elderly, however, are vulnerable to rotavirus infection due to weakening of the immune system with age, so infections can spread through nursing homes and similar facilities. In these cases, the infection may be transmitted from a family member who may have subclinical or clinical disease. The virus can also be transmitted from contaminated surfaces, on which it can survive for some time.
Infected individuals exhibit fever, vomiting, and diarrhea. The virus can survive in the stomach following a meal, but is normally found in the small intestines, particularly the epithelial cells on the villi. Infection can cause food intolerance, especially with respect to lactose. The illness generally appears after an incubation period of about two days and lasts for approximately one week (three to eight days). Without supportive treatment, the illness can cause severe fluid loss, dehydration, and even death. Even with milder illness, repeated infections can potentially lead to malnutrition, especially in developing countries, where rotavirus infection is common due to poor sanitation and lack of access to clean drinking water. Patients (especially children) who are malnourished after an episode of diarrhea are more susceptible to future diarrheal illness, increasing their risk of death from rotavirus infection.
The most common clinical tool for diagnosis is enzyme immunoassay, which detects the virus from fecal samples. Latex agglutination assays are also used. Additionally, the virus can be detected using electron microscopy and RT-PCR.
Treatment is supportive with oral rehydration therapy. Preventive vaccination is also available. In the United States, rotavirus vaccines are part of the standard vaccine schedule and administration follows the guidelines of the World Health Organization (WHO). The WHO recommends that all infants worldwide receive the rotavirus vaccine, the first dose between six and 15 weeks of age and the second before 32 weeks.World Health Organization. “Rotavirus.”

### Gastroenteritis Caused by Noroviruses

Noroviruses, commonly identified as Norwalk viruses, are caliciviruses. Several strains can cause gastroenteritis. There are millions of cases a year, predominately in infants, young children, and the elderly. These viruses are easily transmitted and highly contagious. They are known for causing widespread infections in groups of people in confined spaces, such as on cruise ships. The viruses can be transmitted through direct contact, through touching contaminated surfaces, and through contaminated food. Because the virus is not killed by disinfectants used at standard concentrations for killing bacteria, the risk of transmission remains high, even after cleaning.
The signs and symptoms of norovirus infection are similar to those for rotavirus, with watery diarrhea, mild cramps, and fever. Additionally, these viruses sometimes cause projectile vomiting. The illness is usually relatively mild, develops 12 to 48 hours after exposure, and clears within a couple of days without treatment. However, dehydration may occur.
Norovirus can be detected using PCR or enzyme immunoassay (EIA) testing. RT-qPCR is the preferred approach as EIA is insufficiently sensitive. If EIA is used for rapid testing, diagnosis should be confirmed using PCR. No medications are available, but the illness is usually self-limiting. Rehydration therapy and electrolyte replacement may be used. Good hygiene, hand washing, and careful food preparation reduce the risk of infection.

### Gastroenteritis Caused by Astroviruses

Astroviruses are single-stranded RNA viruses (family Astroviridae) that can cause severe gastroenteritis, especially in infants and children. Signs and symptoms include diarrhea, nausea, vomiting, fever, abdominal pain, headache, and malaise. The viruses are transmitted through the fecal-oral route (contaminated food or water). For diagnosis, stool samples are analyzed. Testing may involve enzyme immunoassays and immune electron microscopy. Treatment involves supportive rehydration and electrolyte replacement if needed.

### Hepatitis

Hepatitis is a general term meaning inflammation of the liver, which can have a variety of causes. In some cases, the cause is viral infection. There are five main hepatitis viruses that are clinically significant: hepatitisviruses A (HAV), B (HBV), C (HCV), D, (HDV) and E (HEV) (). Note that other viruses, such as Epstein-Barr virus (EBV), yellow fever, and cytomegalovirus (CMV) can also cause hepatitis and are discussed in Viral Infections of the Circulatory and Lymphatic Systems.
Although the five hepatitis viruses differ, they can cause some similar signs and symptoms because they all have an affinity for hepatocytes (liver cells). HAV and HEV can be contracted through ingestion while HBV, HCV, and HDV are transmitted by parenteral contact. It is possible for individuals to become long term or chronic carriers of hepatitis viruses.
The virus enters the blood (viremia), spreading to the spleen, the kidneys, and the liver. During viral replication, the virus infects hepatocytes. The inflammation is caused by the hepatocytes replicating and releasing more hepatitis virus. Signs and symptoms include malaise, anorexia, loss of appetite, dark urine, pain in the upper right quadrant of the abdomen, vomiting, nausea, diarrhea, joint pain, and gray stool. Additionally, when the liver is diseased or injured, it is unable to break down hemoglobin effectively, and bilirubin can build up in the body, giving the skin and mucous membranes a yellowish color, a condition called jaundice (). In severe cases, death from liver necrosis may occur.
Despite having many similarities, each of the hepatitis viruses has its own unique characteristics. HAV is generally transmitted through the fecal-oral route, close personal contact, or exposure to contaminated water or food. Hepatitis A can develop after an incubation period of 15 to 50 days (the mean is 30). It is normally mild or even asymptomatic and is usually self-limiting within weeks to months. A more severe form, fulminant hepatitis, rarely occurs but has a high fatality rate of 70–80%. Vaccination is available and is recommended especially for children (between ages one and two), those traveling to countries with higher risk, those with liver disease and certain other conditions, and drug users.
Although HBV is associated with similar signs and symptoms, transmission and outcomes differ. This virus has a mean incubation period of 120 days and is generally associated with exposure to infectious blood or body fluids such as semen or saliva. Exposure can occur through skin puncture, across the placenta, or through mucosal contact, but it is not spread through casual contact such as hugging, hand holding, sneezing, or coughing, or even through breastfeeding or kissing. Risk of infection is greatest for those who use intravenous drugs or who have sexual contact with an infected individual. Health-care workers are also at risk from needle sticks and other injuries when treating infected patients. The infection can become chronic and may progress to cirrhosis or liver failure. It is also associated with liver cancer. Chronic infections are associated with the highest mortality rates and are more common in infants. Approximately 90% of infected infants become chronic carriers, compared with only 6–10% of infected adults.Centers for Disease Control and Prevention. “The ABCs of Hepatitis.” Updated 2016. http://www.cdc.gov/hepatitis/resources/professionals/pdfs/abctable.pdf. Vaccination is available and is recommended for children as part of the standard vaccination schedule (one dose at birth and the second by 18 months of age) and for adults at greater risk (e.g., those with certain diseases, intravenous drug users, and those who have sex with multiple partners). Health-care agencies are required to offer the HBV vaccine to all workers who have occupational exposure to blood and/or other infectious materials.
HCV is often undiagnosed and therefore may be more widespread than is documented. It has a mean incubation period of 45 days and is transmitted through contact with infected blood. Although some cases are asymptomatic and/or resolve spontaneously, 75%–85% of infected individuals become chronic carriers. Nearly all cases result from parenteral transmission often associated with IV drug use or transfusions. The risk is greatest for individuals with past or current history of intravenous drug use or who have had sexual contact with infected individuals. It has also been spread through contaminated blood products and can even be transmitted through contaminated personal products such as toothbrushes and razors. New medications have recently been developed that show great effectiveness in treating HCV and that are tailored to the specific genotype causing the infection.
HDV is uncommon in the United States and only occurs in individuals who are already infected with HBV, which it requires for replication. Therefore, vaccination against HBV is also protective against HDV infection. HDV is transmitted through contact with infected blood.
HEV infections are also rare in the United States but many individuals have a positive antibody titer for HEV. The virus is most commonly spread by the fecal-oral route through food and/or water contamination, or person-to-person contact, depending on the genotype of the virus, which varies by location. There are four genotypes that differ somewhat in their mode of transmission, distribution, and other factors (for example, two are zoonotic and two are not, and only one causes chronic infection). Genotypes three and four are only transmitted through food, while genotypes one and two are also transmitted through water and fecal-oral routes. Genotype one is the only type transmitted person-to-person and is the most common cause of HEV outbreaks. Consumption of undercooked meat, especially deer or pork, and shellfish can lead to infection. Genotypes three and four are zoonoses, so they can be transmitted from infected animals that are consumed. Pregnant women are at particular risk. This disease is usually self-limiting within two weeks and does not appear to cause chronic infection.
General laboratory testing for hepatitis begins with blood testing to examine liver function (). When the liver is not functioning normally, the blood will contain elevated levels of alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), direct bilirubin, total bilirubin, serum albumin, serum total protein, and calculated globulin, albumin/globulin (A/G) ratio. Some of these are included in a complete metabolic panel (CMP), which may first suggest a possible liver problem and indicate the need for more comprehensive testing. A hepatitis virus serological test panel can be used to detect antibodies for hepatitis viruses A, B, C, and sometimes D. Additionally, other immunological and genomic tests are available.
Specific treatments other than supportive therapy, rest, and fluids are often not available for hepatitis virus infection, except for HCV, which is often self-limited. Immunoglobulins can be used prophylactically following possible exposure. Medications are also used, including interferon alpha 2b and antivirals (e.g., lamivudine, entecavir, adefovir, and telbivudine) for chronic infections. Hepatitis C can be treated with interferon (as monotherapy or combined with other treatments), protease inhibitors, and other antivirals (e.g., the polymerase inhibitor sofosbuvir). Combination treatments are commonly used. Antiviral and immunosuppressive medications may be used for chronic cases of HEV. In severe cases, liver transplants may be necessary. Additionally, vaccines are available to prevent infection with HAV and HBV. The HAV vaccine is also protective against HEV. The HBV vaccine is also protective against HDV. There is no vaccine against HCV.

### Key Concepts and Summary

1. Common viral causes of gastroenteritis include rotaviruses, noroviruses, and astroviruses.
2. Hepatitis may be caused by several unrelated viruses: hepatitis viruses A, B, C, D, and E.
3. The hepatitis viruses differ in their modes of transmission, treatment, and potential for chronic infection.

### Multiple Choice

### Fill in the Blank

### Short Answer

### Critical Thinking


# Digestive System Infections

## Protozoan Infections of the Gastrointestinal Tract

### Learning Objectives

By the end of this section, you will be able to:
1. Identify the most common protozoans that can cause infections of the GI tract
2. Compare the major characteristics of specific protozoan diseases affecting the GI tract
Like other microbes, protozoa are abundant in natural microbiota but can also be associated with significant illness. Gastrointestinal diseases caused by protozoa are generally associated with exposure to contaminated food and water, meaning that those without access to good sanitation are at greatest risk. Even in developed countries, infections can occur and these microbes have sometimes caused significant outbreaks from contamination of public water supplies.

### Giardiasis

Also called backpacker’s diarrhea or beaver fever, giardiasis is a common disease in the United States caused by the flagellated protist , also known as Giardia intestinalis or Giardia duodenalis (). To establish infection, G. lamblia uses a large adhesive disk to attach to the intestinal mucosa. The disk is comprised of microtubules. During adhesion, the flagella of G. lamblia move in a manner that draws fluid out from under the disk, resulting in an area of lower pressure that promotes its adhesion to the intestinal epithelial cells. Due to its attachment, Giardia also blocks absorption of nutrients, including fats.
Transmission occurs through contaminated food or water or directly from person to person. Children in day-care centers are at risk due to their tendency to put items into their mouths that may be contaminated. Large outbreaks may occur if a public water supply becomes contaminated. Giardia have a resistant cyst stage in their life cycle that is able to survive cold temperatures and the chlorination treatment typically used for drinking water in municipal reservoirs. As a result, municipal water must be filtered to trap and remove these cysts. Once consumed by the host, Giardia develops into the active tropozoite.
Infected individuals may be asymptomatic or have gastrointestinal signs and symptoms, sometimes accompanied by weight loss. Common symptoms, which appear one to three weeks after exposure, include diarrhea, nausea, stomach cramps, gas, greasy stool (because fat absorption is being blocked), and possible dehydration. The parasite remains in the colon and does not cause systemic infection. Signs and symptoms generally clear within two to six weeks. Chronic infections may develop and are often resistant to treatment. These are associated with weight loss, episodic diarrhea, and malabsorption syndrome due to the blocked nutrient absorption.
Diagnosis may be made using observation under the microscope. A stool ova and parasite (O&P) exam involves direct examination of a stool sample for the presence of cysts and trophozoites; it can be used to distinguish common parasitic intestinal infections. ELISA and other immunoassay tests, including commercial direct fluorescence antibody kits, are also used. The most common treatments use metronidazole as the first-line choice, followed by tinidazole. If the infection becomes chronic, the parasites may become resistant to medications.

### Cryptosporidiosis

Another protozoan intestinal illness is cryptosporidiosis, which is usually caused by  parvum or C. hominis. () These pathogens are commonly found in animals and can be spread in feces from mice, birds, and farm animals. Contaminated water and food are most commonly responsible for transmission. The protozoan can also be transmitted through human contact with infected animals or their feces.
In the United States, outbreaks of cryptosporidiosis generally occur through contamination of the public water supply or contaminated water at water parks, swimming pools, and day-care centers. The risk is greatest in areas with poor sanitation, making the disease more common in developing countries.
Signs and symptoms include watery diarrhea, nausea, vomiting, cramps, fever, dehydration, and weight loss. The illness is generally self-limiting within a month. However, immunocompromised patients, such as those with HIV/AIDS, are at particular risk of severe illness or death.
Diagnosis involves direct examination of stool samples, often over multiple days. As with giardiasis, a stool O&P exam may be helpful. Acid fast staining is often used. Enzyme immunoassays and molecular analysis (PCR) are available.
The first line of treatment is typically oral rehydration therapy. Medications are sometimes used to treat the diarrhea. The broad-range anti-parasitic drug nitazoxanide can be used to treat cryptosporidiosis. Other anti-parasitic drugs that can be used include azithromycin and paromomycin.

### Amoebiasis (Amebiasis)

The protozoan parasite Entamoeba histolytica causes amoebiasis, which is known as amoebic dysentery in severe cases. E. histolytica is generally transmitted through water or food that has fecal contamination. The disease is most widespread in the developing world and is one of the leading causes of mortality from parasitic disease worldwide. Disease can be caused by as few as 10 cysts being transmitted.
Signs and symptoms range from nonexistent to mild diarrhea to severe amoebic dysentery. Severe infection causes the abdomen to become distended and may be associated with fever. The parasite may live in the colon without causing signs or symptoms or may invade the mucosa to cause colitis. In some cases, the disease spreads to the spleen, brain, genitourinary tract, or lungs. In particular, it may spread to the liver and cause an abscess. When a liver abscess develops, fever, nausea, liver tenderness, weight loss, and pain in the right abdominal quadrant may occur. Chronic infection may occur and is associated with intermittent diarrhea, mucus, pain, flatulence, and weight loss.
Direct examination of fecal specimens may be used for diagnosis. As with cryptosporidiosis, samples are often examined on multiple days. A stool O&P exam of fecal or biopsy specimens may be helpful. Immunoassay, serology, biopsy, molecular, and antibody detection tests are available. Enzyme immunoassay may not distinguish current from past illness. Magnetic resonance imaging (MRI) can be used to detect any liver abscesses. The first line of treatment is metronidazole or tinidazole, followed by diloxanide furoate, iodoquinol, or paromomycin to eliminate the cysts that remain.

### Cyclosporiasis

The intestinal disease cyclosporiasis is caused by the protozoan . It is endemic to tropical and subtropical regions and therefore uncommon in the United States, although there have been outbreaks associated with contaminated produce imported from regions where the protozoan is more common.
This protist is transmitted through contaminated food and water and reaches the lining of the small intestine, where it causes infection. Signs and symptoms begin within seven to ten days after ingestion. Based on limited data, it appears to be seasonal in ways that differ regionally and that are poorly understood.Centers for Disease Control and Prevention. “Cyclosporiasis FAQs for Health Professionals.” Updated June 13, 2014. http://www.cdc.gov/parasites/cyclosporiasis/health_professionals/hp-faqs.html.
Some individuals do not develop signs or symptoms. Those who do may exhibit explosive and watery diarrhea, fever, nausea, vomiting, cramps, loss of appetite, fatigue, and bloating. These symptoms may last for months without treatment. Trimethoprim-sulfamethoxazole is the recommended treatment.
Microscopic examination is used for diagnosis. A stool O&P examination may be helpful. The oocysts have a distinctive blue halo when viewed using ultraviolet fluorescence microscopy ().

### Key Concepts and Summary

1. Giardiasis, cryptosporidiosis, amoebiasis, and cyclosporiasis are intestinal infections caused by protozoans.
2. Protozoan intestinal infections are commonly transmitted through contaminated food and water.
3. Treatment varies depending on the causative agent, so proper diagnosis is important.
4. Microscopic examination of stool or biopsy specimens is often used in diagnosis, in combination with other approaches.

### Multiple Choice

### Fill in the Blank

### Short Answer


# Digestive System Infections

## Helminthic Infections of the Gastrointestinal Tract

### Learning Objectives

By the end of this section, you will be able to:
1. Identify the most common helminths that cause infections of the GI tract
2. Compare the major characteristics of specific helminthic diseases affecting GI tract
Helminths are widespread intestinal parasites. These parasites can be divided into three common groups: round-bodied worms also described as nematodes, flat-bodied worms that are segmented (also described as cestodes), and flat-bodied worms that are non-segmented (also described as trematodes). The nematodes include roundworms, pinworms, hookworms, and whipworms. Cestodes include beef, pork, and fish tapeworms. Trematodes are collectively called flukes and more uniquely identified with the body site where the adult flukes are located. Although infection can have serious consequences, many of these parasites are so well adapted to the human host that there is little obvious disease.

### Ascariasis

Infections caused by the large nematode roundworm , a soil-transmitted helminth, are called ascariasis. Over 800 million to 1 billion people are estimated to be infected worldwide.Centers for Disease Control and Prevention. “Parasites–Ascariasis.” Updated May 24, 2016. http://www.cdc.gov/parasites/ascariasis/index.html. Infections are most common in warmer climates and at warmer times of year. At present, infections are uncommon in the United States. The eggs of the worms are transmitted through contaminated food and water. This may happen if food is grown in contaminated soil, including when manure is used as fertilizer.
When an individual consumes embryonated eggs (those with a developing embryo), the eggs travel to the intestine and the larvae are able to hatch. Ascaris is able to produce proteases that allow for penetration and degradation of host tissue. The juvenile worms can then enter the circulatory system and migrate to the lungs where they enter the alveoli (air sacs). From here they crawl to the pharynx and then follow the gut lumen to return to the small intestine, where they mature into adult roundworms. Females in the host will produce and release eggs that leave the host via feces. In some cases, the worms can block ducts such as those of the pancreas or gallbladder.
The infection is commonly asymptomatic. When signs and symptoms are present, they include shortness of breath, cough, nausea, diarrhea, blood in the stool, abdominal pain, weight loss, and fatigue. The roundworms may be visible in the stool. In severe cases, children with substantial infections may experience intestinal blockage.
The eggs can be identified by microscopic examination of the stool (). In some cases, the worms themselves may be identified if coughed up or excreted in stool. They can also sometimes be identified by X-rays, ultrasounds, or MRIs.
Ascariasis is self-limiting, but can last one to two years because the worms can inhibit the body’s inflammatory response through glycan gimmickry (see Virulence Factors of Eukaryotic Pathogens). The first line of treatment is mebendazole or albendazole. In some severe cases, surgery may be required.

### Hookworm

Two species of nematode worms are associated with hookworm infection. Both species are found in the Americas, Africa, and Asia.  is found predominantly in the United States and Australia. Another species, , is found in southern Europe, North Africa, the Middle East, and Asia.
The eggs of these species develop into larvae in soil contaminated by dog or cat feces. These larvae can penetrate the skin. After traveling through the venous circulation, they reach the lungs. When they are coughed up, they are then swallowed and can enter the intestine and develop into mature adults. At this stage, they attach to the wall of the intestine, where they feed on blood and can potentially cause anemia. Signs and symptoms include cough, an itchy rash, loss of appetite, abdominal pain, and diarrhea. In children, hookworms can affect physical and cognitive growth.
Some hookworm species, such as Ancylostoma braziliense that is commonly found in animals such as cats and dogs, can penetrate human skin and migrate, causing cutaneous larva migrans, a skin disease caused by the larvae of hookworms. As they move across the skin, in the subcutaneous tissue, pruritic tracks appear ().
The infection is diagnosed using microscopic examination of the stool, allowing for observation of eggs in the feces. Medications such as albendazole, mebendazole, and pyrantel pamoate are used as needed to treat systemic infection. In addition to systemic medication for symptoms associated with cutaneous larva migrans, topical thiabendazole is applied to the affected areas.

### Strongyloidiasis

Strongyloidiasis is generally caused by , a soil-transmitted helminth with both free-living and parasitic forms. In the parasitic form, the larvae of these nematodes generally penetrate the body through the skin, especially through bare feet, although transmission through organ transplantation or at facilities like day-care centers can also occur. When excreted in the stool, larvae can become free-living adults rather than developing into the parasitic form. These free-living worms reproduce, laying eggs that hatch into larvae that can develop into the parasitic form. In the parasitic life cycle, infective larvae enter the skin, generally through the feet. The larvae reach the circulatory system, which allows them to travel to the alveolar spaces of the lungs. They are transported to the pharynx where, like many other helminths, the infected patient coughs them up and swallows them again so that they return to the intestine. Once they reach the intestine, females live in the epithelium and produce eggs that develop asexually, unlike the free-living forms, which use sexual reproduction. The larvae may be excreted in the stool or can reinfect the host by entering the tissue of the intestines and skin around the anus, which can lead to chronic infections.
The condition is generally asymptomatic, although severe symptoms can develop after treatment with corticosteroids for asthma or chronic obstructive pulmonary disease, or following other forms of immunosuppression. When the immune system is suppressed, the rate of autoinfection increases, and huge amounts of larvae migrate to organs throughout the body.
Signs and symptoms are generally nonspecific. The condition can cause a rash at the site of skin entry, cough (dry or with blood), fever, nausea, difficulty breathing, bloating, pain, heartburn, and, rarely, arthritis, or cardiac or kidney complications. Disseminated strongyloidiasis or hyperinfection is a life-threatening form of the disease that can occur, usually following immunosuppression such as that caused by glucocorticoid treatment (most commonly), with other immunosuppressive medications, with HIV infection, or with malnutrition.
As with other helminths, direct examination of the stool is important in diagnosis. Ideally, this should be continued over seven days. Serological testing, including antigen testing, is also available. These can be limited by cross-reactions with other similar parasites and by the inability to distinguish current from resolved infection. Ivermectin is the preferred treatment, with albendazole as a secondary option.

### Pinworms (Enterobiasis)

, commonly called pinworms, are tiny (2–13 mm) nematodes that cause enterobiasis. Of all helminthic infections, enterobiasis is the most common in the United States, affecting as many as one-third of American children.“Roundworms.”  Although the signs and symptoms are generally mild, patients may experience abdominal pain and insomnia from itching of the perianal region, which frequently occurs at night when worms leave the anus to lay eggs. The itching contributes to transmission, as the disease is transmitted through the fecal-oral route. When an infected individual scratches the anal area, eggs may get under the fingernails and later be deposited near the individual’s mouth, causing reinfection, or on fomites, where they can be transferred to new hosts. After being ingested, the larvae hatch within the small intestine and then take up residence in the colon and develop into adults. From the colon, the female adult exits the body at night to lay eggs ().
Infection is diagnosed in any of three ways. First, because the worms emerge at night to lay eggs, it is possible to inspect the perianal region for worms while an individual is asleep. An alternative is to use transparent tape to remove eggs from the area around the anus first thing in the morning for three days to yield eggs for microscopic examination. Finally, it may be possible to detect eggs through examination of samples from under the fingernails, where eggs may lodge due to scratching. Once diagnosis has been made, mebendazole, albendazole, and pyrantel pamoate are effective for treatment.

### Trichuriasis

The nematode whipworm  is a parasite that is transmitted by ingestion from soil-contaminated hands or food and causes trichuriasis. Infection is most common in warm environments, especially when there is poor sanitation and greater risk of fecal contamination of soil, or when food is grown in soil using manure as a fertilizer. The signs and symptoms may be minimal or nonexistent. When a substantial infection develops, signs and symptoms include painful, frequent diarrhea that may contain mucus and blood. It is possible for the infection to cause rectal prolapse, a condition in which a portion of the rectum becomes detached from the inside of the body and protrudes from the anus (). Severely infected children may experience reduced growth and their cognitive development may be affected.
When fertilized eggs are ingested, they travel to the intestine and the larvae emerge, taking up residence in the walls of the colon and cecum. They attach themselves with part of their bodies embedded in the mucosa. The larvae mature and live in the cecum and ascending colon. After 60 to 70 days, females begin to lay 3000 to 20,000 eggs per day.
Diagnosis involves examination of the feces for the presence of eggs. It may be necessary to use concentration techniques and to collect specimens on multiple days. Following diagnosis, the infection may be treated with mebendazole, albendazole, or ivermectin.

### Trichinosis

Trichinosis (trichenellosis) develops following consumption of food that contains  spiralis (most commonly) or other Trichinella species. These microscopic nematode worms are most commonly transmitted in meat, especially pork, that has not been cooked thoroughly. T. spiralis larvae in meat emerge from cysts when exposed to acid and pepsin in the stomach. They develop into mature adults within the large intestine. The larvae produced in the large intestine are able to migrate into the muscles mechanically via the stylet of the parasite, forming cysts. Muscle proteins are reduced in abundance or undetectable in cells that contain Trichinella (nurse cells). Animals that ingest the cysts from other animals can later develop infection ().
Although infection may be asymptomatic, symptomatic infections begin within a day or two of consuming the nematodes. Abdominal symptoms arise first and can include diarrhea, constipation, and abdominal pain. Other possible symptoms include headache, light sensitivity, muscle pain, fever, cough, chills, and conjunctivitis. More severe symptoms affecting motor coordination, breathing, and the heart sometimes occur. It may take months for the symptoms to resolve, and the condition is occasionally fatal. Mild cases may be mistaken for influenza or similar conditions.
Infection is diagnosed using clinical history, muscle biopsy to look for larvae, and serological testing, including immunoassays. Enzyme immunoassay is the most common test. It is difficult to effectively treat larvae that have formed cysts in the muscle, although medications may help. It is best to begin treatment as soon as possible because medications such as mebendazole and albendazole are effective in killing only the adult worms in the intestine. Steroids may be used to reduce inflammation if larvae are in the muscles.

### Tapeworms (Taeniasis)

Taeniasis is a tapeworm infection, generally caused by pork ( solium), beef (Taenia saginata), and Asian (Taenia asiatica) tapeworms found in undercooked meat. Consumption of raw or undercooked fish, including contaminated sushi, can also result in infection from the fish tapeworm ( latum). Tapeworms are flatworms (cestodes) with multiple body segments and a head called a scolex that attaches to the intestinal wall. Tapeworms can become quite large, reaching 4 to 8 meters long ().  illustrates the life cycle of a tapeworm.
Tapeworms attached to the intestinal wall produce eggs that are excreted in feces. After ingestion by animals, the eggs hatch and the larvae emerge. They may take up residence in the intestine, but can sometimes move to other tissues, especially muscle or brain tissue. When T. solium larvae form cysts in tissue, the condition is called cysticercosis. This occurs through ingestion of eggs via the fecal-oral route, not through consumption of undercooked meat. It can develop in the muscles, eye (ophthalmic cysticercosis), or brain (neurocysticercosis).
Infections may be asymptomatic or they may cause mild gastrointestinal symptoms such as epigastric discomfort, nausea, diarrhea, flatulence, or hunger pains. It is also common to find visible tapeworm segments passed in the stool. In cases of cysticercosis, symptoms differ depending upon where the cysts become established. Neurocysticercosis can have severe, life-threatening consequences and is associated with headaches and seizures because of the presence of the tapeworm larvae encysted in the brain. Cysts in muscles may be asymptomatic, or they may be painful.
To diagnose these conditions, microscopic analysis of stool samples from three separate days is generally recommended. Eggs or body segments, called proglottids, may be visible in these samples. Molecular methods have been developed but are not yet widely available. Imaging, such as CT and MRI, may be used to detect cysts. Praziquantel or niclosamide are used for treatment.

### Hydatid Disease

Another cestode, Echinococcus granulosus, causes a serious infection known as hydatid disease (cystic echinococcosis). E. granulosus is found in dogs (the definitive host), as well as several intermediate hosts (sheep, pigs, goats, cattle). The cestodes are transmitted through eggs in the feces from infected animals, which can be an occupational hazard for individuals who work in agriculture.
Once ingested, E. granulosus eggs hatch in the small intestine and release the larvae. The larvae invade the intestinal wall to gain access to the circulatory system. They form hydatid cysts in internal organs, especially in the lungs and liver, that grow slowly and are often undetected until they become large. If the cysts burst, a severe allergic reaction (anaphylaxis) may occur.
Cysts present in the liver can cause enlargement of the liver, nausea, vomiting, right epigastric pain, pain in the right upper quadrant, and possible allergic signs and symptoms. Cysts in the lungs can lead to alveolar disease. Abdominal pain, weight loss, pain, and malaise may occur, and inflammatory processes develop.
E. granulosus can be detected through imaging (ultrasonography, CT, MRI) that shows the cysts. Serologic tests, including ELISA and indirect hemagglutinin tests, are used. Cystic disease is most effectively treated with surgery to remove cysts, but other treatments are also available, including chemotherapy with anti-helminthic drugs (albendazole or mebendazole).

### Flukes

Flukes are flatworms that have a leaflike appearance. They are a type of trematode worm, and multiple species are associated with disease in humans. The most common are liver flukes and intestinal flukes ().

### Liver Flukes

The liver flukes are several species of trematodes that cause disease by interfering with the bile duct. Fascioliasis is caused by  hepatica and Fasciola gigantica in contaminated raw or undercooked aquatic plants (e.g., watercress). In Fasciola infection, adult flukes develop in the bile duct and release eggs into the feces. Clonochiasis is caused by  in contaminated freshwater fish. Other flukes, such as  (found in fish) and  (found in freshwater snails), also cause infections. Liver flukes spend part of their life cycle in freshwater snails, which serve as an intermediate host. Humans are typically infected after eating aquatic plants contaminated by the infective larvae after they have left the snail. Once they reach the human intestine, they migrate back to the bile duct, where they mature. The life cycle is similar for the other infectious liver flukes, (see ).
When Fasciola flukes cause acute infection, signs and symptoms include nausea, vomiting, abdominal pain, rash, fever, malaise, and breathing difficulties. If the infection becomes chronic, with adult flukes living in the bile duct, then cholangitis, cirrhosis, pancreatitis, cholecystitis, and gallstones may develop. Symptoms are similar for infections by other liver flukes. Cholangiocarcinoma can occur from C. sinensis infection. The Opisthorchis species can also be associated with cancer development.
Diagnosis is accomplished using patient history and examination of samples from feces or other samples (such as vomitus). Because the eggs may appear similar, immunoassay techniques are available that can help distinguish species. The preferred treatment for fascioliasis is triclabendazole. C. sinensis and Opisthorchis spp. infections are treated with praziquantel or albendazole.

### Intestinal Flukes

The intestinal flukes are trematodes that develop in the intestines. Many, such as , which causes fasciolopsiasis, are closely related to liver flukes. Intestinal flukes are ingested from contaminated aquatic plants that have not been properly cooked. When the cysts are consumed, the larvae emerge in the duodenum and develop into adults while attached to the intestinal epithelium. The eggs are released in stool.
Intestinal fluke infection is often asymptomatic, but some cases may involve mild diarrhea and abdominal pain. More severe symptoms such as vomiting, nausea, allergic reactions, and anemia can sometimes occur, and high parasite loads may sometimes lead to intestinal obstructions.
Diagnosis is the same as with liver flukes: examination of feces or other samples and immunoassay. Praziquantel is used to treat infections caused by intestinal flukes.

### Key Concepts and Summary

1. Helminths often cause intestinal infections after transmission to humans through exposure to contaminated soil, water, or food. Signs and symptoms are often mild, but severe complications may develop in some cases.
2. Ascaris lumbricoides eggs are transmitted through contaminated food or water and hatch in the intestine. Juvenile larvae travel to the lungs and then to the pharynx, where they are swallowed and returned to the intestines to mature. These nematode roundworms cause ascariasis.
3. Necator americanus and Ancylostoma doudenale cause hookworm infection when larvae penetrate the skin from soil contaminated by dog or cat feces. They travel to the lungs and are then swallowed to mature in the intestines.
4. Strongyloides stercoralis are transmitted from soil through the skin to the lungs and then to the intestine where they cause strongyloidiasis.
5. Enterobius vermicularis are nematode pinworms transmitted by the fecal-oral route. After ingestion, they travel to the colon where they cause enterobiasis.
6. Trichuris trichiura can be transmitted through soil or fecal contamination and cause trichuriasis. After ingestion, the eggs travel to the intestine where the larvae emerge and mature, attaching to the walls of the colon and cecum.
7. Trichinella spp. is transmitted through undercooked meat. Larvae in the meat emerge from cysts and mature in the large intestine. They can migrate to the muscles and form new cysts, causing trichinosis.
8. Taenia spp. and Diphyllobothrium latum are tapeworms transmitted through undercooked food or the fecal-oral route. Taenia infections cause taeniasis. Tapeworms use their scolex to attach to the intestinal wall. Larvae may also move to muscle or brain tissue.
9. Echinococcus granulosus is a cestode transmitted through eggs in the feces of infected animals, especially dogs. After ingestion, eggs hatch in the small intestine, and the larvae invade the intestinal wall and travel through the circulatory system to form dangerous cysts in internal organs, causing hydatid disease.
10. Flukes are transmitted through aquatic plants or fish. Liver flukes cause disease by interfering with the bile duct. Intestinal flukes develop in the intestines, where they attach to the intestinal epithelium.

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# Circulatory and Lymphatic System Infections

## Introduction

Yellow fever was once common in the southeastern US, with annual outbreaks of more than 25,000 infections in New Orleans in the mid-1800s.Centers for Disease Control and Prevention. “The History of Yellow Fever.” http://www.cdc.gov/travel-training/local/HistoryEpidemiologyandVaccination/page27568.html In the early 20th century, efforts to eradicate the virus that causes yellow fever were successful thanks to vaccination programs and effective control (mainly through the insecticide dichlorodiphenyltrichloroethane [DDT]) of , the mosquito that serves as a vector. Today, the virus has been largely eradicated in North America.
Elsewhere, efforts to contain yellow fever have been less successful. Despite mass vaccination campaigns in some regions, the risk for yellow fever epidemics is rising in dense urban cities in Africa and South America.C.L. Gardner, K.D. Ryman. “Yellow Fever: A Reemerging Threat.”  In an increasingly globalized society, yellow fever could easily make a comeback in North America, where A. aegypti is still present. If these mosquitoes were exposed to infected individuals, new outbreaks would be possible.
Like yellow fever, many of the circulatory and lymphatic diseases discussed in this chapter are emerging or re-emerging worldwide. Despite medical advances, diseases like malaria, Ebola, and others could become endemic in the US given the right circumstances.


# Circulatory and Lymphatic System Infections

## Anatomy of the Circulatory and Lymphatic Systems

### Learning Objectives

By the end of this section, you will be able to:
1. Describe the major anatomical features of the circulatory and lymphatic systems
2. Explain why the circulatory and lymphatic systems lack normal microbiota
3. Explain how microorganisms overcome defenses of the circulatory and lymphatic systems to cause infection
4. Describe general signs and symptoms of disease associated with infections of the circulatory and lymphatic systems
The circulatory and lymphatic systems are networks of vessels and a pump that transport blood and lymph, respectively, throughout the body. When these systems are infected with a microorganism, the network of vessels can facilitate the rapid dissemination of the microorganism to other regions of the body, sometimes with serious results. In this section, we will examine some of the key anatomical features of the circulatory and lymphatic systems, as well as general signs and symptoms of infection.

### The Circulatory System

The circulatory (or cardiovascular) system is a closed network of organs and vessels that moves blood around the body (). The primary purposes of the circulatory system are to deliver nutrients, immune factors, and oxygen to tissues and to carry away waste products for elimination. The heart is a four-chambered pump that propels the blood throughout the body. Deoxygenated blood enters the right atrium through the superior vena cava and the inferior vena cava after returning from the body. The blood next passes through the tricuspid valve to enter the right ventricle. When the heart contracts, the blood from the right ventricle is pumped through the pulmonary arteries to the lungs. There, the blood is oxygenated at the alveoli and returns to the heart through the pulmonary veins. The oxygenated blood is received at the left atrium and proceeds through the mitral valve to the left ventricle. When the heart contracts, the oxygenated blood is pumped throughout the body via a series of thick-walled vessels called arteries. The first and largest artery is called the aorta. The arteries sequentially branch and decrease in size (and are called arterioles) until they end in a network of smaller vessels called capillaries. The capillary beds are located in the interstitial spaces within tissues and release nutrients, immune factors, and oxygen to those tissues. The capillaries connect to a series of vessels called venules, which increase in size to form the veins. The veins join together into larger vessels as they transfer blood back to the heart. The largest veins, the superior and inferior vena cava, return the blood to the right atrium.
Other organs play important roles in the circulatory system as well. The kidneys filter the blood, removing waste products and eliminating them in the urine. The liver also filters the blood and removes damaged or defective red blood cells. The spleen filters and stores blood, removes damaged red blood cells, and is a reservoir for immune factors. All of these filtering structures serve as sites for entrapment of microorganisms and help maintain an environment free of microorganisms in the blood.

### The Lymphatic System

The lymphatic system is also a network of vessels that run throughout the body (). However, these vessels do not form a full circulating system and are not pressurized by the heart. Rather, the lymphatic system is an open system with the fluid moving in one direction from the extremities toward two drainage points into veins just above the heart. Lymphatic fluids move more slowly than blood because they are not pressurized. Small lymph capillaries interact with blood capillaries in the interstitial spaces in tissues. Fluids from the tissues enter the lymph capillaries and are drained away (). These fluids, termed lymph, also contain large numbers of white blood cells.
The lymphatic system contains two types of lymphoid tissues. The primary lymphoid tissue includes bone marrow and the thymus. Bone marrow contains the hematopoietic stem cells (HSC) that differentiate and mature into the various types of blood cells and lymphocytes (see ). The secondary lymphoid tissues include the spleen, lymph nodes, and several areas of diffuse lymphoid tissues underlying epithelial membranes. The spleen, an encapsulated structure, filters blood and captures pathogens and antigens that pass into it (). The spleen contains specialized macrophages and dendritic cells that are crucial for antigen presentation, a mechanism critical for activation of T lymphocytes and B lymphocytes (see Major Histocompatibility Complexes and Antigen-Presenting Cells). Lymph nodes are bean-shaped organs situated throughout the body. These structures contain areas called germinal centers that are rich in B and T lymphocytes. The lymph nodes also contain macrophages and dendritic cells for antigen presentation. Lymph from nearby tissues enters the lymph node through afferent lymphatic vessels and encounters these lymphocytes as it passes through; the lymph exits the lymph node through the efferent lymphatic vessels ().

### Infections of the Circulatory System

Under normal circumstances, the circulatory system and the blood should be sterile; the circulatory system has no normal microbiota. Because the system is closed, there are no easy portals of entry into the circulatory system for microbes. Those that are able to breach the body’s physical barriers and enter the bloodstream encounter a host of circulating immune defenses, such as antibodies, complement proteins, phagocytes, and other immune cells. Microbes often gain access to the circulatory system through a break in the skin (e.g., wounds, needles, intravenous catheters, insect bites) or spread to the circulatory system from infections in other body sites. For example, microorganisms causing pneumonia or renal infection may enter the local circulation of the lung or kidney and spread from there throughout the circulatory network.
If microbes in the bloodstream are not quickly eliminated, they can spread rapidly throughout the body, leading to serious, even life-threatening infections. Various terms are used to describe conditions involving microbes in the circulatory system. The term bacteremia refers to bacteria in the blood. If bacteria are reproducing in the blood as they spread, this condition is called septicemia. The presence of viruses in the blood is called viremia. Microbial toxins can also be spread through the circulatory system, causing a condition termed toxemia.
Microbes and microbial toxins in the blood can trigger an inflammatory response so severe that the inflammation damages host tissues and organs more than the infection itself. This counterproductive immune response is called systemic inflammatory response syndrome (SIRS), and it can lead to the life-threatening condition known as sepsis. Sepsis is characterized by the production of excess cytokines that leads to classic signs of inflammation such as fever, vasodilation, and edema (see Inflammation and Fever). In a patient with sepsis, the inflammatory response becomes dysregulated and disproportionate to the threat of infection. Critical organs such as the heart, lungs, liver, and kidneys become dysfunctional, resulting in increased heart and respiratory rates, and disorientation. If not treated promptly and effectively, patients with sepsis can go into shock and die.
Certain infections can cause inflammation in the heart and blood vessels. Inflammation of the endocardium, the inner lining of the heart, is called endocarditis and can result in damage to the heart valves severe enough to require surgical replacement. Inflammation of the pericardium, the sac surrounding the heart, is called pericarditis. The term myocarditis refers to the inflammation of the heart’s muscle tissue. Pericarditis and myocarditis can cause fluid to accumulate around the heart, resulting in congestive heart failure. Inflammation of blood vessels is called vasculitis. Although somewhat rare, vasculitis can cause blood vessels to become damaged and rupture; as blood is released, small red or purple spots called petechiae appear on the skin. If the damage of tissues or blood vessels is severe, it can result in reduced blood flow to the surrounding tissues. This condition is called ischemia, and it can be very serious. In severe cases, the affected tissues can die and become necrotic; these situations may require surgical debridement or amputation.

### Infections of the Lymphatic System

Like the circulatory system, the lymphatic system does not have a normal microbiota, and the large numbers of immune cells typically eliminate transient microbes before they can establish an infection. Only microbes with an array of virulence factors are able to overcome these defenses and establish infection in the lymphatic system. However, when a localized infection begins to spread, the lymphatic system is often the first place the invading microbes can be detected.
Infections in the lymphatic system also trigger an inflammatory response. Inflammation of lymphatic vessels, called lymphangitis, can produce visible red streaks under the skin. Inflammation in the lymph nodes can cause them to swell. A swollen lymph node is referred to as a bubo, and the condition is referred to as lymphadenitis.

### Key Concepts and Summary

1. The circulatory system moves blood throughout the body and has no normal microbiota.
2. The lymphatic system moves fluids from the interstitial spaces of tissues toward the circulatory system and filters the lymph. It also has no normal microbiota.
3. The circulatory and lymphatic systems are home to many components of the host immune defenses.
4. Infections of the circulatory system may occur after a break in the skin barrier or they may enter the bloodstream at the site of a localized infection. Pathogens or toxins in the bloodstream can spread rapidly throughout the body and can provoke systemic and sometimes fatal inflammatory responses such as SIRS, sepsis, and endocarditis.
5. Infections of the lymphatic system can cause lymphangitis and lymphadenitis.

### Multiple Choice

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### Short Answer

### Critical Thinking