Etiology
Acute diarrhea can be classified based on pathophysiology or etiology.[13]
Pathophysiologic classification of diarrhea
A commonly used pathophysiologic classification divides diarrhea into two categories.
Inflammatory diarrhea
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 ischemia, radiation injury, or inflammatory bowel disease.
It is usually associated with mucoid and bloody stool, tenesmus, fever, and severe crampy abdominal pain.
Infectious inflammatory diarrhea 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 diarrhea 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 centers. Protozoa and parasites are common causes of acute diarrhea in developing countries.
Examination of the stool may show leukocytes, and tests for fecal occult blood may be positive. The test for fecal 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 diarrhea.
Noninflammatory diarrhea
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 fecal leukocytes.
Histologically the GI architecture is preserved.
Noninflammatory diarrhea can be subdivided into:
A) Secretory diarrhea
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 diarrhea 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: intestinal vaso-active peptide, small-cell cancer of the lung, and neuroblastoma.
Laxative use, intestinal resection, bile salts, and fatty acids.
It is also seen in chronic diarrhea with celiac sprue, collagenous colitis, hyperthyroidism, and carcinoid tumors.
B) Osmotic diarrhea
Stool volume is relatively small (compared with secretory diarrhea), and diarrhea 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 diarrhea) is always isosmotic (260 to 290 mOsml/L).
Osmotic diarrhea 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 ischemia, post bowel resection (short bowel syndrome), and in mucosal disease (celiac disease).
Etiologic classification of acute diarrhea
Diarrhea can be classified into two broad categories based on etiologic factors: infectious and noninfectious.
Infectious diarrhea
The most common cause of acute diarrhea worldwide is infection (viruses, bacteria, and parasites). Most are acquired through the fecal-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 diarrhea are positive in only 1.5% to 5.6% of patients.[14] However, bacterial infections are much more likely to be responsible for severe cases of diarrhea.
Bacterial infections
Escherichia coli: this is a more common cause of diarrhea in developing than in developed countries. It is the most common cause of infectious diarrhea leading to hospitalizations in developing countries.[15] 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 traveler's diarrhea (enterotoxigenic) and diarrhea in children and can also affect the colon (enteroinvasive and enterohemorrhagic, enteroaggregative E coli). It is complicated by dysentery in the enteroinvasive subtype. Enterohemorrhagic E coli (most notably E coli O157:H7) causes hemolytic uremic syndrome, with associated high mortality.[16] Some studies have suggested that use of antibiotics to treat E coli O157:H7 leads to a greater incidence of hemolytic uremic syndrome or mortality.[17][18] 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.[19][20]
Campylobacter: infection is generally acquired from undercooked contaminated poultry in developed countries. Campylobacter is one of the two most commonly documented foodborne diseases in the US (the other being salmonella).[21] Diarrhea 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.[22][23]
Salmonella: nontyphoidal salmonellosis is the joint leading cause of foodborne disease in the US and a common cause of diarrhea leading to outpatient care in developed countries.[21]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 diarrhea. Shigella continues to be a major problem in day care centers 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 hospitalized patients. C difficile colonizes 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. Leukemoid reaction and hypoalbuminemia, renal failure, and shock are seen in severe disease. Colectomy is necessary in severe cases. Diagnosis is by the detection of toxins A and B or B alone, cell cytotoxicity assay, or detection of toxigenic C difficile in the stool.[24]
Yersinia: infection is usually from eating pork meat or pig intestine. It causes acute or chronic colitis and can mimic Crohn disease or acute appendicitis.
Aeromonas: this is a common isolate in asymptomatic patients, but has been implicated as a cause of diarrhea, mainly traveler's diarrhea.[25]
Plesiomonas: this has been documented in outbreaks of diarrhea associated with contaminated water and oysters containing the microorganism.[26]
Listeria: is relatively rare; there are 0.1 to 10 cases of listeriosis per 1 million people per year, depending on the country/region.[27] It is usually transmitted by contaminated dairy or water. It can grow at refrigerator temperature.
Staphylococcus aureus: leads to vomiting, and in some instances diarrhea, within 4 to 8 hours following the ingestion of food contaminated with preformed toxin.
Bacillus cereus: heat-stable preformed toxins cause symptoms within 6 hours of ingestion. In rare cases, infection causes acute liver necrosis.[28]
Clostridium perfringens: causes watery diarrhea secondary to preformed 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 hemorrhagic necrosis of the jejunum.[29]
Vibrio cholerae: the hallmark of this infection is severe, toxin-induced, large-volume, nonbloody, secretory, dehydrating diarrhea. 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 ill patient. It is diagnosed by detecting the bacteria or choleratoxin in stool. It is a vaccine-preventable disease.[5][30]
Klebsiella oxytoca: this has been associated with some cases of C difficile-negative antibiotic-associated hemorrhagic colitis.[31]
Viral infections
Rotavirus: in the US, there are approximately 2.7 million children each year with rotavirus gastroenteritis, resulting in approximately 500,000 office visits, 50,000 hospitalizations, and 30 deaths.[32] It is the leading known cause of severe viral gastroenteritis in infants and young children worldwide. It is a vaccine-preventable disease.[33] It causes diarrhea 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 nonbacterial gastroenteritis in the US.[34] Surveillance studies of foodborne 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 diarrhea, especially in day care centers.
Astrovirus: this is responsible for 4% to 7% of diarrheas in day care centers and is a known cause of nosocomial disease in young children.[37][38] Astrovirus also causes illness in immunocompromised people and older institutionalized 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 diarrhea may be the only presenting symptom. COVID-19-associated diarrhea 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 amebiasis generally has a subacute onset, usually over 1 to 3 weeks. Symptoms range from mild diarrhea to severe dysentery, producing abdominal pain (12% to 80%), diarrhea (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 etiology of waterborne and foodborne diarrhea, day care center outbreaks, and diarrhea in international travelers 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 aging population.[44] The diarrhea 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 traveler's diarrhea in normal hosts. It is also associated with chronic diarrhea in immunosuppressed patients.
Cyclospora: this organism is a cause of prolonged traveler's diarrhea.[45] Infected patients may have a single self-limited 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 diarrhea.
Noninfectious diarrhea
Drugs: a number of drugs are associated with acute diarrhea. These include, but are not limited to, antacids containing magnesium, antiarrhythmics (e.g., quinidine), antibiotics (as a primary cause or by causing C difficile infection), antihypertensives (beta-blockers, hydrochlorothiazide), anti-inflammatories (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], gold salts), antineoplastic agents (including immune checkpoint inhibitors, which may lead to diarrhea and colitis), antiretroviral drug, acid-reducing agents (e.g., H2 antagonists, proton-pump inhibitors), colchicine, prostaglandin analogs (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 diarrhea.
Acute diarrhea can be seen as an initial presentation of chronic diarrhea such as seen in inflammatory bowel disease, bowel ischemia, and radiation injury.
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