Evaluation of Acute Infectious Diarrhea

Epidemiology

• 1.

  What is acute diarrhea?

  The most important defining aspect of diarrhea is a change in frequency or consistency of bowel movements from baseline. For research purposes, acute diarrhea is defined as production of abnormally loose stools, with more than three episodes daily for less than 14 days . Generally a daily output increase from the normal of 100 to 200 mg per day is associated with the excessive frequency of defecation. Acute diarrhea commonly results as part of a response to enteric infection (although severe systemic infections may be associated with diarrhea as well) or preformed toxins, or as part of medication effects, malabsorptive and osmotic processes, inflammatory bowel disease (IBD), or vascular diseases.

• 2.

  How frequently does acute diarrhea caused by infection occur in the United States?

  Based on recent Centers for Disease Control and Prevention estimates, approximately 9.4 million cases of foodborne illness, with approximately 56,000 hospitalizations and more than 1300 deaths, occur annually in the United States and are attributable to known pathogens. A majority of illnesses are caused by Norovirus, Salmonella, preformed toxins, and Campylobacter . An additional 38.4 million illnesses with 72,000 hospitalizations occur annually as a result of unidentified pathogen.

• 3.

  Which bacterial organisms produce preformed toxins that cause acute diarrhea?

  Symptoms that occur rapidly (< 12 hours) after ingestion and include nausea, vomiting, or diarrhea are consistent with the ingestion of a preformed toxin. Some of these toxins are heat stable thus persist despite cooking of foods. The most common syndromes are caused by the (1) heat stable Staphylococcus aureus enterotoxin, (2) Bacillus cereus enterotoxins (often associated with rice), and (3) Clostridium perfringens (rewarmed meats such as ham). Symptoms are generally self-limited. Point source outbreaks with multiple cases associated with one recent meal is typical. Additionally, ciguatera and scombroid seafood poisoning, caused by heat-stable toxins from bioaccumulation and spoilage, respectively, are common and can present with diarrhea as part of their syndromes.

• 4.

  What is persistent diarrhea?

  Diarrhea symptoms that last 14 days or longer are generally classified as persistent . The differential diagnosis of persistent diarrhea differs somewhat from acute or chronic diarrhea. In terms of infection, bacterial enteric pathogens, parasites, and protozoa are more likely to result in persistent disease and viral pathogens are less common. The following organisms should be considered in the differential diagnosis of persistent diarrhea:

  • Bacteria: Campylobacter, Vibrio, Escherichia coli, Shigella, Salmonella, Clostridium difficile, syphilis, chlamydia (lymphogranuloma venereum [LGV])

  • Parasites (helminths): Strongyloides infection may lead to colitis

  • Protozoa: Giardia, Isospora, Cyclospora, Cryptosporidium

  • Malabsorptive: Tropical sprue, celiac sprue, lactose intolerance

• 5.

  What are the characteristics of noninflammatory and inflammatory diarrhea syndromes?

  Noninflammatory diarrhea consists of a syndrome of watery, nonbloody, nonpurulent diarrhea, and often lacks prominent systemic signs and symptoms such as fever or myalgias. Specific etiologic factors often go undiagnosed and course is often self-limited. Inflammatory diarrhea consists of frequent, smaller volume, mucoid or bloody stools, often associated with tenesmus, fever, and more prominent or severe abdominal pain. On laboratory evaluation, inflammatory diarrhea exhibits positive fecal leukocytes and positive stool lactoferrin, and will almost always involve the colon (colitis) when there are large sheets of leukocytes present.

• 6.

  What disorders and infections are associated with inflammatory diarrhea?

  Inflammatory diarrhea is generally associated with disorders that cause mucosal disruption. Mucosal compromise may be due to a primary (IBD) or secondary (invasive infectious organism) process. Invasive infectious agents associated with diarrhea include Salmonella, Shigella, Campylobacter, enterohemorrhagic E. coli (EHEC; O157:H7), enteroinvasive E. coli, and other Shiga toxin–producing E. coli (STEC), C. difficile, E. histolytica, and Yersinia enterocolitica. Noninfectious causes of inflammatory diarrhea include ulcerative colitis, Crohn’s disease, radiation enteritis, ischemic and vascular diseases, and diverticulitis.

• 7.

  What disorders and infections are associated with noninflammatory diarrhea?

  Noninflammatory diarrhea is generally caused by infection with noninvasive pathogens that generate toxins or use other means to promote a secretory process. Causative agents include Vibrio cholerae, enterotoxigenic E. coli, staphylococcal and clostridial toxins, viruses, protozoa, Cryptosporidium, and Giardia .

• 8.

  Who is most at risk (morbidity and mortality) from acute diarrheal illness?

  The very young, older adults, and the immune compromised are most at risk for morbidity and mortality from acute diarrheal illness. Other risk factors include travel to developing countries, those who work in or attend a daycare, and those who are receiving or have recently received antibiotics, although among the young and healthy mortality is extremely rare.

  Children younger than the age of 5 in developing countries, mainly sub-Saharan Africa and Asia, suffer disproportionately from diarrheal disease. Acute and persistent diarrheal infections are a major source of pediatric mortality and morbidity. Annually, 800,000 pediatric deaths are attributable to diarrheal diseases.

  Meanwhile, travelers’ diarrhea affects upward of 20 million people per year and is the most common illness to affect travelers.

• 9.

  What vaccine-preventable viral pathogen is a major cause of pediatric diarrhea in developing and developed countries?

  Rotavirus infection is a major cause of outbreak and sporadic diarrhea worldwide. Among children and older adults, outbreaks of rotavirus diarrhea result in significant morbidity and mortality and on recent surveys are the most common cause of moderate to severe diarrhea among infants and toddlers in the developing world.

• 10.

  What is the most common cause of outbreak and sporadic cases of acute infectious gastroenteritis and diarrhea in Western countries?

  Norovirus infection remains the most common cause of acute sporadic and outbreak-associated diarrhea and gastroenteritis in western countries . In the United States, 21 million cases of Norovirus gastroenteritis are estimated to occur annually. Noroviruses are members of the Calicivirus family and fall into five genogroups (G.I through G.V). Although some genogroups can infect and are present in both humans and animals, most outbreaks result from human-to-human transmission. The majority of pandemic strains have been G.II.4 subtypes.

• 11.

  What organisms are most likely to present with bloody diarrhea or acute dysentery?

  Invasive bacterial pathogens, and to a lesser extent amoebae, are more likely to present with a diarrhea accompanied by fever or dysentery. Among bacterial pathogens Shigella spp., nontyphoid Salmonella, Campylobacter spp., STEC, and EHEC variants are the most common. Entamoeba histolytica, the agent of amebic dysentery, may also cause bouts of watery or bloody diarrhea with colitis.

• 12.

  What are the diarrheagenic subtypes of E. coli?

  There are six subtypes of diarrheagenic E. coli:

  • Enterotoxigenic E. coli (ETEC) —notable for toxin production, either heat labile, heat stable, or both, and is the most common cause of travelers’ diarrhea in many developing countries.

  • Diffusely adherent E. coli and enteropathogenic E. coli —common in children of younger than 2 years. Tight adherence to small bowel.

  • Enteroinvasive E. coli (EIEC) —able to invade mucosal lining (type 3 secretory apparatus); causes a presentation similar to Shigella enterocolitis.

  • Enteroadherent/aggregative E. coli (EAEC) —associated cause of persistent chronic diarrhea in children and travelers. A common cause of traveler’s diarrhea in addition to ETEC.

  • EHEC —associated colitis and bloody diarrhea, and the hemolytic uremic syndrome (HUS). Pathologic findings are secondary to Shigalike toxin production. Serotype O157:H7 is the most common EHEC representative. It is most commonly transmitted through food supply, in particular contaminated beef products. It is isolated on Sorbitol-MacConkey agar and toxin production with enzyme-linked immunosorbent assay (does not ferment sorbitol). HUS occurs in approximately 5% to 15% of pediatric cases in which antibiotic therapy has been associated with the onset of HUS.

  • STEC —Shiga toxin–producing strains other than EHEC. A recent outbreak of O104:H4 in 2011 resulted in illness in primarily adults and was associated with HUS in some cases.

• 13.

  What are the epidemiologic features and species most commonly associated with shigellosis?

  Shigella infections in developed countries such as the United States are more commonly associated with Shigella sonnei strains. Shigella flexneri infections are more common in developing countries and are the second most common Shigella species isolated from patients in the United States. Shigella dysenteriae is less common but can cause of a more severe infection and epidemic dysentery. In the United States, shigellosis is most commonly associated with children in daycare settings, institutionalized individuals, and among men who have sex with men. Shigellosis is also an important cause of watery diarrhea and dysentery among travelers.

• 14.

  Which antibiotic class should be avoided in acute diarrhea acquired by a traveler to southeast Asia?

  Quinolone resistance is prevalent among Campylobacter strains found in southeast Asia and increasingly elsewhere, with rising incidence in Russia, India, and some eastern European countries. The high rate of resistance to this antibiotic class makes them a poor choice for the empiric treatment of traveler’s diarrhea in these locations. Azithromycin is currently the agent of choice for empiric treatment of traveler’s diarrhea in areas where Campylobacter infection is likely to be resistant . Campylobacter is also among the more common causes of dysentery, and avoidance of quinolones to treat such clinical presentations is reasonable regardless of geographic location.

• 15.

  What agents of acute diarrhea are most likely to be acquired from ingestion of raw oysters?

  Oysters and other filter-feeding organisms, whether farmed or harvested from natural environments, are able to harbor and concentrate enteric pathogens. Both viral and bacterial enteric infections may be acquired by the ingestion of raw oysters. Common pathogens of concern include Vibrio species, in particular Vibrio parahaemolyticus , which causes a diarrheal illness. Norovirus outbreaks have also been attributed to raw oyster consumption. Vibrio vulnificus infection has been associated with these ingestions but is more associated with causing septicemia and bullous necrotizing fasciitis in immunocompromised patients and those with end-stage liver disease or cirrhosis.

• 16.

  What specific unique etiologic factors exist for acute diarrheal illness in immunocompromised hosts?

  See Chapter 56 for further discussion. Immunoglobulin A deficiency, human immunodeficiency virus (HIV) and acquired immune deficiency syndrome, organ transplantation, rheumatologic disease on immune-suppressing agents, and chemotherapy all may predispose individuals to enteric infection. These hosts are susceptible to common causes of acute diarrhea but also to agents not commonly problematic for normal hosts: Mycobacteria, Cyclospora, Isospora , Cryptosporidium , cytomegalovirus (CMV), and herpes.

• 17.

  What infectious agents are associated with acute and persistent diarrheal illness in HIV patients?

  The degree of immune deficiency influences the differential diagnosis. Generally, the same pathogens as seen among immunocompetent community dwellers is seen among patients with HIV infection, but persistent and chronic presentations may be more common for these same organisms. In addition, symptoms suggestive of invasive disease may occur with infections caused by normally noninvasive pathogens. Highly active antiretroviral therapy and direct viral involvement by HIV may also be common contributors to diarrhea.

  Among bacterial contributors, Salmonella (nontyphoidal bacteremia) is of particular concern and can be recurrent. Other contributors are Campylobacter and Shigella. Mycobacterium avium complex may be present even without significant diarrhea, and is often part of an overall wasting syndrome.

  Parasite contributors are Cryptosporidium parvum , Microsporidium (a common cause of chronic diarrhea in HIV), Giardia lamblia, Entamoeba histolytica, Strongyloides stercoralis, Isospora belli, and Cyclospora cayetanensis.

• 18.

  What are the common causes of acute diarrheal illness among solid organ transplant patients?

  Valganciclovir use has resulted in less CMV-related disease. Community viral pathogens, in particular Norovirus, are more common. In the setting of colitis, CMV remains the most common etiologic factor. CMV presence on biopsy polymerase chain reaction (PCR) does not always correlate to causative agent when on suppressive antiviral therapy and tissue evidence of CMV disease (histopathologic) is desirable.

  Parasitic infection rates in organ transplant recipients are not entirely known and are more common in developing countries. Clues of infection may be bronchopneumonia, prolonged fever, and meningitis. Pathways to infection include de novo, reactivation of latent infection, or transmission from the graft.

• 19.

  Which bacterial agent of acute diarrhea has humans as its most important reservoir and is more likely to spread and cause disease outbreaks from person-to-person contact?

  Shigella species (s onnei, dysenteriae, flexneri, and boydii ) are highly adapted to human hosts and humans are the most significant reservoir that may contribute to outbreaks within close contacts in family, daycare settings, and through contamination of food. S. dysenteriae causes severe disease resulting from high Shiga toxin production and is associated with epidemic outbreaks in the developing world.

• 20.

  What presentation and historical features are useful in defining the etiologic factors of acute diarrhea syndromes?

  Host factors (age, immune status, medications, comorbid conditions), geography, and socioeconomic status heavily influence the infectious differential diagnosis of diarrheal illness. Diarrhea type, and location of presentation are useful determinants. Table 54-1 groups the common diarrheal syndromes with epidemiologic features.

  Table 54-1

  Prevalence and Infectious Causes of Common Infectious Diarrhea by Syndrome Type

  Presentation	Estimated Prevalence (%)	Developed Countries	Developing Countries
  Acute watery diarrhea	90	Viral, preformed toxins	Enterotoxigenic E. coli , other diarrheogenic E. coli , C. jejuni, Salmonella, Shigella
  Acute dysentery	5-10	Shigella , enteroinvasive E. coli , Campylobacter	Shigella , enteroinvasive E. coli , C. jejuni, E. histolytica
  Persistent diarrhea (> 2 wk)	3-4	Enteropathogenic E. coli , Giardia , Yersinia, Campylobacter	Enteropathogenic E. coli , Giardia
  Large voluminous/rice-water stool	1	Salmonella , enterotoxigenic E. coli	Vibrio cholerae , enterotoxigenic E. coli
  Hemorrhagic colitis	< 1	Enterohemorrhagic E. coli, STEC	Enterohemorrhagic E. coli

  STEC, Shiga toxin–producing E. coli .

• 21.

  What is the most common cause of traveler’s diarrhea?

  ETEC infection is the most common identified cause of traveler’s diarrhea in most of the world. ETEC strains cause a watery diarrhea syndrome of varying severity resulting from the production of one or two enterotoxins: heat-stable toxin and heat-labile toxin (LT). The LT variant is closely related to cholera toxin and results in profuse, watery diarrhea. Other diarrheagenic E. coli (EAEC), Campylobacter, Shigella, and Salmonella infections are common as well. Viral and parasitic infection cause a minority of episodes.