Diarrhea

Diarrhea may be infectious or noninfectious and presents with acute (<14 days) or persistent (>14 days) symptoms. Community-acquired disease is most common. Viruses (norovirus predominates) are the most common cause of acute infectious diarrhea in community dwellers. Bacterial diarrhea represents only 1-5% of diarrhea cases and is often associated with clustering of cases or outbreaks. Clostridium difficile cases, while often nosocomially acquired, are increasing in community dwellers. Parasites are an infrequent or rare cause of acute diarrhea and tend to be sporadic in nature except in at-risk populations (eg, returned travelers, immunocompromised individuals).

Diagnosis

Indications for Testing

  • Symptoms
    • Persistent or chronic diarrhea
    • Bloody diarrhea
    • Diarrhea in association with systemic illness
  • Patient history
    • Immunocompromised status
    • Returned traveler
    • Hospitalized patient
  • Outbreak identification

Laboratory Testing

Differential Diagnosis

Background

Epidemiology

Risk Factors

  • Immunocompromised status
    • HIV,  primary immunodeficiency
      • Most common organisms include viruses, C. difficile, Campylobacter jejuniSalmonella spp, E. coli, Giardia, Cryptosporidium spp, and microsporidia
    • Transplantation (solid organ and stem cell)
      • Usually noninfectious
      • Infectious diarrhea most commonly caused by viruses (norovirus predominates), C. difficile, and microsporidia
  • Advanced age (>65 years)
    • Salmonella spp and Shigella spp may require treatment, so identification is important
  • Comorbid illnesses (eg, chronic heartliver, or kidney disease; diabetes mellitus)
    • Increased risk of complications (eg, sepsis)
  • Institutional residency
    • Norovirus
  • Daycare setting
    • Norovirus
    • Giardia
    • Cryptosporidium spp
    • Salmonella spp

Clinical Presentation

  • Community acquired
    • Acute diarrhea (acute gastroenteritis)
      • Duration – 1-14 days
      • Transmission – foodborne, waterborne, or outbreak associated
      • Most commonly caused by viruses and occasionally bacteria
    • Persistent diarrhea
      • Duration – >14 days, often longer
      • Often noninfectious
      • Testing for parasites may be considered
      • Persistent diarrhea may lead to malabsorption following an infectious diarrhea
  • Hospital acquired
    • Presentation may be similar to community-acquired disease
    • Most commonly caused by viruses
    • Rule out bacterial agent C. difficile if patient history is correct

Organisms Associated with Diarrhea

  • The following organisms are associated with diarrhea (CDC, 2014).
    • Norovirus
      • Epidemiology
        • Incidence
          • Leading cause of nonbacterial gastroenteritis worldwide
          • Norovirus causes millions of infections annually, with outbreaks commonly occurring in all age groups and in varied environments
            • Cruise ships
            • Restaurants (salad bar contamination most common)
            • Schools
            • Daycares
            • Healthcare facilities
        • Transmission
          • Fecal-oral route by ingestion of contaminated food (eg, shellfish) or water
          • Can be airborne (in vomitus)
          • Low infectious dose; can survive relatively high levels of disinfectants and varying temperatures
      • Clinical presentation
        • Usually mild or self-limiting disease with high transmission rates
        • Onset of symptoms occurs 24-48 hours after infection
        • Symptoms – generally last 12-60 hours
          • Acute onset diarrhea
          • Vomiting with abdominal cramps
          • Nausea
          • Fever
          • Headache
        • Transplant patients often have chronic diarrhea
          • Symptoms in small bowel transplant patients resemble allograft rejection 
    • Rotavirus
      • Epidemiology
        • Incidence
          • Most important cause of severe dehydrating diarrhea worldwide in children <5 years
            • Declined 67% in U.S. since introduction of vaccine
            • Universal infection – nearly all children have circulating antibodies by 2-3 years
        • Transmission
          • Fecal-oral route
      • Clinical presentation
        • Varies from asymptomatic to severe dehydration leading to death
        • Mild fever and emesis for 2-3 days
        • Watery diarrhea for 3-5 days following fever
          • Bloody diarrhea rare
        • Severe and prolonged disease may occur in patients with the following
        • May involve extra intestinal sites – central nervous system, liver, spleen, or kidney, especially in immunocompromised children 
    • Campylobacter
      • Epidemiology
        • Incidence
          • Leading cause of bacterial gastroenteritis worldwide
          • Peak incidence in children <5 years
        • Occurrence
          • Sporadic, but most cases occur in spring and fall
        • Transmission
          • Associated with incorrect food handling practices, consumption of poorly cooked poultry or raw milk, contact with pets, travel
          • Outbreaks most often associated with raw milk and contaminated water
      • Clinical presentation
        • Varies from asymptomatic infection to severe inflammatory diarrhea
        • Onset of symptoms occurs 2-5 days after ingestion of contaminated food or water
        • Symptoms – generally last 7-10 days
          • Abdominal pain
          • Watery stools containing blood and mucous
          • Fever
          • Nausea or vomiting
        • Complications
    • Salmonella
      • Epidemiology
        • Incidence
          • Most U.S. cases are related to international travel or immigrant status
          • Remaining cases are from large, sporadic outbreaks
            • Incidence nearly equal to Campylobacter
        • Transmission
          • Undercooked or uncooked foods (eg, raw meat and vegetables, poultry, eggs, milk, salad dressing, shrimp, peanut butter)
          • Contact with infected animals
          • Contact with nonsymptomatic patients
      • Clinical presentation
        • Typhoid fever
          • Incubation period is 3-21 days
          • Prodrome of chills, headache, sore throat, fever, anorexia, cough
          • Progresses to rash (rose spots), epistaxis, diarrhea, relative bradycardia
          • Blood cultures are of higher yield than stool cultures for typhoid fever
            • 90% have positive blood cultures in week 1; drops to 50% by week 3
          • Complications
            • Late complications found in untreated adults – intestinal perforation, gastrointestinal hemorrhage
            • Rare complications –  pancreatitis, hepatic and splenic abscesses, endocarditis, pericarditis, orchitis, meningitis, parotitis, osteomyelitis
            • Up to 5% of infected patients develop chronic carrier state
              • Usually occurs in patients with gall bladder disease or gastric carcinomas
        • Enteritis
          • Onset of symptoms occur 6-48 hours after exposure
          • Symptoms – gererally last 1-2 days
            • Fever, headache
            • Intestinal symptoms – diarrhea (watery), abdominal pain 
    • Shiga-toxigenic E. coli
      • Epidemiology
        • Incidence
          • Under-recognized illness
          • Not uncommon
        • Transmission
          • Person-to-person contact in daycare facilities and nursing homes
          • Consumption of undercooked meats and produce (washing produce has been shown to be ineffective)
      • Clinical presentation
    • Shigella spp
      • Epidemiology
        • Incidence
          • Common in countries with poor sanitation
          • Accounts for small percentage of reported outbreaks of foodborne illness in U.S.
        • Transmission
          • Fecal-oral route; no nonhuman hosts
          • Higher-risk groups – daycare personnel and clients, nursing home residents, and men who have sex with men
      • Clinical presentation
        • Onset of symptoms occurs 12-50 hours after exposure
        • Symptoms
          • Diarrhea
            • Frequently bloody
            • May contain mucous or pus
          • Fever
          • Abdominal pain, cramps
          • Dysentery (10-30 stools/day)
        • Associated with Reiter syndrome (arthritis, uveitis, urethritis)
        • Complications
          • Reactive arthritis (increased risk of development if patient is positive for HLA-B27 allele)
          • Hemolytic uremic syndrome (HUS) (usually S. dysenteriae type 1) 
    • Yersinia spp
      • Epidemiology
        • Incidence
          • Most often in young children
          • Y. pseudotuberculosis and Y. pestis are uncommon causes of gastrointestinal disease
        • Transmission
          • Soil, water, animals, food
          • Y. enterocolitica found in meats (eg, beef, pork), oysters, fish, and unpasteurized milk
      • Clinical presentation
        • Onset of symptoms occurs 24-48 hours after ingestion of contaminated food or drink
        • Symptoms
          • Diarrhea (loose, watery, or bloody stools)
          • Abdominal pain
          • Fever 
          • Infections with Y. enterocolitica and Y. pseudotuberculosis can be asymptomatic, mild, or severe, with infection resolving within a few weeks (with or without use of antibiotics)
          • Yersinia infections are known for mimicking appendicitis
        • Complications include reactive arthritis which can manifest 1-4 weeks post infection (increased risk of development if patient is positive for HLA-B27 allele)
          • The most commonly affected joints are knees and ankles, but other joints such as toes, fingers, and wrists can be involved
          • In most cases, 2-4 joints become involved sequentially and asymmetrically over a period of a few days to 2 weeks
            • Joint fluid is sterile
          • Chronic joint disease or ankylosing spondylitis occurs rarely
          • Acute arthritis persists for 1-4 months
          • Reiter syndrome (arthritis, uveitis, and urethritis) may occur
          • Less common nonsuppurative sequelae of Y. enterocolitica infections include reactive uveitis, iritis, conjunctivitis, glomerulonephritis, urethritis, hemolytic uremic syndrome (HUS) 
    • Vibrio spp
      • Epidemiology
        • Incidence
          • Vibrio cholerae 
            • Several pandemics have occurred
            • No major outbreaks in U.S. since 1911
          • V. vulnificus 
            • Outbreak reported in New Orleans after hurricane Katrina
            • Usually several lethal cases annually in Florida, typically in summer months
        • Transmission
          • Ingestion of contaminated seafood (eg, crab, shrimp, lobster)
            • V. parahaemolyticus is the leading cause of bacterial diarrhea associated with seafood
          • Through open wounds in sea water
      • Clinical presentation
        • Onset of symptoms occurs within 16 hours of ingestion of contaminated seafood for healthy individuals
        • Symptoms
          • Watery diarrhea
          • Abdominal pain
          • Cramps
          • Vomiting
        • Immunocompromised individuals and patients with cirrhosis may present with primary septicemia
          • Associated with >50% mortality
        • No associated long-term complications 
    • Giardia duodenalis (synonyms Giardia lamblia, Giardia intestinalis)
      • Epidemiology
        • Incidence
          • Most common cause of parasite-associated diarrhea in the U.S.
          • Increased frequency in children, men who have sex with men, and residents of institutional care facilities
        • Transmission
          • Waterborne, foodborne, or fecal-oral
      • Clinical presentation
        • Most infections are asymptomatic
        • Symptoms may last from weeks to months
          • Acute or chronic nonbloody diarrhea, nausea, vomiting, dehydration, abdominal discomfort, malabsorptive symptoms (eg, flatulence, greasy malodorous stools)
        • Intermittent or recurrent symptoms are common 
    • Cryptosporidium spp
      • Epidemiology
        • Incidence
          • Increased risk in patients with HIV, residents of households with infected patients, daycare personnel and clients, and returned travelers
        • Transmission
          • Waterborne, sporadic, or outbreak associated
            • Found in large outbreaks associated with contaminated water sources
            • Can occur year round when artificial water storage systems are involved
      • Clinical presentation
        • Immunocompetent patients
          • Usually asymptomatic or mild, self-limiting gastroenteritis
          • Nonbloody, watery diarrhea, dehydration, nausea, vomiting, abdominal pain, low-grade fever, and malaise lasting from a few days to >30 days
        • Immunocompromised patients
          • General immunodeficiencies (particularly T-cell deficiencies) – chronic diarrhea (often more severe than expected for pathogen), dehydration, weight loss
          • HIV – chronic diarrhea; others include cholecystitis, hepatitis, pancreatitis 
    • Entamoeba histolytica
      • Epidemiology
        • Incidence
          • Increased risk in men who have sex with men, recent immigrants, residents of institutional care facilities, returned travelers, and HIV patients
          • Typically limited to individual cases with possible spread to sex partners or close contacts
        • Transmission
          • Waterborne, foodborne, or fecal-oral
      • Clinical presentation
        • Most individuals are asymptomatically colonized (~90%)
          • Subacute onset
        • Disease may be intestinal or extraintestinal
          • Intestinal disease
            • Fulminant or chronic, with abdominal pain, tenderness, tenesmus, and bloody diarrhea
          • Extraintestinal disease
            • May include liver, brain, and lung abscesses 
    • Cystoisospora belli
      • Epidemiology
        • Incidence
          • Increased risk in HIV patients, recent immigrants, and travelers from endemic regions
        • Transmission
          • Waterborne
      • Clinical presentation
        • Immunocompetent patients
          • Acute, self-limiting watery or malodorous diarrhea (similar to Giardia or Cryptosporidium infection)
        • Immunocompromised patients
          • General immunodeficiencies – chronic diarrhea (occasionally severe), dehydration, weight loss
          • HIV – diarrhea, cholecystitis, reactive arthritis 
    • Microsporidia
      • Epidemiology
        • Incidence
          • Undetermined in non-HIV populations
          • Increased risk in HIV patients presenting with chronic diarrhea
            • Predominately affects immunocompromised hosts
            • Includes Enterocytozoon bieneusi, Encephalitozoon intestinalis, Pleistophora, Septata, Vittaforma spp
            • ~15% prior to combination antiretroviral therapy (cART)
            • Rates are lower for patients on cART
        • Transmission
          • Waterborne
      • Clinical presentation
        • Immunocompetent patients
          •  Rare cause of acute, self-limiting diarrhea
        • Immunocompromised patients (most often with HIV)
          • Chronic diarrhea, dehydration, anorexia, weight loss, abdominal pain, nausea, vomiting 
    • Cyclospora cayetanensis
      • Epidemiology
        • Incidence
          • Unknown in U.S.; usually tropical/subtropical regions
        • Transmission
          • Foodborne or waterborne
          • Clustered outbreaks associated with contaminated food products
          • Recent outbreaks occurring at higher frequency
            • Not associated with foreign travel, but rather, foreign food products sold domestically
        • Clinical presentation
          • Immunocompetent patients
            • Anorexia, nausea, emesis, flatulence, watery diarrhea, low grade fever, fatigue, cramping
            • Typically does not resolve without treatment
          • Immunocompromised patients
            • May cause chronic diarrhea
          • Endemic – frequent mild or asymptomatic cases 

ARUP Lab Tests

Aid in the diagnosis of GI infections caused by viral pathogens, including adenovirus (serotypes 40 and 41), astrovirus, norovirus (genogroups 1 and 2), rotavirus, and sapovirus

Use as a sensitive alternative to traditional antigen testing

Detect Norovirus groups 1 and 2

Diagnose rotavirus-associated gastroenteritis

For antigen testing panel that includes adenovirus and rotavirus, refer to rotavirus and adenovirus 40-41 antigens

Preferred test for suspected bacterial diarrhea evaluation

Can be used to rule out Aeromonas and Plesiomonas; specify the pathogen to rule out

For C. difficile testing, refer to Clostridium difficile toxin B gene by PCR

If an isolate requires testing for Shiga-like toxin (eg, STEC), refer to E. coli Shiga-like toxin by EIA​

Testing includes cultures for Salmonella, Shigella, Campylobacter, E. coli O157, and EIA for Shiga-like toxin from E. coli

Use as a sensitive alternative to traditional stool culture to detect the most common gastrointestinal bacterial pathogens: Salmonella, Shigella/Enteroinvasive E. coli, Campylobacter jejuni/coli, and shiga-toxigenic E. coli

This test can also detect Campylobacter upsaliensis, which cannot be readily cultured

A negative result does not rule out the presence of PCR inhibitors in the patient specimen or test-specific nucleic acid in concentrations below the level of detection by this test

Do not order for patients with diarrhea developed during prolonged hospitalization

Most comprehensive and sensitive alternative to traditional, insensitive ova and parasite examinations of stool specimens for the evaluation of gastrointestinal infections

Detect Cryptosporidium hominis, C. parvum, Cyclospora cayetanensis, Dientamoeba fragilis, Entamoeba histolytica, Giardia lamblia/intestinalis/duodenalis, and microsporidia by PCR​

Recommended rapid, stand-alone diagnostic test for C. difficile-associated diarrhea

Do not order for patients with diarrhea developed during prolonged hospitalization

Use as a sensitive alternative to traditional, insensitive ova and parasite examinations of stool specimens

Detect Cryptosporidium hominis, C. parvum, Cyclospora cayetanensis, Dientamoeba fragilis, Entamoeba histolytica, and Giardia lamblia/intestinalis/duodenalis​

Test for persistent diarrhea (>14 days) or known risk factors if Giardia duodenalis (synonyms Giardia lamblia, Giardia intestinalis) is the suspected infectious agent

Test for persistent diarrhea (>14 days) or known risk factors if Cryptosporidium spp is the suspected infectious agent

Test for persistent diarrhea (>14 days) or known risk factors if Cryptosporidium, Cyclospora, or Cystoisospora is the suspected infectious agent

Preferred test to diagnose microsporidia in immunocompromised patients with persistent diarrhea if Encephalitozoon spp (E. instestinalis/E. hellem/E. cuniculi) or Enterocytozoon bieneusi is the suspected infectious agent

The nucleic acid from E. intestinalis, E. hellem, and E. cuniculi will be detected by this test but cannot be differentiated

A negative result does not rule out the presence of PCR inhibitors in the patient specimen or test-specific nucleic acid in concentrations below the level of detection by this test

Can be used for follow-up of negative PCR result when suspicion of microsporidia infection remains high

Test for persistent diarrhea (>14 days) or known risk factors if E. histolytica is the suspected infectious agent

If parasite infection is suspected as cause of persistent diarrhea (>14 days), specific pathogen testing is recommended

Do not order for patients who develop diarrhea during a prolonged hospitalization

Due to the various shedding cycles of many parasites, 3 separate stool specimens collected over a 5- to 7-day period are recommended for ova and parasite examination

A single negative result does not rule out the possibility of a parasitic infection

Stool antigen testing is the optimal test method for determining the parasitic presence of Giardia, Cryptosporidiumspp, or Entamoeba histolytica

Does not specifically detect Cryptosporidium, Cyclospora, Cystoisospora, or microsporidia

For Cryptosporidium, refer to the Cryptosporidium antigen by EIA test; for Cyclospora and Cystoisospora, refer to parasitology stain by modified acid-fast; for microsporidia, refer to microsporidia stain

Related Tests

Detect presence of bacteria in blood

May help in differentiation of bacterial from nonbacterial infection

Presence of anemia (low hemoglobin/hematocrit) suggestive of inflammatory or malignant process and not bacterial diarrhea

Not recommended; poor positive predictive value

Aid in the detection of amebic liver abscess

Test is not useful for intestinal infection

Test detects the Shiga toxins, sensitive markers of toxigenic Escherichia coli

CDC recommends stool specimens also be cultured for E. coli O157:H7 (O157 STEC)

Cannot determine specific strains of E. coli (eg, E. coli O157:H7)

Includes IgG, IgA, and IgM

May be used to determine past exposure to S. typhi (eg, infection or vaccination) and S. paratyphi

This test cannot be used to confirm acute salmonellosis

If systemic symptoms of acute salmonellosis are present, the preferred tests are stool culture and E. coli Shiga-like toxin by EIA and blood culture if typhoid fever is suspected

Detects antibodies directed against 5 Salmonella typhi and paratyphi antigens: O Type D; O Type Vi; H Type A; H Type B; or H Type D

Identify presence of Campylobacter species in stool as potential cause of diarrhea in patients with appropriate exposure history or risk factors

Diagnose Yersinia-associated diarrhea in patients with appropriate exposure history or risk factors

Diagnose Vibrio-associated diarrhea in patients with appropriate exposure history or risk factors

Aid in the diagnosis of strongyloides

Positive results in patients from endemic areas may not represent active infection

False-positive results may occur with prior exposure to other helminth infections; testing low-prevalence populations may also result in false-positive results

If results are equivocal  (1.0 IV), consider retesting in 2-4 weeks, if clinically indicated

Immunoblot can be used as an adjunct tool in the diagnosis of Yersinia enterocolitica infection

The presence of IgA and IgG antibodies to Y. enterocolitica Yop proteins can also aid in the diagnosis of postinfectious autoimmune disorders associated with Y. enterocolitica (eg, reactive arthritis, erythema nodosum, Graves disease, and Hashimoto thyroiditis)

Immunoblot can be used as an adjunct tool in the diagnosis of Yersinia enterocolitica infection

The presence of IgA and IgG antibodies to Y. enterocolitica Yop proteins can also aid in the diagnosis of postinfectious autoimmune disorders associated with Y. enterocolitica (eg, reactive arthritis, erythema nodosum, Graves disease, and Hashimoto thyroiditis)

Immunoblot can be used as an adjunct tool in the diagnosis of Yersinia enterocolitica infection

The presence of IgA and IgG antibodies to Y. enterocolitica Yop proteins can also aid in the diagnosis of postinfectious autoimmune disorders associated with Y. enterocolitica (eg, reactive arthritis, erythema nodosum, Graves disease, and Hashimoto thyroiditis)

Immunoblot can be used as an adjunct tool in the diagnosis of Yersinia enterocolitica infection

The presence of IgA and IgG antibodies to Y. enterocolitica Yop proteins can also aid in the diagnosis of postinfectious autoimmune disorders associated with Y. enterocolitica (eg, reactive arthritis, erythema nodosum, Graves disease, and Hashimoto thyroiditis)

Immunoblot can be used as an adjunct tool in the diagnosis of Yersinia enterocolitica infection

The presence of IgA and IgG antibodies to Y. enterocolitica Yop proteins can also aid in the diagnosis of postinfectious autoimmune disorders associated with Y. enterocolitica (eg, reactive arthritis, erythema nodosum, Graves disease, and Hashimoto thyroiditis)

Medical Experts

Contributor

Couturier

Marc Roger Couturier, PhD, D(ABMM)
Associate Professor of Clinical Pathology, University of Utah
Medical Director, Parasitology/Fecal Testing, Infectious Disease Antigen Testing, Bacteriology, and Molecular Amplified Detection, ARUP Laboratories
Contributor

Fisher

Mark A. Fisher, PhD, D(ABMM)
Associate Professor of Clinical Pathology, University of Utah
Medical Director, Bacteriology, Special Microbiology, and Antimicrobial Susceptibility Testing, ARUP Laboratories
Contributor
Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®