The causes of diarrhoea vary depending on the type of practice, but in all settings gastrointestinal infections are a common cause of acute diarrhoea (Box 13.2). It is clinically useful to divide acute causes of diarrhoea into clinical syndromes, watery (non-inflammatory) diarrhoea, blood (inflammatory) diarrhoea, food poisoning, diarrhoea in the traveller, diarrhoea associated with recent antibiotics or other drug use and diarrhoea in the HIV-positive (Fig 13.1) or male homosexual patient. Overlap may occur between the categories. Of course, an illness may begin as watery diarrhoea, only to progress to bloody diarrhoea later.

Box 13.2 Features favouring medically important diarrhoea

• Severe prolonged diarrhoea

• High fever/systemic toxicity

• Severe abdominal pain

• Blood in the stool

• Signs of volume depletion

• Immunocompromised host

Figure 13.1 Practical approach to HIV-associated diarrhoea.

The clinical approach to those with acute diarrhoea should focus initially on:

• separating minor from severe illness;

• selecting patients who need further investigation; and

• instituting specific therapy, where appropriate.

History

A careful history is important in evaluating patients with acute diarrhoea and in separating minor from severe illness. Features that suggest the diarrhoea may not be self-limiting include severe diarrhoea, blood in the stool, severe abdominal pain or a high fever (Box 13.2).

Ask about the duration of symptoms as well as severity. An abrupt onset of diarrhoea, which then gradually improves, suggests an infective process. Systemic features with infectious diarrhoea include fever, myalgia, malaise, nausea and vomiting. The onset of diarrhoea with food poisoning is often severe but short-lived. With prolonged watery diarrhoea, volume depletion is more likely to develop, especially when there is associated vomiting. Large volume, watery diarrhoea may be of small bowel origin. The presence of blood in the stool is usually due to an intestinal inflammatory process (see Box 13.3).

The setting in which diarrhoea occurs also provides clues as to the diagnosis. Recent travel or consumption of food eaten from fast-food outlets suggests infective diarrhoea or food poisoning, especially if other people who ate at the same time and place are affected. A drug history is important with particular attention to antibiotics (Clostridium difficile infection), over-the-counter and herbal preparations. A dietary history including dairy products (lactose intolerance) and sorbitol ingestion may be helpful.

Chronic illnesses may first present with acute diarrhoea. Recent blood diarrhoea, for example, may be the initial onset of inflammatory bowel disease.

Physical examination

The physical examination will help assess the effects of the diarrhoeal illness and may provide clues as to its cause.

Effects may include volume depletion (dry mouth and orthostatic hypertension) and signs of toxicity (high fever, tachycardia and shock).

The abdominal examination may reveal tenderness (inflammatory bowel disease or diverticulitis) a mass or visceromegaly (e.g. colon cancer deposits in the liver). The stool should be examined and the presence of blood noted. A rectal examination is mandatory and may document faecal impaction (overflow diarrhoea in the elderly) or a tumour.

Investigations

The history and physical examination will help differentiate those with minor diarrhoea from those with a more severe illness.

Those with minor resolving diarrhoea need no investigations and no specific therapy beyond maintenance of hydration. Those with features outlined in Box 13.2, where a definitive diagnosis is likely to alter management and outcome, should usually be further investigated. Those diagnostic tests should be targeted, where possible, towards a specific diagnosis according to clues from the history and physical examination.

Therapy

Acute diarrhoea illnesses range from minor, self-limiting episodes of diarrhoea to devastating illnesses with overwhelming sepsis and profound dehydration. Therapy will need to be tailored depending on the severity of the illness, the nature of the underlying aetiology and the competence of the host’s defence mechanism.

Hospitalisation is usually necessary for those with sepsis or severe dehydration, and should be considered for those who have an impaired immune response.

Hydration

Maintenance of adequate hydration is the only treatment necessary for most episodes of acute diarrhoea. In the presence of nausea, this may require the frequent intake of small amounts of fluid orally. Soups and fruit juice will usually supply the sodium, potassium and glucose necessary for adequate fluid absorption. Oral rehydration solutions are available commercially or can be prescribed, and are used for mild-to-moderate dehydration. Oral rehydration solutions play an important role in developing countries where gastrointestinal infections are common and medical facilities are limited. Intravenous fluids are indicated for severe dehydration.

Diet

The tradition of limiting food during intakes of diarrhoea carries the disadvantage of restricting caloric intake during a catabolic event. Restriction of milk and milk products is usually indicated as secondary lactase deficiency may be present. Products containing sorbitol, including some fruit juices, will exacerbate diarrhoea and are best avoided. Anorexia is obviously a factor during diarrhoeal illnesses, but the maintenance of caloric intake should be encouraged.

Antidiarrhoeal agents

Agents such as loperamide and diphenoxylate are widely used for the symptomatic relief of diarrhoea. They are usually effective and have few side effects. However, they should be avoided in patients with colitis in view of the potential to cause toxic megacolon. They should also be avoided in young children as they are usually infective and may prolong intestinal recovered.

Antibiotics

Antibiotics should be avoided in the routine treatment of acute diarrhoea. They are usually ineffective in reducing the duration of the illnesses and in some cases may prolong excretion of the pathogen. They also have significant side effects and indiscriminate use will increase drug resistance. There are a limited number of situations where antibiotics may be helpful. Box 13.4 outlines the indication for antibiotics and these are discussed in more detail under disease headings.

Conditions Causing Food-borne Illnesses

Food-borne illnesses are caused by the consumption of contaminated food and result in significant worldwide morbidity and mortality. They can be caused by the consumption of bacteria or bacterial toxins, viruses, parasites or chemicals.

Clinical syndromes resulting from such diverse aetiological agents vary, but nausea, vomiting, diarrhoea and abdominal pain are common to most. Neurological, hepatic and renal syndromes may also occur. The rapid onset of symptoms (within 6 hours) suggests ingestion of a preformed toxin. A longer incubation period is associated with bacterial or viral agents.

Some of the common causes of food-borne illnesses are discussed below under aetiological headings.

Bacterial food-borne illnesses

Common causes of food-borne illnesses include Salmonella and Campylobacter species and E. coli—these are discussed later in this chapter. Other major bacterial causes of food-borne illnesses are discussed below.

Clostridium perfringens

C. perfringens is a common food-borne pathogen with an incubation period of 8–24 hours. The illness usually results from the ingestion of meat or poultry and results in watery diarrhoea and crampy abdominal pain. The symptoms are short-lived and usually last 24 hours. Symptomatic therapy with attention to hydration is usually all that is necessary.

C. perfringens may also cause a severe and often fatal illness—enteritis necroticans or ‘pigbel’—which is seen only in underdeveloped tropical countries. Abdominal pain and bloating, vomiting and diarrhoea with shock occur, usually after a feast.

Stool and food can be tested for toxin in special laboratories.

Staphylococcus aureus

Staphylococcal food poisoning results in profuse vomiting, followed by crampy abdominal pain and diarrhoea. These symptoms result from staphylococcal toxins and occur 1–6 hours after the ingestion of contaminated food. Symptomatic therapy only is necessary, with recovery occurring within 24–48 hours, although occasional deaths have been reported.

Diagnosis is clinical, but food and vomitus can be tested for toxin.

Bacillus cereus

Food poisoning with B. cereus is associated with two distinct syndromes: a vomiting syndrome and a diarrhoeal syndrome. Ingestion of a preformed toxin will result in vomiting similar to that of S. aureus lasting about 12 hours. Fried rice has been implicated as the vehicle in the majority of cases. The diarrhoeal illness occurs 6–14 hours after the ingestion of contaminated food and results from the production of an enterotoxin. Diarrhoea, crampy abdominal pain and, less commonly, vomiting last for 20–36 hours.

Vibrio parahaemolyticus

V. parahaemolyticus is associated with seafood and causes food poisoning outbreaks after the ingestion of shellfish or raw fish. It causes explosive watery diarrhoea with an incubation period of 12–24 hours. The diarrhoea may be associated with nausea, vomiting and fever and occurs in about 25% of patients. Occasionally, a dysenteric syndrome may result with blood diarrhoea. A specific request must be made to the laboratory for culturing the organism. Symptoms are generally short-lived and require no specific therapy.

Clostridium botulinum

C. botulinum produces a heat-labile neurotoxin and outbreaks of food-borne botulism have been reported from ingestion of home-preserved foods that have been improperly prepared.

Symptoms usually begin within 12–24 hours and consist of bilateral cranial neuropathy with symmetrical descending paralysis. The diagnosis is made by demonstrating the toxin in serum, stool or food ingested.

Respiratory support may be necessary and an anti-toxin that can prevent further paralysis is available. Full recovery may take months.

Non-bacterial food-borne illnesses

Heavy metals including zinc, iron, tin, copper and cadmium can cause gastric irritation with abdominal pain, nausea and vomiting. Poisoning usually results from storage of food or beverages in metal containers.

Neurotoxin food-poisoning syndromes can be caused by scombroid fish, ciguatera fish (see below), shellfish and mushrooms.

Viral (hepatitis A) and parasitic (Trichinella spiralis and Giardia lamblia) food poisoning are further examples of non-bacterial food-borne illnesses.

Ciguatera fish poisoning (ciguatoxin)

This results from the ingestion of fish containing a neurotoxin, which originates in algae. Symptoms begin within 5 minutes to 30 hours and consist of nausea, vomiting, diarrhoea as well as photophobia, blurred vision and paraesthesia. Bradycardia, heart block and hypotension may also occur. No specific antidote is known.

Scombroid poisoning

Diarrhoea occurs within minutes to hours of consumption of certain fish and occasionally certain cheeses and presents with flushing, urticaria and dizziness related to biogenic amines.

Mushroom toxins can also produce gastrointestinal and neurological symptoms.

Travellers’ Diarrhoea

International travel is now a common event and, of those travelling to developing countries, 30–50% will develop diarrhoea. Symptoms are generally short-lived but carry the potential to disrupt a well-planned holiday excursion or business trip. Pre-travel advice should include recommendations for prevention as well as treatment.

Aetiology and transmission

Travellers’ diarrhoea is predominantly due to gastrointestinal infective illnesses, with an enteropathogen being documented in up to 80% of cases (Table 13.1). Causes vary considerably with country of destination, but the commonest pathogen isolated in most studies is enterotoxigenic E. coli, which accounts for up to 50% of travellers’ diarrhoea. In about 20% of cases no pathogen is isolated and this group may represent known pathogens not identified due to insensitive or inadequate culture technique, unknown pathogens or non-infectious causes of diarrhoea, such as stress, alcohol and medications.

Travellers’ diarrhoea is acquired through the ingestion of contaminated food or water. Enteropathogens may be found in tap water, ice, diary products, vegetables, unpeeled fruit and raw shellfish. Contaminated food is the most important cause of travellers’ diarrhoea, although waterborne transmission also occurs.

Clinical manifestations

The onset of travellers’ diarrhoea is usually abrupt, with symptoms beginning within 3–4 days of arrival at the country of destination. Typically, the illness is mild, with less than six bowel actions daily, and it lasts 3–4 days in 85% of untreated sufferers. Occasionally, symptoms may be more severe with profuse watery diarrhoea leading to dehydration, or are associated with a high fever and blood in the stool. The presence of blood suggests invasive disease (see ‘Conditions causing acute blood diarrhoea’ later in this chapter).

Prevention

Diet

The logical approach to prevention is to avoid ingesting enteropathogenic agents. Hence, common advice to travellers is to avoid tap water, raw shellfish, dairy products, uncooked vegetables, unpeeled fruit and eating from street vendors (‘boil it, cook it, peel it or forget it’). Unfortunately, studies examining the efficacy of the recommendations have failed to demonstrate that they significantly reduce the incidence of diarrhoea. This is partly because it is difficult to follow such strict dietary advice when on holidays and partly because enteropathogens can be found in food from five-star hotels, bottled drink and food too hot to touch. Nevertheless, it remains prudent to avoid foods that obviously carry a higher risk of contamination.

Antibiotics

Antibiotics have been documented to be of value in reducing the incidence of diarrhoea when taken prophylactically. A wide range of antibiotics, including sulfonamides, doxycycline, cotrimoxazole, ciprofloxacin and rifaximin have been shown to reduce the attack rate for travellers’ diarrhoea by 30–85%. Despite this efficacy, routine prophylaxis cannot be recommended as travellers’ diarrhoea is usually self-limiting and effective treatment is available. Also, side effects may occur and drug resistance will undoubtedly increase if millions of travellers take antibiotics each year. Exceptions to this rule may include those especially inconvenienced by travellers’ diarrhoea or those who are at risk of severe illness, such as those immunocompromised or those with impaired gastric acidity.

Investigations

Mild resolving diarrhoea does not require investigation. The presence of blood in the stool, high fever or severe watery diarrhoea should prompt stool cultures and examination, as noted under investigation of acute diarrhoea.

Treatment

Hydration

The only treatment necessary for most sufferers of travellers’ diarrhoea is maintenance of adequate hydration. Proprietary rehydration solutions or fruit juice and soups with added salt will help replace sodium, potassium and fluid losses.

Antibiotics

Antibiotics have been shown to be effective in shortening the length of the illness and should be considered in those with moderate-to-severe symptoms. Norfloxacin, ciprofloxacin, doxycycline, cotrimoxazole and rifaximin (a non-absorbable antibiotic) have all been shown to be effective.

Antidiarrhoeal agents

Agents such as loperamide or diphenoxylate are widely used for symptomatic relief of symptoms, although there is limited evidence to show that they shorten the course of the illness. In addition, in some settings they may prolong the excretion of pathogens and should be avoided in children and in those who have bloody diarrhoea, severe abdominal pain, a high fever.

Medical advice

Medical advice should be sought by those with bloody diarrhoea, persisting severe symptoms, severe abdominal pain or a high fever not responding to antibiotics.

Conditions Causing Acute Watery Diarrhoea

Giardia lamblia

G. lamblia is a flagellated protozoan. It exists as a trophozoite, the active form, and as a cyst, the inactive form. The trophozoites multiply by binary fission and encyst as they pass down the intestine. The cystic form is shed in the stool and can survive in the environment.

G. lamblia has a worldwide distribution and transmission is by way of contaminated water or food when large outbreaks may occur, or by direct person-to-person spread. The latter is common in daycare centres and various institutions.

Clinical manifestations

Ingestion of G. lamblia cysts results in a spectrum of symptoms, ranging from asymptomatic cyst passage to an acute diarrhoeal illness or chronic diarrhoea with malabsorption. After an incubation period of 1–2 weeks, a minority of patients will develop a symptomatic infection with prolonged passage of cysts. Those who develop symptoms will report watery diarrhoea with crampy abdominal pain, nausea and excessive flatus. The stools are often malodorous and may develop typical features of malabsorption, becoming greasy, bulky, pale and floating. The symptoms usually settle after 1–3 weeks but prolonged infection with marked weight loss has been reported. Blood and pus are not found in the stool and fever is not a feature of the illness.

Diagnosis

A stool examination for cysts is relatively simple but not very sensitive since G. lamblia cysts are excreted intermittently—examination of three samples yields a positive diagnosis in only 50–70% of cases. Duodenal aspiration and duodenal mucosal biopsies are accurate in 95% of cases, but are relatively invasive for what is usually a self-limiting illness. Immunoassay kits using antibodies directed against trophozoites or cysts have now been developed and they have a sensitivity and specificity range of 90–100%. Serology is not of value in the diagnosis of acute giardiasis and suffers from the drawback that antibodies persist after infection has resolved. The polymerase chain reaction test is only experimental and in practice a therapeutic trial of metronidazole or tinidazole is more often carried out.

Treatment

Metronidazole or tinidazole remains the treatment of choice and can be administered as a single dose. Albendazole has also been reported to have a high efficacy in children. Treatment failures are uncommon, but persisting infection can be treated with repeated courses or prolonged therapy. Treatment of other members of the family may be necessary to prevent person-to-person spread.

Cholera

Cholera is a severe diarrhoeal illness due to Vibrio cholerae, a gram-negative bacterium that elaborates an enterotoxin. It is endemic in Asia and Africa, from where pandemics spread around the world. The high mortality rate (which can exceed 50% if untreated) is due to dehydration. Stool output can exceed 1 L per hour and death may result within 2–3 hours of the onset of the illness. There are two major biotypes of cholera: ‘classical’ and El tor. They cause a similar clinical illness, although the El tor infection tends to be milder.

Pathogenesis

Cholera organisms elaborate an enterotoxin composed of five binding (B) subunits and an active (A1) subunit. The B subunits bind to a specific receptor on the enterocyte surface. The A subunit then becomes internalised in the cell membrane and irreversibly activates adenylate cyclase on the inner cell membrane. This results in a continuing conversion of ATP to cAMP, and raised intracellular levels of cAMP change the net absorption of fluids into the small intestine into the net excretion. Fluid loss from the small intestine results and diarrhoea occurs when the capacity of the colon to absorb excess fluid is overwhelmed.

‘Rice water’ stools may result when the purging action of the diarrhoea clears all pigment from the stool which then becomes clear fluid with flecks of mucus.

Clinical features

There is a spectrum of clinical manifestations from asymptomatic carrier state or mild diarrhoea through to massive faecal fluid loss with hypovolaemic shock. Symptoms usually begin with abdominal discomfort leading to cramping abdominal pain. This is followed by diarrhoea that increases rapidly, reaching faecal outputs of 15–20 L per 24 hours in some patients. These large-volume ‘rice water’ stools become isotonic with plasma. Vomiting may also occur, compounding severe dehydration. There is a significant mortality associated with untreated cholera infection due to hypovolaemic shock.

Diagnosis

The diagnosis is made by stool culture using appropriate culture media. A presumptive diagnosis may be made by examining stools under dark field or phase microscopy, where Vibrio organisms display a typical ‘shooting star’ motility. Polymerase chain reaction and monoclonal-based stool tests are primarily used in epidemiological studies. Vibriocidal antibodies peak 7 days after infection and therefore are not useful in acute infection, but can be used retrospectively to confirm the diagnosis.

Treatment

The treatment of cholera involves adequate fluid replacement. The glucose-sodium co-transport system is not affected by the cholera toxin and oral rehydration solutions may be adequate for mild-to-moderate dehydration. Patients with more severe dehydration or persisting vomiting will require intravenous fluids. Hypokalaemia may be severe, necessitating oral or intravenous replacement. Bicarbonate is required when acidosis supervenes. Antibiotics are not used for the standard treatment of cholera, but have been shown to reduce fluid losses and marginally reduce the time of excretion of Vibrio organisms.

Parenteral killed whole cell vaccine provides less than 50% protection and is not recommended. Newer oral vaccines may provide an increased level of protection and, since the B subunit of cholera is antigenically similar to the heat labile enterotoxin of ETEC (enterotoxigenic E. coli) it may provide a dual protection but the cost–benefit ratio needs to be considered.

Viral infections

Occurrence and transmission

Viral gastroenteritis has become recognised as a common cause of diarrhoea in adults and children. The rotavirus has been identified as a leading cause of gastroenteritis in young children and the norovirus (previously termed ‘Norwalk virus’) documented as a cause of epidemics of acute infectious diarrhoea in older children and adults. Other viruses implicated in causing diarrhoea include enteric adenoviruses and astroviruses. However, new viruses almost certainly remain to be discovered, as no viral agent can be identified in up to a third of cases of suspected viral gastroenteritis.

Rotavirus

Rotavirus causes gastroenteritis in children aged 6–24 months and is more likely to occur in winter months. The symptoms of vomiting and watery diarrhoea typically begin after an incubation period of 48–72 hours. The diarrhoea usually lasts 4–8 days, and the combination of diarrhoea and vomiting often leads to dehydration. A milder disease occurs in older children and adults, but most children have been found to develop antibodies to rotavirus by the age of 24 months. Human colostrum and milk contain antibodies to rotavirus and it is known that breastfeeding reduces the incidence of gastroenteritis in children. Transmission is mainly by the orofaecal route and viruses can be shed in the faeces for up to 21 days.

Rotavirus infection can be diagnosed by an immunoassay using an ELISA test, by polymerase chain reaction technique or by isolated from stool samples.

There are no effective antiviral agents against rotavirus and treatment involves adequate oral or, if needed, intravenous hydration. There are two live attenuated oral vaccines RV 5 and RV1 available. RV1 should not be used in individuals with latex allergy.

Norovirus

The norovirus is a common cause of epidemics of acute gastroenteritis. Orofaecal and waterborne spread has been reported and direct person-to-person spread also occurs. The virus typically causes symptoms in older children and adults and is usually mild, with diarrhoea, nausea and vomiting occurring after an incubation period of 24–48 hours. Cramping abdominal pain, fever and myalgia may also occur and treatment is symptomatic with fluid replacement as appropriate.

Conditions Causing Acute Blood Diarrhoea

The differential diagnosis is summarised in Box 13.3.

Shigella spp.

Occurrence and transmission

Shigella spp. organisms are more common in developing countries with poor sanitation and overcrowding, but Shigella infections can also occur in developed countries. There are four major subgroups (S. boydii, S. dysenteriae, S. flexneri, S. sonnei) and all are capable of causing dysentery, a term that refers to diarrhoea containing blood and pus. Shigella infections occur only in humans and transmission is by the orofaecal route. The organism is highly contagious and direct person-to-person spread can occur. resulting in a high secondary household transmission rate.

Clinical manifestations

Symptoms following ingestion of Shigella spp. organisms vary from fever, with or without mild watery diarrhoea, to typical dysentery with diarrhoea containing blood and pus. There is associated cramping abdominal pain, frequently with tenesmus.

These organisms produce intestinal damage both by direct invasion of the colonic epithelium and by production of an enterotoxin. The capacity to invade colonic cells is essential for virulence and results in a localised severe inflammatory response. The development of oedema, crypt abscesses and ultimately mucosal ulceration gives rise to the typical dysenteric stool.

Complications include rectal prolapse, toxic megacolon and colonic perforation. Extraintestinal symptoms include the haemolytic uraemic syndrome, febrile seizures in young children, reactive arthritis and pneumonia.

Diagnosis

The diagnosis of shigellosis is made by stool culture, and antibiotic sensitivity should be performed at the same time, as drug resistance is common.

A patchy colitis with ulceration may be demonstrated at sigmoidoscopy and biopsies will help to exclude inflammatory bowel disease and amoebic colitis.

The differential diagnosis includes other infectious cases of colitis (enteroinvasive E. coli, C. jejuni, Y. enterocolitica, C. difficile and E. histolytica) and inflammatory bowel disease.

Treatment

General supportive measures include maintaining hydration and lowering high fever, especially in children. Antidiarrhoeal drugs should be avoided.

Antibiotics are indicated in most patients with Shigella infections as they reduce the severity and shorten the duration of the illness. Trimethoprim-sulfamethoxazole and ciprofloxacin are generally effective, but drug resistance is emerging as a significant problem, especially for ampicillin.

Salmonella spp.

Salmonella organisms are gram-negative motile bacilli that can cause a wide clinical spectrum of illness in humans, including gastroenteritis, typhoid fever, bacteraemia and localised infection. An asymptomatic carrier state also occurs.

Serotypes include S. typhi, S. paratyphi, S. enterica (previously called S. choleraesuis) and S. enteritidis. The term ‘non-typhoidal salmonellosis’ refers to enteric disease caused by infection with Salmonella organisms other than S. typhi.

Non-typhoidal salmonellosis

Non-typhoidal salmonellosis is a common cause of food-borne disease around the world, and its incidence has increased in many developed countries. Food-borne epidemics are frequent and animal products, especially eggs and poultry, are recognised sources of infection. In addition, pets such as turtles and ducklings have been implicated in the spread of salmonellosis. Direct person-to-person spread seems to be uncommon.

The incubation of S. enteritidis is short, within the range of 24–48 hours. There is a spectrum of symptoms ranging from mild diarrhoea to severe watery diarrhoea with cramping abdominal pain and fever. Risk factors for severe disease or complications include extremes of age, haemolytic disease, immunocompromised hosts and the presence of prosthetic devices (Box 13.5).

Complications include bacteraemia, osteomyelitis, localised abscesses, meningitis and pneumonia.

Diagnosis

The diagnosis of non-typhoidal salmonellosis relies upon isolating Salmonella organisms from stool or blood culture.

Treatment

Maintenance of hydration with fluid and electrolyte replacement is indicated, as appropriate. The routine use of antibiotics should be avoided, as they do not shorten the average illness and may prolong excretion of the organisms. Antibiotics should be reserved for those with severe symptoms or at risk of complications (see Box 13.5). Antimicrobial resistance is an emerging problem. Antibiotics that are effective include quinolones, trimethoprim-sulfamethoxazole and amoxicillin.

Typhoid fever

Typhoid fever is a distinctive clinical syndrome usually associated with S. typhi or S. paratyphi. The clinical features include a prolonged fever with bacteraemia leading to the stimulation of the reticuloendothelial system and metastatic spread. Multiple organ damage follows, and may include the intestine, but despite the term ‘enteric fever’ gastrointestinal symptoms are not prominent, especially early in the syndrome.

Clinical manifestations

The incubation period varies from 1 week to 3 weeks, but can range up to 60 days. The illness evolves over a period of 4 weeks, beginning with a high fever, headache and chills. A bradycardia relative to the fever may occur and the typical ‘rose spots’ rash is seen during the first week in some patients. Hepatosplenomegaly is common. Intestinal manifestations are not prominent early in the disease and both constipation and mild diarrhoea may occur.

The fever is persistent over a period of 4 weeks with the illness becoming more severe during the second and third week: persistent high fever, delirium and complications from waves of bacteraemia including meningitis, nephritis, osteomyelitis and hepatitis. Diarrhoea may develop at this stage of the disease with haemorrhage or perforation.

Symptoms generally start to abate after the third week, but relapses may occur.

Diagnosis

The diagnosis is established by isolating the organism, on either blood or stool culture. Blood cultures are positive in up to 90% of cases during the first week and stool cultures do not usually become positive until the second or third week. Bone marrow culture is positive in over 90% of patients. Serological tests are less reliable and may indicate previous exposure in endemic areas.

Transmission

Transmission of S. typhi is usually by water or food contaminated by an individual who either has typhoid fever or is an asymptomatic carrier.

Campylobacter jejuni

Occurrence and transmission

C. jejuni is a common cause of acute diarrhoea illness, and in many developed countries it is the most common pathogen detected in patients with diarrhoea. It is usually a food-borne illness and sources of infection include contaminated milk, sick pets, occupational exposure to poultry and contaminated water.

Clinical manifestations

After an incubation period of 2–6 days, symptoms begin with the onset of diarrhoea or prodromal features of lassitude, fever, myalgia and headaches. The diarrhoea is initially watery, but may progress to contain blood and mucus. Cramping abdominal pain is common and may be severe. It can present atypically like pseudoappendicitis and colitis. Late onset complications include a reactive arthritis and Guillain-Barré syndrome.

Diagnosis

The diagnosis is made by stool culture. Special incubating techniques at 42°C with microaerobic conditions are necessary. Sigmoidoscopy may demonstrate colitis in up to 80% of cases, although this finding does not help in making a specific diagnosis.

Treatment

Maintenance of hydration is all that is usually necessary in those patients with a self-limiting illness, and in whom symptoms are usually improving at the time of diagnosis. For those with more severe symptoms or who are immunosuppressed, erythromycin is the antibiotic of choice. Quinolones are also effective, although resistance is an emerging problem.

Yersinia enterocolitica

Occurrence and transmission

Y. enterocolitica has a worldwide distribution and causes a gastrointestinal illness that more commonly affects children and young adults. Transmission is via the orofaecal route and numerous food and waterborne epidemics have been reported. Direct person-to-person spread has also been documented.

Clinical manifestations

Diarrhoea and abdominal pain are the two dominant symptoms resulting from Y. enterocolitica infection, but the clinical manifestations tend to vary according to age. The incidence of bloody diarrhoea in reported series is higher in children and less commonly seen in adults. The illness is self-limiting and usually last less than 2 weeks.

In older children and adults, the diarrhoea may be associated with right iliac fossa pain due to an infective ileitis. These symptoms may be clinically indistinguishable from acute appendicitis or Crohn’s disease.

Infrequently, a more severe illness may result with enterocolitis, septicaemia and extraintestinal infective complications, such as meningitis or abscesses in bones, joints or sinuses. This is more likely to occur in immunosuppressed individuals or those with iron-overload states (e.g. haemochromatosis or haemolytic diseases) who seem particularly predisposed to infection with Y. enterocolitica.

Postinfective sequelae of Y. enterocolitica include reactive arthritis, Reiter’s syndrome, pericarditis, erythema nodosum, erythema multiforme, glomerulonephritis and thyroiditis.

Diagnosis

The diagnosis is established by culture of the organism, usually in the stool. It may also be cultured from atypical cases at surgery from lymph nodes or from free peritoneal fluid. Serological tests are also available, but their sensitivity and specificity are serotype-dependent, can cross-react with other bacteria and other inflammatory conditions and their titre can fluctuate in individuals with chronic sequelae.

Treatment

The illness is usually self-limiting and symptomatic treatment without antibiotics is all that is needed. Antibiotics should be administered to those with septicaemia or extraintestinal abscesses and those predisposed to Y. enterocolitica infection. Quinolones, trimethoprim-sulfamethoxazole and tetracyclines are usually effective.

Escherichia coli

E. coli is a common inhabitant of the gastrointestinal tract in humans, where it may be present either as a commensal or as a pathogen. There are currently five recognisable categories of E. coli that cause diarrhoea, each with distinct clinical and epidemiological features: enterotoxigenic E. coli (ETEC), enteropathogenic E. coli (EPEC), enteroinvasive E. coli (EIEC) enterohaemorrhagic E. coli (EHEC), and enteroaggregative E. coli (EAEC). Further categories may emerge in the future.

Clinical manifestations

ETEC is a common cause of diarrhoea in children in the developing world and it is also a leading cause of travellers’ diarrhoea. Transmission is usually by contaminated food or water, with direct person-to-person spread being uncommon.

ETEC adheres to gut mucosa and produces several enterotoxins, one of which is very similar to the cholera toxin. The clinical syndrome that results consists of watery diarrhoea, cramping abdominal pain and nausea. The illness is usually mild with 5–6 loose stools per day and lasts 3–5 days. Les frequently, a cholera-like illness with profuse watery diarrhoea and dehydration may occur. Natural immunity to ETEC after infection has been documented.

EPEC is a cause of diarrhoea usually in infants and young children. The clinical illness consists of watery diarrhoea, which may occasionally follow a prolonged course. Vomiting, fever and failure to thrive may also occur. It lacks invasive and toxin-producing properties with pathogenicity apparently related to its enteroadhesive properties.

EIEC has the capacity to invade intestinal mucosa causing diarrhoea that often contains blood and mucus. Constitutional symptoms with fever, myalgia and general malaise are common. The illness usually last for 3–4 days, but may persist for up to 2 weeks.

EHEC causes haemorrhagic colitis with bloody diarrhoea after an incubation period of 3–4 days. Outbreaks from restaurants and nursing homes have been reported. EHEC does not invade the intestinal mucosa but produces several toxins, one of which is very similar to the Shigella toxin.

Complications of infection with EHEC (e.g. subtype 0157:H7) include the haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura and toxic megacolon. The haemolytic uraemic syndrome occurs most often in children where the incidence ranges from 5–10%, In this syndrome, there is haemolytic anaemia, thrombocytopenia and fibrin occlusion of small renal vessels, which causes renal failure.

Diffusely adhering EAEC produces mild symptoms in some volunteers given this strain of E. coli. It may play a more significant role in children and further studies are needed.

Diagnosis

DNA probes are the ‘gold standard’ for detecting various pathogenic E. coli, but are not widely available, except in research laboratories. Patients with persistent bloody diarrhoea should have a sigmoidoscopy or colonoscopy and other infective and non-infective causes of colitis excluded.

Treatment

Mild illness resulting from pathogenic E. coli does not require any specific therapy beyond maintenance of hydration. The use of antibiotics in the treatment of enterohaemorrhagic E. coli infection remains controversial because of the potential risk that the incidence of haemolytic uraemic syndrome may be increased. The management of travellers’ diarrhoea is discussed elsewhere.

Entamoeba histolytica

Occurrence and transmission

E. histolytica is a protozoan parasite that exists as an invasive trophozoite and as an infective cyst. It resides in the large intestine where asymptomatic colonisation is usual, but it has the potential to become invasive, resulting in colitis or spreading to involve the liver and, rarely, other organs.

There is a worldwide distribution of E. histolytica with a prevalence ranging from 1% in industrialised nations up to 50% in some developing nations. The cystic form can survive in the environment and is responsible for spread of the disease via the faecal–oral route. Direct person-to-person transmission is usual, but food- and waterborne spread can occur. Several other species of amoebae, including E. dispar, reside in the lumen of the large intestine and are non-pathogenic but need to be distinguished from E. histolytica.

Clinical manifestations

The motile trophozoites live in the lumen of the large intestine where they require either bacteria or tissue substrates for survival. Factors responsible for triggering invasion are incompletely understood, but include the strain of E. histolytica, intestinal factors such as the nature of bacteria within the colon, and host resistance. Host factors that increase susceptibility to invasion include extremes of age, malnutrition, pregnancy and immunosuppressive states, including AIDS.

Symptoms following invasion vary from mild diarrhoea through to fulminating amoebic dysentery. A majority of patients develop a diarrhoeal illness lasting 3–4 weeks. The stools frequently contain blood and pus and most attacks resolve spontaneously or with treatment, but chronic amoebiasis or fulminating disease may result. The latter is characterised by a high fever, profuse diarrhoea with bleeding, and abdominal pain and tenderness.

Complications of amoebic infection include perforation, strictures, amoeboma and involvement of extraintestinal sites, usually the liver.

A liver abscess may occur during the acute attack or present weeks to months later. It may also complicate asymptomatic infections and be present in patients with no history of preceding diarrhoea. Fever, malaise and right upper quadrant pain are the common manifestations. The onset may be abrupt or insidious.

Diagnosis

The diagnosis of intestinal amoebiasis may be made by the identification of cysts or trophozoites in the stool or in the colonic biopsies. However, microscopic identification of the organism does not differentiate between pathogenic and non-pathogenic species of Entamoeba, which can be done by faecal and serum antigen testing. E. histolytica but not E. dispar results in the formation of detectable antibodies within 5–7 days of infection; these persist for years and hence do not distinguish acute from chronic infection. Sigmoidoscopy or colonoscopy may detect cysts or trohozoites at the edge of ulcers. The colonic lesions could be non-specific thickening or classic flask-shaped ulcers.

The diagnosis of liver abscess depends on imaging and serological tests as amoebae are seldom demonstrated either in intestinal cultures or from abscess aspirate. The indirect haemagglutination assay is positive in up to 99% of patients with amoebic liver abscess, although the test may be negative early in the course of the illness.

Treatment

Metronidazole is the drug of choice for intestinal amoebiasis as well as amoebic liver abscess. A prolonged course may be necessary as encysted organisms can survive in the intestine and can be followed by asymptomatic passage of cysts over a long period of time. Elimination of luminal cysts requires a second agent such as diloxande furoate, paromomycin or diodohydroxyquin.

Antibiotic-associated Diarrhoea and C. difficle Colitis

Introduction

Antibiotics can cause diarrhoea through a variety of mechanisms, including an osmotic diarrhoea due to an impairment of colonic fermentation of unabsorbed carbohydrates as well as toxin-producing C. difficile infection. Of those infected with C. difficile, less than half will develop a diarrhoeal illness.

Occurrence and transmission

C. difficile becomes established in the large bowel, usually after the normal flora of the colon have been changed by antibiotics. Hospital acquisition of infection is common, as the two conditions for colonisation (antibiotic therapy and environmental contamination) often occur together. C. difficile forms heat-resistant spores, which act as a source of recurrent infection.

Clinical manifestations

Exposure to C. difficile results in a spectrum of illness ranging from asymptomatic carriage to severe pseudomembranous colitis. More than 50% of healthy neonates are asymptomatic carriers and the majority of hospital inpatients exposed to C. difficile are asymptomatic.

Those who develop symptoms usually do so during or shortly after antibiotic therapy. The illness begins as diarrhoea with cramping abdominal pain. A low-grade fever may be present together with lower abdominal tenderness. A small proportion of patients progress to colitis, which may become life-threatening, with severe bloody diarrhoea, diffuse abdominal tenderness and abdominal distension. Fulminating colitis with toxic megacolon has been reported.

Diagnosis

The diagnosis is made by demonstrating the specific cytotoxin in the stool. Cytotoxin assay and culture of C. difficile must be specifically requested and a careful history of preceding antibiotic usage taken. The toxin is demonstrated by tissue culture assay and is neutralised by a specific C. difficile antitoxin. Cytotoxicity assay have been the gold standard for long time but are expensive and time-consuming. They are highly sensitive in detecting as little as 10 g of toxin B.

Enzyme immunoassay is the practical mode of testing in most hospitals and it is important to test for both toxins A and B since some strains have mutations in toxin A and others produce only toxin B. It is a rapid test with a good specificity but with a variable sensitivity of 60–95%. The higher false negative rate is because it requires 100 to 1000 μg of toxin.

Anaerobic culture is less frequently used, but is extremely sensitive. It does not distinguish between toxin-producing and non-toxin-producing strains.

The polymerase chain reaction test targets a region of the toxin B gene and is highly sensitive and specific.

Sigmoidoscopy or colonoscopy may document the typical raised white plaques of pseudomembranous colitis. Although characteristic, these are uncommon, except in those with more severe symptoms. A diffuse or patchy colitis may be present and biopsy may reveal non-specific colitis ore even pseudomembranous colitis in the absence of plaques. Patchy colitis beyond the reach of the flexible sigmoidoscope has been reported. In fulminant colitis colonoscopy can be hazardous.

Treatment

Antibiotic therapy should be discontinued where possible. If symptoms are severe, or mild symptoms fail to settle spontaneously, therapy with oral metronidazole or oral vancomycin is indicated. Vancomycin is expensive and to prevent the risk of development of resistant organisms such as enterococci it should be reserved for very ill patients or those who fail to respond to metronidazole. Parenteral metronidazole diffuses from the serum and interstitial fluid into the colon and hence can be used via this route in fulminant disease. Other useful drugs are rifaximin, rifampicin, teicoplannin, fusidic acid, nitazoxanide and baxitracin.

Anion-binding agents like colestipol and cholestyramine are not effective as primary therapy, but can be used as an adjunct. Tolevamer is a newer toxin-binding resin. Resins can bind antibiotics and hence must be taken a few hours apart from the antibiotics. Intravenous immunoglobin and faecal bacterotherapy have also been tried.

Patients with fulminant colitis may need a combination of parenteral metronidazole and oral vancomycin. In the event of fulminant disease with severe ileus, toxic megacolon or signs of peritonitis a subtotal colectomy may be required.

Symptomatic recurrence can occur in 15–30% of patients. Some of these are reinfections while others are true recurrences. These are initially treated with conventional approaches, but pulsed and tapered courses of vancomycin can be used; the principle is to allow spores to germinate so that antibiotics can be effective, as well to allow the normal colonic flora that is protective to recover.

Cryptosporidiosis

Occurrence and transmission

Cryptosporidium parvum is a protozoan parasite that causes diarrhoea in both normal and immunocompromised populations. Orofaecal transmission occurs from contaminated water and food and large epidemics have been reported. Direct person-to-person spread is also common. It has been estimated that C. parvum is responsible for 5–10% of infectious diarrhoea in developing countries and 1–3% of cases in the developed world.

Clinical manifestations

Profuse watery diarrhoea with abdominal pain and nausea is the usual presentation. Vomiting may occur and a low-grade fever is common. The illness usually abates after 1–2 weeks, although in some individuals voluminous diarrhoea and weight loss may persist.

In immunocompromised individuals, chronic diarrhoea is common and this is usually indolent, but may be devastating with profound fluid loss.

Diagnosis

Cryptosporidium parvum oocysts may be identified in stool samples with appropriate concentration and staining techniques. Organisms can also be demonstrated at the luminal surface by duodenal or colon biopsies. Enzyme immunoassay kits are available and are highly sensitive and specific.

Treatment

No effective treatment is available. A variety of antibiotics have been trialled with little persistent effect noted. Immune reconstitution in immunocompromised individuals is the most effective treatment available.

Diarrhoea Associated with AIDS

Diarrhoea is a common gastrointestinal symptom in AIDS with a frequency ranging from 30% to 90%, depending on the stage of the illness and environmental factors. The host immunodeficiency results in persisting infection and frequent reinfection. In addition, severe illness with septicaemia and infections with organisms not usually pathogenic are common. Malnutrition may result from associated malabsorption or a chronic diarrhoea illness with anorexia. The presence of chronic diarrhoea influences quality of life as well as morbidity and mortality.

Aetiology

Potential pathogens involved in AIDS diarrhoea are listed in Table 13.2 and vary with the stage of the illness and degree of immunocompetence of the host. Some patients with AIDS develop diarrhoea without any detectable pathogens and non-infectious causes of diarrhoea, including drugs, pancreatic insufficiency and tumour invasion, may be involved. The AIDS virus itself and small bowel bacterial overgrowth may also be responsible for diarrhoea in some patients.

Table 13.1 Aetiology of travellers’ diarrhoea

Source	Rate (%)
Escherichia coli	50
Shigella spp.	10
Salmonella spp.	5
Campylobacter jejuni	3
Yersinia enterocolitica	2
Entamoeba histolytica	1
Giardia lamblia	4
Cryptosporidium parvum	3
Viruses	3
Unknown	19

Table 13.2 Pathogens associated with AIDS diarrhoea

Bacterium	Virus	Protozoan
Myocobacterium avium–intracellulare (MAI)	Cytomegalovirus	Cryptosporidium parvum
Salmonella spp.	Herpes simplex virus	Giardia lamblia
Shigella spp.	Adenovirus	Isospora belli
Campylobacter jejuni		Entamoeba histolytica
Clostridium difficile		Microsporidium spp.