Healthcare-Associated Gastrointestinal Illness

Healthcare-Associated Gastrointestinal Illness

Shannon J. Koh

Trish M. Perl

Diarrheal illness has a substantial global health impact. Worldwide, it is the eighth leading cause of death among all populations and the fifth leading cause of death in children under 5 years old.1 It has been a scourge throughout history and linked to poor hygiene and unsanitary living conditions since the 18th century.2 However, prior to the second half of the 19th century, little was known about how these infections were transmitted and how to prevent them. In 1856, one of the first epidemiologic investigations was performed by Dr. John Snow during the devastating outbreak of cholera in South London. Despite not knowing the causative organism of cholera, he was able to identify the source and route of transmission of the outbreak based on epidemiological mapping and implemented appropriate interventions. The source, the Broad Street pump, supplied contaminated water from the Thames River and once removed halted transmission.3 These data defied the accepted hypothesis of miasma (transmission of disease by noxious air). Instead, Snow displayed his data elegantly through maps of the affected areas, clearly demonstrating fecal-oral transmission through a tainted water source. This investigation led to one of the first documented public health interventions. Since this time, the treatment of potable water has been shown to be one of the most important strategies to enhance the public’s health and decrease mortality.

Living conditions improved with the advancement of technology and urbanization. As cities created and improved sewage systems, bacterial and parasitic causes of diarrhea decreased, primarily in high-income countries (HIC). Even today, diarrheal infection still plays a substantial role in the public health of low- and middle-income countries (LMIC). It was not until over a century after John Snow discovered the transmission of cholera, and other bacterial causes of diarrhea were described, that viral causes of gastroenteritis were discovered. In 1972, norovirus (NoV) was identified by electron microscopy.4 Soon after other viral causes of gastroenteritis were discovered, and the role in the gastrointestinal track spread of diseases such as coronavirus continues to unfold.5

Healthcare-associated (HA) gastrointestinal illness is commonly seen in the form of gastroenteritis or diarrhea and is seen in all types of healthcare settings to varying degrees. Any pathogen that causes gastroenteritis or diarrheal illness in the community can also cause outbreaks in the healthcare setting. There are many factors that contribute to the development of HA diarrhea, of which infections play only a small part. For some pathogens, the healthcare setting may be more advantageous. This is true for Clostridioides difficile, the leading cause of HA diarrhea, which is discussed in Chapter 17.

Beyond C difficile, the leading infectious cause of HA gastroenteritis is NoV in adults and rotavirus (RV) in children. There is a wealth of information on NoV and RV in the healthcare setting, and thus these infections will be used as examples of the impact of HA gastroenteritis outside of C difficile. The etiology of HA gastroenteritis in LMIC includes NoV and RV, but bacterial causes are also common including Salmonella, Shigella, and, in the setting of disaster, Vibrio cholerae. Overall, most of our knowledge of HA gastroenteritis is a limited patchwork of data from single-center epidemiological studies and outbreaks mainly from HIC. Less information regarding the role of HA gastroenteritis in LMIC is available.

This chapter discusses the causes of HA gastroenteritis other than C difficile in both the developed (HIC) and developing worlds (LMIC) and the infection prevention and control measures pertaining to them. We will review the accepted definitions, epidemiology, pathogenesis, causes, and infection and prevention strategies around this subject and highlight areas where further information is needed. In putting this chapter together, the need for more robust and detailed information about HA gastroenteritis cannot be overemphasized. These data are needed to prevent infections from occurring in vulnerable patient populations in healthcare setting.


The exact incidence and prevalence of HA diarrhea are unknown and the burden is poorly defined in both HIC and LMIC. Diarrhea commonly presents in hospitalized adult patients and has a myriad of infectious and noninfectious causes (Tables 18-2 and 18-3). The lack of surveillance data results from the diversity of etiologies, limited access to an expensive testing, and nonspecific definitions. A 2016 study conducted in the United Kingdom examined a cross section of 141 general medical, surgical, and geriatric wards in 32 hospitals.8 The overall point prevalence of HA diarrhea was 4.5%, with teaching hospitals having a higher prevalence than community hospitals (5.9% vs 2.8%).8 Most patients had at least one cause of diarrhea identified, and 85% had multiple causes.8 The authors report that among patients with HA diarrhea, 47% had underlying medical conditions associated with diarrhea, 54% had exposure to at least one antimicrobial within 24 hours of the onset of diarrhea, and 85% of patients were taking medications that could themselves cause diarrhea (the most common being laxatives, proton pump inhibitors, and selective serotonin reuptake inhibitors).8

Thirty-five percent of patients had stool studies performed to look for a microbiological cause, with 33% tested for C difficile infection (CDI), and only 7% (16) of patients in total were tested for NoV.8 Interestingly, almost two-thirds of patients with HA diarrhea had no medical assessment of the cause. The implication being that clinicians may not consider the etiology of diarrhea to be important.8 Previous epidemiological studies in HA diarrhea are over a decade old and have primarily been performed in single, large academic centers. Hence, it is difficult to generalize the findings of these studies to other healthcare environments. These initial studies found the prevalence of HA diarrhea ranged from 32% (in 1995) to 12.4% (in 2004).7,9 The first study identified prospectively HA diarrhea among patients in a Seattle, Washington, general medical ward over an 11-month time period. Of the one-third of patients that developed HA diarrhea (126 of 382), 29.4% (37/126) patients had an infectious etiology, 45.2% (57/126) had iatrogenic and noninfectious causes (medication, enteral feeding, etc.), and 25.4% (32/126) had no identified cause.7 The latter study demonstrated that the prevalence of HA diarrhea among all patients increased from 12.4% to 26% in patients hospitalized for over 21 days.9 The investigators noted that beyond testing for CDI, little was done to identify the causes of HA diarrhea.9 Both of these studies reveal the use of antibiotics, enteral feeding, and prolonged hospital stays to be risk factors for HA diarrhea.7,9 The lower point prevalence in the 2016 UK study discussed above may be due to the exclusion of intensive care units (ICUs) and other specialty wards where a higher prevalence of HA diarrhea is expected.8

Several patient populations are particularly at risk for HA diarrhea, including pediatric and older patients. One prospective survey study conducted in three pediatric hospitals in Northern Europe reported 12.2% of patient developed a HA infection with the majority (5.6%) of them being viral gastroenteritis.10 A 2009 Canadian point prevalence study found the prevalence of all HA infections among children to be 8.7%, of which 1.3% were viral gastroenteritis and 0.2% were necrotizing enterocolitis.11

In LMIC, there is even less published information. However, from the sparse data available, infants are primarily affected. In Bangladesh from 2007 to 2010, among three hospitals, the incidence of HA diarrhea was 4.8 cases per 1000 patient-days, including adults and children.12 Children <1 year old were more likely to develop HA diarrhea than older children (OR of 6.6, 95% CI 3.8-11.4) and to die.12 This study’s findings parallel others and found that each hospitalized day over 72 hours incrementally increased the risk (OR 1.13, 95% CI 1.09-1.18) of developing HA diarrhea.12

TABLE 18-2 Medications Associated With Diarrhea



Mechanism of diarrhea

Alpha glucosidase inhibitors

Acarbose, miglitol

Osmotic, noninflammatory


Digoxin toxicity, quinidine, procainamide

Digoxin: secretory

Quinidine: osmotic, secretory

Procainamide: osmotic


Beta-lactams, clindamycin, fluoroquinolones

Amoxicillin-clavulanate: secretory

Clindamycin, cephalosporins, ampicillin: inflammatory

Macrolides: motility



Secretory and inflammatory

Anti-inflammatory agents

Olsalazine, gold agents, auranofin, colchicine, NSAIDs

NSAIDsa, olsalazine, aurafin: secretory

Colchicine: motility and secretory


ACE inhibitors, hydralazine



Nelfinavir, didanosine



Carvedilol, metoprolol, propranolol


Cholinergic drugs

Donepezil, pyridostigmine, rivastigmine


Cytotoxic chemotherapeutic agents

Irinotecan, idarubicin, 5-FU, capecitabine

5-FUa, methotrexate, irinotecan, cisplatin, doxorubicin: inflammatory

Irinotecan: motility

Glucose-lowering agents

Metformin, glipizide

Metformin: secretory


Mycophenolate, tacrolimus, azathioprine



Polyethylene glycol, lactulose, senna, bisacodyl

Polyethylene glycol and lactulose: osmotic

Senna and bisacodyl: motility

Magnesium-containing drugs

Mg sulfate, Mg hydroxide

Osmotic, noninflammatory




Oral electrolyte replacement solutions


Poorly absorbable carbohydrates

Lactulose, sorbitol, fructose


Promotility agents



Prostaglandin analogs

Latanoprost, travoprost, misoprostol

Secretory, noninflammatory

Proton pump inhibitors

Omeprazole, pantoprazole, lansoprazole


Selective serotonin reuptake inhibitors

Fluoxetine, sertraline, escitalopram, citalopram, paroxetine


Tyrosine kinase inhibitors

Erlotinib, sorafenib, sunitinib, imatinib, dasatinib, etc.

Inflammatory and noninflammatory

Thyroid supplement


Motility and steatorrhea

a 5-FU, 5-fluorouracil; NSAIDs, nonsteroidal anti-inflammatory drugs.

As these studies demonstrate, HA diarrhea is a common occurrence among hospitalized patients. The exact etiology is commonly not investigated, is frequently unknown whether it is infectious or noninfectious, and commonly is attributed to multiple contributing factors. Most testing focused on C difficile, unless there was an outbreak situation present.


The causes of HA diarrhea are complex and multifactorial. There are many internal and external factors that lead to hospitalized patients developing diarrhea, which may or may not be related to infectious etiology. Internal or host factors consist of immune and nutritional status, as well as disease state.6 Extremes of age, both older adults and infants have impaired immunity as do patients with AIDS, organ transplantation, and hematologic malignancy. These conditions in themselves often lead to diarrhea, subsequent malabsorption, and other consequences. This further complicates the overlap between comorbidities as the nutritional status depends on disease state and socioeconomic patient-related factors, which in turn influences the acquisition of infection and treatment. For these reasons, HA diarrhea contributes more to infant mortality in LMIC. Furthermore, in the healthcare setting, the host is exposed to a number of external factors that can disrupt the GI system such as antimicrobials, other medications, nutritional supplementation, food and water contamination, and exposure to other infected persons6,13 (Fig. 18-1).

In healthcare settings, medications are primary offenders of most HA diarrhea6,13,14 (Table 18-2). A common side effect of medications is diarrhea and other GI symptoms, and these develop through a number of mechanisms including toxicity, side effects (osmotic, secretory, inflammatory, and increased motility), and alteration of the gut microbiome.14,15,16 The list is long and spans many classes of
agents. The most common offenders include laxatives, proton pump inhibitors, antibiotics, and selective serotonin reuptake inhibitors.6,13,14

TABLE 18-3 Noninfectious Causes of Healthcare-Associated Diarrhea

Medications—see Table 18-2

Enteral feeding


Underlying illness:

Constipation with overflow diarrhea

Abdominal surgery or previous bowel resection

Diverticular disease


Colorectal cancer

Inflammatory bowel disease


Gastrointestinal bleed

Liver disease


Biliary sepsis

Irritable bowel syndrome

Short gut syndrome

Alcohol withdrawal

Fecal incontinence

Graft versus host disease

Ischemic colitis

Pancreatic insufficiency


Adapted from article #8 (Mawer paper).

The role of antibiotics in the pathogenesis of HA diarrhea requires further consideration given recent experimental and clinical work. In the past decade, there has been immense investigation into the role of the microbiome, especially the gut microbiome, through non-culture-based techniques such as 16S rRNA and whole genome sequencing (WGS).17,18 The gut microbiome is compromised primarily by microbiota from four different phyla: Bacteroidetes, Firmicutes, Actinobacteria, and Proteobacteria.17 Normally, in a healthy individual, Bacteroidetes and Firmicutes comprise >90% of the gut bacteria.18 The gut microbiome protects against organism invasion and infections through its welldeveloped mucosal immunity systems and colonization resistance. Colonization resistance prevents both exogenous bacteria from establishing dominance in gut environment and pathologic overgrowth of indigenous bacteria.17 Colonization resistance is conferred by direct and indirect means. Direct mechanisms of colonization resistance include mechanisms by the commensal bacterial factors themselves and do not involve the host. Examples of direct mechanisms include competing for nutrients, production of bacteriocins, which are ribosomally synthesized peptides that have activity against other bacteria, and secretion systems, which can deliver toxins to pathogenic bacteria.17 Indirect mechanisms of colonization resistance involve the commensal bacteria and host interaction and include antimicrobial peptides produced by host epithelial and Paneth cells, maintenance of the epithelial barrier, and bile-acid metabolism.17

There are still many unknowns related to the complex role of the microbiome. However, it is well established that the gut microbiome and its protective effects are disrupted by exposure to antimicrobials. Several studies have shown that antimicrobial exposure leads to a decrease in the diversity of the microbiota, which can be long lasting, for months and sometimes years.18,19,20 In general, hospitalized patients who receive antibiotics and have CDI, or HA diarrhea without CDI, have a decrease in the diversity of the gut microbiome and specifically the phylum Firmicutes.20 Other studies have shown patients with suspected HA diarrhea have a predominance of Proteobacteria compared to healthy controls.21 Antibiotic exposure also leads to compromise of other mechanisms of colonization resistance such as changes in the formation of protective short-chain fatty acids (SCFAs) and bile acids.20 Anaerobes that produce butyrate, a SCFA that is protective against CDI, are less prevalent after exposure to antibiotics.19,20 Hospitalized patients are often exposed to antimicrobials and other insults, which lead to alterations in the gut microbiome, and can manifest as HA diarrhea.

In addition to medication insults, the body is exposed to altered nutritional sources while hospitalized. Many hospitalized patients require enteral nutrition, especially patients in the ICU. Diarrhea is a common side effect of enteral nutrition, which has been reported to affect up to 95% of patients on enteral tube feeds.22 Enteral feeding can influence the diversity of the microbiome, as well as alter the secretion and absorption of the GI system through hyperosmolar formulas, decrease transit time, and high rates of feeding that can overwhelm the absorptive function of the gut, all of which contribute to the development of diarrhea.14,22,23 Most enteral feeding formulas contain fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs) that can cause distention of the GI lumen and stimulate the enteric nervous system also leading to diarrhea.24 There are also many noninfectious illnesses that manifest with diarrhea and can contribute to the development of HA diarrhea (Table 18-3).

The infectious etiologies of HA diarrhea will be discussed further in the next section. One common element of the infectious causes is their transmission though fecaloral means. Food, water, hands, and fomites contaminated by pathogens from body secretions such as feces and vomit are the vectors for infection. NoV is the classic example of a highly infectious pathogen that transmits well in the healthcare environment. It contaminates environmental surfaces and is resistant to many nonsporicidal disinfectants that are used in hospitals. It is primarily transmitted through contamination of food and water or environmental surfaces and has also been shown to have an airborne mode of transmission associated with not only vomitus but also flushing of toilets. This has not been described with other gastrointestinal pathogens. Each pathogen survives in these different environments depending on the surface, humidity, and temperature, among other factors. The form of transmission of each pathogen may vary in that some are primarily foodborne, waterborne, spread through person-to-person contact, or have the ability to survive on surfaces, but all require an inoculum to be consumed and
exposed to the gut of the host. In conditions where there is extensive contamination, maintaining sanitary conditions can be challenging, especially if there is limited opportunity for hand hygiene and environmental cleaning and disinfection. This can lead to person-to-person and environment-to-person transmission. Therefore, it is important to know if an infectious cause of diarrhea is present in order to break any potential cycle of transmission.

FIGURE 18-1 Factors that can disrupt the gastrointestinal system.


Infectious causes of HA diarrhea depend on the setting and population of patients involved, with some pathogens more common in long-term care facilities (LTCF), some primarily affecting children, others more common in LMIC countries, and some varying based on weather and geography. Below, diagnostic and then specific infectious etiologies of HA diarrhea will be discussed. The most common infectious causes of HA gastroenteritis outside of CDI will be highlighted; these include NoV and RV.


Infectious causes of HA gastroenteritis generally compromise a shorter list than causes of acute gastroenteritis (AGE) and traveler’s diarrhea. Studies done in the 1990s demonstrated the low yield of traditional stool studies (bacterial stool cultures, stool ova, and parasite) in patients who develop symptoms after 72 hours of hospitalization in both adult and pediatric populations.25,26,27 This led to the “3-day rule” in which routine stool studies, except for CDI testing (and NoV in the case of clusters), were discouraged in order to increase the value of medical testing. Some exemptions to the rule include patients who are immunocompromised, and studies have shown exempting this population from the 3-day rule still allows testing to find relevant causes of HA diarrhea without unnecessary testing.28 There are several studies demonstrating the use of the 3-day rule or modified 3-day rule in clinical decision support tools that decreased the cost of unnecessary testing.29

With the development of molecular diagnostics, there has been an increase in culture-independent diagnostic testing (CIDT) in infectious diseases. Among these CIDT are nucleic acid (NAAT or PCR-based tests) and antigen-based testing (EIA).30,31 Many clinical laboratories are adopting the use of multiplex or syndromic PCR assays, which can detect the nucleic acid of a variety of bacterial, viral, and parasitic causes of gastroenteritis.30,31,32 There are advantages and disadvantages with the use of these CIDT, in particular the multiplex PCR assays. The CIDT have a faster turnaround time (if the test does not need to be sent to outside laboratory) and are more sensitive than traditional culture-based methods. This can allow for timelier discontinuation of unnecessary antibiotics and implementation of appropriate infection prevention and public health measures.31 However, there is ambiguity in interpreting the results.31,33 PCR-based testing may lead to overdetection of certain pathogens, as these tests can detect nucleic acid of nonviable organisms, or organisms that could be considered commensals.33 Additionally, there is a lack of agreement between different multiplex PCR assays, and in general there is no gold standard to compare the results too, as traditional culture-based methods are also imperfect means of detecting pathogens.31,33 Guidelines for diagnosis and management of AGE discuss the use of multiplex PCR assays and advise clinical correlation when interpreting results.34,35

CIDT also pose a challenge for public health surveillance data, as the use of CIDT leads to increases in reporting of certain pathogens. In 2016, only 60% of positive CIDT had attempted reflex culture.32 The CIDT can skew surveillance data as they may be ordered more frequently due to changes in healthcare provider behavior and laboratory practices, in addition to the possibility of more false positives, both of which can falsely increase the incidence of a disease.32 Additionally, these results do not give information
on antimicrobial susceptibilities or subtypes of bacteria, which is important in surveillance and tracking infection prevention measures.32 New techniques in metagenomics may be a way to combat these issues in the future. Metagenomics can provide information on identification, subtyping, resistance, and virulence factors in future CIDT.30

While there is no perfect means of testing, practitioners need to consider the pretest probability of a diagnosis when ordering a test. Thus, it is important to consider the population, immunocompromised or not, and risk factors the patients were exposed to during their hospitalization. Testing may also be ordered for both diagnostic purposes and surveillance, and different tests may be more appropriate in certain situations. For example, while PCR-based assays are becoming more available, they are still expensive and oftentimes send-out tests that may not be as useful for outbreak situations. In these cases, antigen-based testing, if available, would be more appropriate. Overall, appropriate testing for HA gastroenteritis should consist of testing for CDI. If the patient is immunocompromised, then it may be appropriate to order more diagnostic workup such as stool culture or multiplex PCR assay. If there is a suspected or known outbreak, appropriate testing of stool cultures, antigen testing, or multiplex PCR assay, if these can be performed quickly, can be done for surveillance.


NoV is the leading cause of AGE worldwide. Although identified in 1968 during an outbreak in Norwalk, Ohio, it was not until the 1990s with the advent of molecular diagnostics that the virus and burden of disease could be further characterized.36,37 Since then, there has been an immense increase in knowledge regarding NoV’s epidemiology and transmission.36 It is estimated in 2010 NoV accounted for 677 million cases of diarrhea globally, 213 515 deaths, and 18% of all AGE worldwide from a recent meta-analysis.38,39 In the United States, Hall et al. concluded that NoV causes 570-800 deaths, 56 000-71 000 hospitalizations, and 400 000 emergency department evaluations annually based on the analysis of previous papers looking at the prevalence and incidence of NoV.40,41

Importantly, it is the predominant cause of outbreaks of gastroenteritis in adults and pediatrics in HIC.42,43 In temperate climates, the outbreaks are seasonal and occur mainly in the winter months. Most outbreaks of NoV occur in LTCF or acute care hospitals rather than restaurants, daycares, and cruises in both adult and pediatric populations.44,45,46 The incidence and prevalence of HA NoV have been described in various healthcare settings in HIC (Dutch, United States, and United Kingdom).46,47,48 One Dutch study found that from 2002 to 2007 in a tertiary care hospital, of 197 patients who were diagnosed with NoV, over half (57%) were HA.47 The most affected populations included the very young and the older adults.47 In Avon, England, from 2002 to 2003, 51% of the outbreaks were attributed to NoV.49 Globally, including community and HA NoV mortality is primarily in the young children and infants, in HA NoV the mortality is seen in infants but also predominantly in the older adults.39,50,51 In countries that have introduced RV vaccination in children, NoV has surpassed RV as the leading cause of AGE and is a common HA cause of GE in children.43,52 Immunocompromised patients are especially susceptible to HA NoV and can have more prolonged period of symptoms and shedding of the virus.53

There is a substantial economic burden, morbidity, and mortality associated with HA NoV outbreaks. It is estimated globally NoV causes $4.2 billion in direct health systems costs and $60.3 billion in societal costs, with 84%-99% of costs from productivity loss.54 In England, HA gastroenteritis was estimated to cost $184 million dollars in 2002, of which NoV makes up a substantial cause of these cases.48 Other studies have estimated an outbreak of NoV to cost anywhere from $40,675 to $657 644 when taking into account decreased staff, closure of units, testing, and cost of cleaning and replacing supplies.55,56 Other studies have demonstrated that NoV outbreaks in nursing facilities have been associated with increased hospitalizations and mortality.57

NoV is a single-stranded RNA virus, part of the Caliciviridae family of viruses. There are seven genogroups of NoV, and GI, GII, and GIV can infect humans, with GI and GII being the most common.42,45 There are 9 genotypes of GI, 22 of GII, and 2 genotypes of GIV. Certain genotypes have been present in particular outbreak situations. For example, despite the diversity of genotypes, GII.4 is the most common worldwide and is the most common cause of HA outbreaks.36,45 Non-GII.4 genotypes (GI.3, GI.6, GI.7, GII.3, and GII.6) have been linked more commonly to foodborne outbreaks.45,58 Every 2-3 years, there have been new pandemics of GII.4 NoV (Table 18-4).36,42,59 The adaptability of the GII.4 NoV is driven, in part, from antigenic drift or mutations in the capsid P2 domain.59,60 These variants are formed due to pressure of the current herd immunity present in the population and allow the virus to circumvent that protective mechanism.36,59 Another way NoV evades immunity is forming variants by RNA recombination, leading to antigenic shift.42,59 One of the most common recombinant NoV is GII. Pb/GII.3, which has persisted, mainly in children.59 NoV is transmitted either by person-to-person contact, foodborne, waterborne, and even airborne routes, with the first two being the most common.37,61 Although there are genogroups that infect other animals, there is no reported zoonotic infection.36 What makes NoV an ideal pathogen for nosocomial transmission includes its ability to cause infection with few viral particles (18-1000), the large amount of viral shedding from diarrhea and vomitus, and short period of immunity to previous strains.37,44 This is exacerbated in healthcare settings as hospitalized patients, especially immunocompromised persons, can have chronic diarrhea
and prolonged shedding and the virus may live on environmental areas.44,45 NoV can also contaminate the environments and has been isolated from hospital surfaces including bathrooms and high-touch surfaces. These features lead to high attack rates, and an outbreak can spread quickly throughout a unit or hospital. Risk factors for an outbreak include an index patient in a multioccupancy room (with higher number of people in the room making it more likely to start an outbreak), close proximity to infected patient, vomiting, having multiple comorbidities, and onset of symptoms occurring after admission to the ward.62 Infection prevention and control measures unique to NoV will be discussed in the Management section.

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Jun 8, 2021 | Posted by in INFECTIOUS DISEASE | Comments Off on Healthcare-Associated Gastrointestinal Illness
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