Aetiology
Acute diarrhoea can be classified based on pathophysiology or aetiology.[14]
Pathophysiological classification of diarrhoea
A commonly used pathophysiological classification divides diarrhoea into two categories.
Inflammatory diarrhoea
This indicates the presence of an inflammatory process, which can be due to bacterial, viral, or parasitic infection, or may develop early in the course of bowel ischaemia, radiation injury, or inflammatory bowel disease.
It is usually associated with mucoid and bloody stool, tenesmus, fever, and severe crampy abdominal pain.
Infectious inflammatory diarrhoea is usually small in volume, with frequent bowel movements. It therefore does not usually result in volume depletion in adults, but may do so in children or older adults.
The most common cause of infectious diarrhoea in the US is bacterial infection: mainly Campylobacter, Salmonella, Shigella, Escherichia coli, or Clostridium difficile. Viruses are more common among children who attend day care centres. Protozoa and parasites are common causes of acute diarrhoea in developing countries.
Examination of the stool may show leukocytes, and tests for faecal occult blood may be positive. The test for faecal leukocytes is plagued by a high rate of false-negative results leading to low sensitivity, but a positive test is very informative.
Histology of the gastrointestinal (GI) tract is abnormal in inflammatory diarrhoea.
Non-inflammatory diarrhoea
This is usually watery, large-volume, frequent stool (>10 to 20 per day).
Volume depletion is possible due to high volume and frequency of bowel movements.
There is no tenesmus, blood in the stool, fever, or faecal leukocytes.
Histologically the GI architecture is preserved.
Non-inflammatory diarrhoea can be subdivided into:
A) Secretory diarrhoea
There is an altered transport of ions across the mucosa, which results in increased secretion and decreased absorption of fluids and electrolytes from the GI tract, especially in the small intestine. Secretory diarrhoea tends not to decrease by fasting. Examples of causes are:
Enterotoxins: these can be from infection such as Vibrio cholerae, Staphylococcus aureus, enterotoxigenic E coli, and possibly HIV and rotavirus.
Hormonal agents: vaso-active intestinal peptide, small-cell cancer of the lung, and neuroblastoma.
Laxative use, intestinal resection, bile salts, and fatty acids.
It is also seen in chronic diarrhoea with coeliac sprue, collagenous colitis, hyperthyroidism, and carcinoid tumours.
B) Osmotic diarrhoea
Stool volume is relatively small (compared with secretory diarrhoea), and diarrhoea improves or stops with fasting. It results from the presence of unabsorbed or poorly absorbed solute (magnesium, sorbitol, and mannitol) in the intestinal tract that causes an increased secretion of liquids into the gut lumen. Measuring stool electrolytes shows an increased osmotic gap (>50), but the test has very limited practical value. Stool (normal or diarrhoea) is always isosmotic (260 to 290 mOsml/L).
Osmotic diarrhoea can be subdivided into:
Maldigestion - refers to impaired digestion of nutrients within the intestinal lumen or at the brush border membrane of mucosal epithelial cells. It can be seen in pancreatic exocrine insufficiency and lactase deficiency.
Malabsorption - refers to impaired absorption of nutrients. It can be seen in small bowel bacterial overgrowth, in mesenteric ischaemia, post bowel resection (short bowel syndrome), and in mucosal disease (coeliac disease).
Aetiological classification of acute diarrhoea
Diarrhoea can be classified into two broad categories based on aetiological factors: infectious and non-infectious.
Infectious diarrhoea
The most common cause of acute diarrhoea worldwide is infection (viruses, bacteria, and parasites). Most are acquired through the faecal-oral route, from contaminated water or food. Most infections are self-limiting or treated easily. Specific investigations are warranted when resources are available in moderate to severe disease, or if there is a public health risk such as high risk for spreading disease to others.[2] Worldwide, most cases of acute infectious gastroenteritis are viral, as indicated by the observation that bacterial stool cultures in patients with acute diarrhoea are positive in only 1.5% to 5.6% of patients.[15] However, bacterial infections are much more likely to be responsible for severe cases of diarrhoea.
Bacterial infections
Escherichia coli: this is a more common cause of diarrhoea in developing than in developed countries. It is the most common cause of infectious diarrhoea leading to hospitalisations in developing countries.[16] It usually occurs in epidemics in the summer season. Sources of infection include: beef, pork, fast food restaurants (undercooked hamburger), apple cider, leaf lettuce, milk, cheese, spinach, and sprouts. It is most common in very young or old people and can affect the small intestine (enterotoxigenic and enteropathogenic E coli). It is a common cause of traveller's diarrhoea (enterotoxigenic) and diarrhoea in children and can also affect the colon (enteroinvasive and enterohaemorrhagic, enteroaggregative E coli). It is complicated by dysentery in the enteroinvasive subtype. Enterohaemorrhagic E coli (most notably E coli O157:H7) causes haemolytic uraemic syndrome with associated high mortality.[17] Some studies have suggested that use of antibiotics to treat E coli O157:H7 leads to a greater incidence of haemolytic uraemic syndrome or mortality.[18][19] However, this finding is not consistent through the few trials, and overall there is no clear evidence as to whether antibiotics are beneficial or detrimental.[20][21]
Campylobacter: infection is generally acquired from undercooked contaminated poultry in developed countries.[22]Campylobacter is one of the two most commonly documented foodborne diseases in the US (the other being salmonella). Diarrhoea can be watery or bloody and is frequently associated with crampy abdominal pain. It has been linked to serious complications such as reactive arthritis and Guillain-Barre syndrome.[23][24]
Salmonella: non-typhoidal salmonellosis is the joint leading cause of food-borne disease and a common cause of diarrhoea leading to outpatient care in developed countries.[22]Salmonella is most commonly associated with ingestion of poultry, eggs, and milk products. The patient can become an asymptomatic carrier.
Shigella: this is the classic cause of colonic or dysenteric diarrhoea. Shigella continues to be a major problem in day care centres and institutional settings. It presents with bloody stools, fever, abdominal cramps, and tenesmus.
Clostridioides difficile: this is one of the most common hospital-acquired (nosocomial) infections and is a frequent cause of morbidity and mortality among older hospitalised patients. C difficile colonises the human intestinal tract and after the normal microbiota has been altered by antibiotic therapy it can lead to pseudomembranous colitis. Recurrent disease is common and thought to be due to altered host immunity. C difficile produces toxins, which are implicated in the disease. Leukaemoid reaction and hypoalbuminaemia, renal failure, and shock are seen in severe disease. Colectomy is necessary in severe cases. Diagnosis is by detection of toxins A and B or B alone, cell cytotoxicity assay, or detection of toxigenic C difficile in the stool.[25]
Yersinia: infection is usually from eating pork meat or pig intestine. It causes acute or chronic colitis and can mimic Crohn's disease or acute appendicitis.
Aeromonas: this is a common isolate in asymptomatic patients, but has been implicated as a cause of diarrhoea, mainly traveller's diarrhoea.[26]
Plesiomonas: this has been documented in outbreaks of diarrhoea associated with contaminated water and oysters containing the micro-organism.[27]
Listeria: is relatively rare; there are 0.1 to 10 cases of listeriosis per 1 million people per year, depending on the country/region.[28] It is usually transmitted by contaminated dairy or water. It can grow at refrigerator temperature.
Staphylococcus aureus: leads to vomiting, and in some instances diarrhoea, within 4 to 8 hours following the ingestion of food contaminated with pre-formed toxin.
Bacillus cereus: heat-stable pre-formed toxins cause symptoms within 6 hours of ingestion. In rare cases, infection causes acute liver necrosis.[29]
Clostridium perfringens: causes watery diarrhoea secondary to pre-formed toxins. Ingestion of C perfringens spores is usually from the consumption of poultry, meat, and gravy. It can rarely result in a serious complication, enteritis necroticans, a haemorrhagic necrosis of the jejunum.[30]
Vibrio cholerae: the hallmark of this infection is severe, toxin-induced, large-volume, non-bloody, secretory, dehydrating diarrhoea. It can be asymptomatic; present as mild disease indistinguishable from gastroenteritis; or present as severe disease (cholera gravis) in which a healthy individual can deteriorate quickly to a gravely unwell patient. It is diagnosed by detecting the bacteria or choleratoxin in stool. It is a vaccine-preventable disease.[5][31]
Klebsiella oxytoca: this has been associated with some cases of C difficile-negative antibiotic-associated haemorrhagic colitis.[32]
Viral infections
Rotavirus: the leading known cause of severe viral gastroenteritis in infants and young children worldwide. It is a vaccine-preventable disease.[33] It causes diarrhoea that results in volume depletion in children and young adults. This infection peaks during cooler weather.
Norovirus: this is a major cause in epidemic viral gastroenteritis. Noroviruses are the most common cause of outbreaks of non-bacterial gastroenteritis in the US.[34] Surveillance studies of food-borne diseases show that two-thirds of all food-related illnesses are due to noroviruses.[35] It is becoming the leading cause of medically attended acute gastroenteritis in countries with high rotavirus vaccine coverage.[36]
Adenovirus: enteric adenovirus is second to rotavirus in causing diarrhoea, especially in day care centres.
Astrovirus: responsible for 4% to 7% of diarrhoeas in day care centres, and is a known cause of nosocomial disease in young children.[37][38] Astrovirus also causes illness in immunocompromised people and older institutionalised patients.[39] Unlike norovirus, astrovirus is an uncommon cause of epidemic gastroenteritis.
COVID-19 (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) infection: gastrointestinal symptoms are common in COVID-19 infection and diarrhoea may be the only presenting symptom. COVID-19-associated diarrhoea may be severe, but it is usually mild and self-limiting.[40]
Parasites/protozoa infections
Entamoeba histolytica: worldwide, approximately 40 to 50 million people develop colitis or extraintestinal disease annually, with 40,000 deaths.[41] It is commonly asymptomatic. Clinical amoebiasis generally has a subacute onset, usually over 1 to 3 weeks. Symptoms range from mild diarrhoea to severe dysentery, producing abdominal pain (12% to 80%), diarrhoea (94% to 100%), and bloody stools (94% to 100%). Weight loss is present in just under 50% of patients.[42] Fever is also seen.
Giardia lamblia: causes both epidemic and sporadic disease, and is an important aetiology of water-borne and food-borne diarrhoea, day care centre outbreaks, and diarrhoea in international travellers and adoptees.[43] It is seen more commonly in patients with immunoglobulin A deficiency. Diagnosis is by stool Giardia antigen test (higher sensitivity than stool ova and parasite).
Cryptosporidium: has been known since 1976, but has become more prevalent with the increased prevalence of HIV/AIDS, with the increase in transplants and need for immunosuppression, and with an ageing population.[44] The diarrhoea may be acute or chronic; transient, intermittent, or continuous; and scant or voluminous with up to 25 L/day of watery stool.
Microsporidiosis: this is a less well known cause of traveller's diarrhoea in normal hosts. It is also associated with chronic diarrhoea in immunosuppressed patients.
Cyclospora: this organism is a cause of prolonged traveller's diarrhoea.[45] Infected patients may have a single self-limiting episode, but a prolonged waxing and waning course of GI symptoms lasting for weeks or months is common.[46]
Helminthic parasites (worms) (except Strongyloides in immunocompromised hosts) rarely cause diarrhoea.
Non-infectious diarrhoea
Drugs: a number of drugs are associated with acute diarrhoea. These include, but are not limited to, antacids containing magnesium, anti-arrhythmics (e.g., quinidine), antibiotics (as a primary cause or by causing C difficile infection), anti-hypertensives (beta-blockers, hydrochlorothiazide), anti-inflammatories (e.g., non-steroidal anti-inflammatory drugs [NSAIDs], gold salts), antineoplastic agents (including immune checkpoint inhibitors, which may lead to diarrhoea and colitis), antiretroviral drug, acid-reducing agents (e.g., H2 antagonists, proton-pump inhibitors), colchicine, prostaglandin analogues (e.g., misoprostol), theophylline, vitamins and mineral supplements, herbal drugs, heavy metals, and overuse of drugs for constipation.[47][48] The mechanism differs between drug classes. Most of these drugs are thought to cause secretory diarrhoea.
Acute diarrhoea can be seen as an initial presentation of chronic diarrhoea, such as seen in inflammatory bowel disease, bowel ischaemia, and radiation injury.
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