Diarrhea

Etiology

Diarrhea is categorized into acute or chronic and infectious or non-infectious based on the duration and type of symptoms. Acute diarrhea is defined as an episode lasting less than 2 weeks. Infection most commonly causes acute diarrhea. Most cases result from a viral infection, and the course is self-limited. Chronic diarrhea is defined as a duration lasting longer than 2 weeks and tends to be non-infectious. Common causes include malabsorption, inflammatory bowel disease, and medication side effects.[3] Following are some important considerations to be made while diagnosing and managing diarrhea, as the identification of the etiological agent is very important:

• Stool characteristics vary between different causes, such as consistency, color, volume, and frequency
• The presence or absence of associated intestinal symptoms, such as nausea/vomiting, fever, and abdominal pain
• Exposure to child daycare where commonly encountered pathogens are rotavirus, astrovirus, calicivirus; Shigella, Campylobacter, Giardia, and Cryptosporidium species
• History of the ingestion of infected food, such as raw or contaminated foods
• History of water exposure from swimming pools, camping, or marine environment
• Travel history is crucial as common pathogens affect certain regions; enterotoxigenic Escherichia coli is the predominant pathogen [4]
• Animal exposure has been historically linked with diarrhea, such as young dogs/cats: Campylobacter; turtles: salmonella [5]
• Predisposing factors such as hospitalization, antibiotic use, immunosuppression [6]

Epidemiology

Norovirus is associated with approximately one-fifth of all infectious diarrhea cases, with similar prevalence in children and adults. It is estimated to cause over 200,000 deaths annually in developing countries.[7] Historically, rotavirus was the most common cause of severe disease in young children globally. Rotavirus vaccination programs have decreased the prevalence of diarrhea cases associated with rotavirus.

In developing regions, an average of 3 episodes of diarrhea per child per year is reported in children less than 5 years old. However, certain other areas report 6 to 8 episodes per year per child. In these circumstances, malnutrition plays an additional role in the development of diarrhea.[8]

A common cause of chronic diarrhea includes inflammatory bowel disease, Crohn disease, and ulcerative colitis. In Europe, the incidence of ulcerative colitis and Crohn disease has increased overall from 6.0 per 100,000 person-years in ulcerative colitis and 1.0 per 100,000 person-years in Crohn disease in 1962 to 9.8 per 100,000 person-years and 6.3 per 100,000 person-years in 2010, respectively.[9]

A study conducted by Lübbert et al observed the occurrence of Clostridium difficile-related infection in Germany to be 83 cases/100,000 population in 2012. The chance of recurrence escalated with each relapse in these cases.[10]

In the United States, before specific antirotavirus immunization was introduced in 2006, a cumulative occurrence of 1 hospitalization for the cases of diarrhea per 23-27 children by the age of 5 years was noted. Moreover, over 50,000 hospitalizations were noted. Based on these facts, rotavirus was found to be responsible for 4-5% of all childhood hospitalizations, costing nearly 1 billion US dollars.[11]

Pathophysiology

Diarrhea results from reduced water absorption by the bowel or increased water secretion. Most acute diarrheal cases have an infectious etiology. Chronic diarrhea is commonly categorized into 3 groups: watery, fatty (malabsorption), or infectious. Another way of classifying the pathophysiology of diarrhea is into secretory and osmotic forms.

Lactose intolerance causes watery diarrhea, which causes increased water secretion into the intestinal lumen.[12] Patients typically have symptoms of bloating and flatulence along with watery diarrhea. The enzyme lactase breaks down lactose in the intestine. The byproducts are readily absorbed by the epithelial cells. When lactase is decreased or absent, lactose cannot be absorbed and remains in the gut lumen. Lactose is osmotically active, and it retains and attracts water, leading to watery diarrhea.

Common causes of fatty diarrhea include celiac disease and chronic pancreatitis. The pancreas releases enzymes that are necessary for the breakdown of food. Enzymes are released from the pancreas and aid in the digestion of fats, carbohydrates, and proteins. Once broken down, the products are available for uptake in the gut. Patients with chronic pancreatitis have insufficient enzyme release, leading to malabsorption. Symptoms often include upper abdominal pain, flatulence, and foul-smelling, bulky, pale stools due to malabsorption of fats.[12]

In the secretory form of diarrhea, bacterial and viral infections are the common causes. In this instance, the watery stool results from injury to the gut epithelium. Epithelial cells line the intestinal tract and facilitate water absorption, electrolytes, and other solutes. Infectious etiologies cause damage to the epithelial cells, which leads to increased intestinal permeability. The damaged epithelial cells cannot absorb water from the intestinal lumen, leading to loose stool.

History and Physical

In developed regions, acute diarrhea is almost always a benign, self-resolving condition that subsides in a few days. The duration of illness and clinical presentation vary depending on the etiology of diarrhea and the host factors. For instance, rotavirus diarrhea commonly presents with vomiting, dehydration, and more workdays lost than nonrotavirus diarrhea.

Knowledge of certain diarrhea-associated factors, such as volume, consistency, color, and frequency, helps distinguish the source. The following table outlines these characteristics that can be utilized to narrow down the list of differential diagnoses:

Daycare centers are also responsible for certain causes of diarrhea:[13]

• Certain pathogens spread quickly in daycare. These include rotavirus, astrovirus; calicivirus, and Shigella, Giardia, Campylobacter, and Cryptosporidium

• The increasing trend of daycare usage has increased the occurrence of rotavirus and Cryptosporidium-related infections.[14]

As various foods can lead to gastrointestinal infections, food history is important:

• Consumption of raw or contaminated food items is commonly associated with infectious diarrhea.

• Organisms that are commonly found associated with infectious diarrhea include the following:

  • Dairy products - Campylobacter and Salmonella species[15]

  • Eggs - Salmonella species

  • Meats - Clostridium perfringens, Campylobacter, Aeromonas, and Salmonella species

  • Poultry - Campylobacter species

  • Ground beef - Enterohemorrhagic E coli[16]

  • Seafood - Astrovirus, Aeromonas, Plesiomonas, and Vibrio species

  • Pork - C perfringens, Y enterocolitica[17]

  • Oysters - Calicivirus, Plesiomonas, and Vibrio species

  • Vegetables - Aeromonas species and C perfringens

  • The American Academy of Pediatrics advises that when evaluating children with persistent diarrhea, excessive flatulence, bloating, and abdominal pain, the provider should determine the quantity of juice consumed.[18]

Swimming pools harbor Shigella species, and Aeromonas organisms are causative agents of infectious diarrhea in the marine environment. 

Giardia, Cryptosporidium, and Entamoeba stay unaffected by water chlorination; therefore, suspicion for these parasites should be high in contaminated water. Also, there is an association between Campylobacter infection, agriculture, and drinking water.[19]

Travel history is important as it may direct towards the underlying causative agent of infectious diarrhea. Enterotoxigenic E coli is by far the leading cause of traveler's diarrhea. Following are some common associations between certain areas and causative pathogens:

Evaluation

A patient with acute diarrhea typically has a self-limited course and is not require labs or imaging. A stool culture is warranted in a patient with bloody diarrhea or severe illness to rule out bacterial causes. Bloody stools require additional testing for Shiga toxin and lactoferrin. A recent antibiotic or hospitalization patient requires testing for Clostridium difficile infection. Imaging is not ordered routinely in a patient with acute diarrhea. However, an abdominal CT may be required when a patient presents with significant peritoneal signs.

A thorough history is important to determine what labs and imaging need to be ordered to distinguish the cause of chronic diarrhea.[20] Basic lab work for a patient with chronic diarrhea includes a complete blood count, basic metabolic panel, stimulating thyroid hormone, erythrocyte sedimentation rate, liver panel, and a stool analysis. The physician should categorize the type of chronic diarrhea as either watery, fatty, or inflammatory based on the patient’s history and physical exam. Once a probable diagnosis is determined, additional labs and testing specific to the suspected etiology should be ordered.

A stool pH under 5.5 or an abundance of reducing substances in diarrhea signifies carbohydrate intolerance, usually secondary to viral illnesses.[21] It is transient. Enteroinvasive infections affecting the large bowel cause neutrophils and other leucocytes to be shed into the stool. The presence of leukocytes in stools eliminates the possibility of enterotoxigenic E coli, Vibrio, and viruses.

If the stool sample can not be cultured within 2 hours of specimen collection, it should be refrigerated at 4°C or placed in a transport medium. The yield of stool cultures is low; however, it is helpful when the culture is positive. Stool should always be cultured for Salmonella, Shigella, Campylobacter, C Difficile, and Yersinia enterocolitica if there are signs of colitis or fecal leucocytosis.[22]

Looking for Clostridium difficile is advisable in the presence of colitis or blood in stools. An important note is that acute-onset diarrhea secondary to C difficile infection may occur with no antibiotic use history. In diarrheal cases with a history of ground beef ingestion and enterohemorrhagic E coli present in the stool, one should determine the type of E coli. Hemolytic uremic syndrome can result from infection with E coli O157:H7.[23]

Rotavirus antigen is tested by enzyme immunoassay and latex agglutination of the stool. Enzyme immunoassay can also be used to detect adenovirus antigens. The best way to find parasites is to examine the stool for ova and parasites. The stool examination should be performed every 3 days or on alternate days.

Treatment / Management

An important aspect of diarrhea management is replenishing fluid and electrolyte loss.[24] Patients should be encouraged to drink diluted fruit juice, Pedialyte, or Gatorade. In more severe cases of diarrhea, IV fluid rehydration may become necessary.[25] Eating foods that are lower in fiber may aid in making stool firmer. A bland 'BRAT' diet, including bananas, toast, oatmeal, white rice, applesauce, and soup/broth, is well tolerated and may improve symptoms.[26] Anti-diarrheal therapy with anti-secretory or anti-motility agents may be started to reduce the frequency of stools. However, they should be avoided in adults with bloody diarrhea or high fever because they can worsen severe intestinal infections. Empiric antibiotic therapy with an oral fluoroquinolone can be considered in patients with more severe symptoms. Probiotic supplementation has been shown to reduce the severity and duration of symptoms and should be encouraged in patients with acute diarrhea.

The treatment of chronic diarrhea is specific to its etiology.[28] The first step is categorizing diarrhea as watery, fatty, or inflammatory. Once categorized, an algorithm can be used to determine the next step in management. Most cases require additional fecal studies, lab work, or imaging. More invasive procedures like colonoscopy or upper endoscopy may be required.

In 2003, the recommendations were put forward by the Center for Disease Control (CDC) for treating acute diarrhea in children on both an outpatient and inpatient basis, including indications for referral.[27](A1)

Indications for referral and further medical evaluation of children include the following:

• Under 3 months old
• Weighs less than 8 kg (17.6 lbs)
• History of premature birth, chronic illnesses, or concurrent medical conditions
• Fever of 38ºC (100.4 F) or higher in children less than 3 months old or 39ºC (102.2 F) or higher in children between 3 and 36 months of age
• Grossly bloody stool
• High-output diarrhea
• Persistent vomiting
• Signs of dehydration, such as sunken eyes, decreased tear film, dry mucous membranes, and oliguria/anuria
• Mental status alterations
• Inadequate response to oral rehydration or the caregiver's inability to administer oral rehydration

Treatment of dehydration is summarized in the following table:

Therapies advised for some nonviral causes of diarrhea include the following:

• E coli - Trimethoprim-sulfamethoxazole (TMP-SMX). Parenteral second or third-generation cephalosporins are indicated for systemic complications.
• Aeromonas species - Third-generation and fourth-generation cephalosporins (cefixime).
• Campylobacter species - Erythromycin
• C difficile - Discontinue causative antibiotics. Use oral metronidazole or vancomycin. Vancomycin is reserved for a child who is seriously ill.
• C perfringens - Antibiotics are not recommended for treatment.
• Cryptosporidium parvum - paromomycin and nitazoxanide.
• Entamoeba histolytica - Metronidazole followed by paromomycin or iodoquinol.
• G lamblia - Metronidazole or nitazoxanide.
• Plesiomonas species - TMP-SMX or any other cephalosporin.
• Salmonella species—Treatment prolongs carrier state. TMP-SMX is the first-line medication, but resistance exists. For invasive disease, use ceftriaxone and cefotaxime.
• Shigella species - Treatment shortens illness duration. TMP-SMX is the first-line medication, but there is resistance. Cefixime, ceftriaxone, and cefotaxime are recommended for invasive diseases.
• V cholerae - Doxycycline is the first-line, and erythromycin is the second-line antibiotic.
• Yersinia species: TMP-SMX, cefixime, cefotaxime, and ceftriaxone are used.

Differential Diagnosis

The following are the differentials that need to be considered when dealing with a patient with diarrhea:

• Appendicitis
• Carcinoid tumor
• Giardiasis
• Glucose-galactose malabsorption
• Intestinal enterokinase deficiency
• Intussusception
• Meckel diverticulum imaging
• Pediatric Crohn disease
• Pediatric hyperthyroidism
• Pediatric malabsorption syndromes

Prognosis

In developed regions, with proper management, the prognosis is very good. However, data reveal an increase in diarrhea-related mortality among US children between the mid-1980s and 2006. Between 2005 and 2007, 1087 diarrhea-related infant deaths were recorded, with 86% of deaths occurring in low birthweight (less than 2500 g) infants. These risk factors included male gender, black ethnicity, and low Apgar score (less than 7).[28]

Dehydration and secondary malnutrition become the common causes of death. Parenteral fluids should be given for severe dehydration. Once malnutrition ensues, the prognosis becomes grave unless parenteral nutrition is started in a hospital setting.

Complications

Common complications of common pathogens are:

• Aeromonas caviae - Intussusception, hemolytic-uremic syndrome (HUS), gram-negative sepsis
• Campylobacter species - Bacteremia, meningitis, urinary tract infection, pancreatitis, cholecystitis, Reiter syndrome (RS)
• C difficile - Chronic diarrhea
• C perfringens - Enteritis necroticans
• Plesiomonas species - Septicemia
• Enterohemorrhagic E coli O157:H7 - HUS
• Enterohemorrhagic E coli - Hemorrhagic colitis
• Salmonella species - Seizures, RS, HUS, perforation, enteric fever
• Vibrio species - Rapid dehydration
• Giardia species - Chronic fat malabsorption
• Rotavirus - Isotonic dehydration, carbohydrate intolerance
• Y enterocolitica - Appendicitis, intussusception, perforation, toxic megacolon, peritonitis, cholangitis, bacteremia, RS
• Cryptosporidium species - Chronic diarrhea
• Entamoeba species - Liver abscess, colonic perforation