Резюме
Дорошенко О.В., Шоп И.В. Дифференциальная диагностика внутрибольничной диареи у больных с сопутствующей патологией
Диарея является распространенной патологией у госпитализированных пациентов, но причины внутрибольничной или нозокомиальной диареи отличны от тех, что приводят к развитию диарей вне стационара. В данной публикации изложены современные тенденции в понимании патофизиологических механизмов развития внутрибольничной диареи, рассматриваются основные принципы дифференциальной диагностики при этом синдроме, отличительные особенности диареи инфекционного и неинфекционного генеза.
Ключевые слова: нозокомиальная диарея, антибиотикоассоциированная диарея, Clostridium difficile, антибактериальная терапия.

Резюме
Дорошенко О.В., Шоп І.В. Диференційна діагностика внутрішньолікарняної діареї у хворих з супутньою патологією.
Діарея є поширеною патологією у госпіталізованих пацієнтів, але причини внутрішньолікарняної або нозокоміальної діареї відмінні від тих, що призводять до розвитку діарей поза стаціонару. У даній публікації викладені сучасні тенденції у розумінні патофізіологічних механізмів розвитку внутрішньолікарняної діареї, розглядаються основні принципи диференціальної діагностики при цьому синдромі, відмітні особливості діареї інфекційного та неінфекційного ґенезу.
Ключові слова: нозокоміальна діарея, антибіотикоасоційована діарея, Clostridium difficile, антибактеріальна терапія.

Summary
Doroshenko O.V., Shop I.V. Differential diagnosis of nosocomial diarrhea in patients with concomitant diseases
Diarrhea is a common pathology in hospitalized patients, but the causes of nosocomial or hospital-acquired diarrhea are district from those that lead to the development of diarrhea outside the hospital. This publication describes the modern trends in the understanding of the pathophysiological mechanisms of nosocomial diarrhea, describes basic principles of differential diagnosis in this syndrome and the distinctive features of infectious and non-infectious diarrhea genesis.
Key words: nosocomial diarrhea, antibiotic-associated diarrhea, Clostridium difficile, antimicrobial therapy.

Рецензент: д.мед.н., проф. В.О. Тєрьошин

УДК 616.34-008.314.4-06-079.4

Харьковская медицинская академия последипломного образования

Kharkov medical academy of Postgraduate Education

dorosenkoo@i.ua

The most cases of nosocomial diarrhea have  a noninfectious etiology. Apart from  Clostridium difficile (CDI), the frequency of infectious causes such as norovirus and toxigenic strains of Clostridium perfringens, Klebsiella oxytoca, Staphylococcus aureus, and Bacteroides fragilis remains largely undefined and test availability is limited. Cinical studies indicate that 12%–32% of hospitalized patients develop diarrhea but ≤20% of cases are attributable to CDI [1]. Other infectious causes are rare, but the changes of intestinal microflora, joining during prolonged stay in hospital nosocomial infection appears to play a significant role in many patients [2-5].  This article will be considered to infectious and non-infectious causes of nosocomial diarrhea, as well as an algorithm for the diagnosis and management of patients with nosocomial diarrhea.

Nosocomial diarrhea is an acute episode of diarrhea, which was not available at admission and occurs after 3 or more days after admission [6]. Diarrhea is defined as at least for one day were ≥ 3  unformed stools or significant increase in acts of defecation above baseline [6,7]. Such  definition is clinically useful because the probability of the development of community-acquired viral, bacterial or parasitic infection after the third hospital day is  quite low. Therefore, physicians can be focused on the causes of diarrhea, which is more common in hospitalized patients.

Nosocomial diarrhea is common and is registered in 22% - 32% of patients [6]. In a recent study of 485 hospitalized patients diarrhea was found in 12% of cases, including 27% of patients hospitalized for 3 weeks or more [1]. In high-risk groups such as patients after stem cell transplant, diarrhea was found in 80% of cases [12].

Traditionally distinguished osmotic diarrhea, secretory and inflammatory. However, such division of hospitalized patients appears simplified due to the fact that they are often simultaneously by several factors: injury, inflammation, infection, diet modification, exposure to drugs and others [13]. In recent years, much attention is paid to the role of the intestinal microflora, which is a complex community, including ≥ 10¹³ microorganisms living in the gut, and plays an important role in maintaining human health [5,13]. In healthy microbiota and the host interact on the basis of mutual community: the owner provides the power supply and the environment, and the microbiota involved in digestion, metabolism, immune homeostasis, resistance to infection. In hospitalized patients taking antibiotics and other interventions, disrupting the balance, cause diarrhea [2-4]. Thus, broad spectrum antibiotics and high concentrations of antimicrobial agents in the intestinal  increases the risk of developing antibiotic- associated diarrhea (AAD).

Under the AAD meant diarrhea developing in patients receiving antibiotics and has no other reasons. Currently there are three main mechanisms of development of the AAD. First, antibiotics can have a direct effect on the mucous membrane of the gastrointestinal tract (GIT). This mechanism is not affiliated with the characteristic of this class of drugs antibacterial activity. For example, macrolides are agonists of motilinovie receptors and are able to accelerate the gastric motility, thus causing diarrhea. Clavulanic acid, part of the amoxicillin-clavulanic acid was also able to stimulate the motility of the small intestine. A penicillin is very rare  cause segmental colitis [11]. In such cases, antibiotic removal of bacteria that normally produce butyrate, a colonic epithelial cell nutrient, and break down undigested carbohydrates results in epithelial dysfunction and an increased osmotic load within the intestinal lumen, leading to diarrhea [3,4]. Another potential mechanism for AAD is decreased bacterial metabolism of bile acids because bile acids have a profound secretory effect on colonic epithelium [4]. Similar mechanisms by which microbiota alterations result in an increased susceptibility to infection (eg, with C. difficile) and contribute to the diarrhea associated with enteral feeding, chemotherapy, and radiotherapy are also being studied [13]. CDI also alters the intestinal flora [5]. In addition, the importance attached to individual differences in the microbial metagenome, which may play a role in predisposing patients to diarrhea, infection or severe disease [13].

Nosocomial diarrhea differs from diarrhea occurred outside the hospital, in several ways. Unlike acute diarrhea, which is often contagious, nosocomial diarrhea is not associated with dangerous epidemic periods [1, 6, 14]. Furthermore, the diagnosis of infections in hospitalized patients is complicated by  asymptomatic carriage (eg, C. difficile) and the lack of readily available diagnostic testing for other potential infectious diseases [7, 10, 15]. The rapid detection of infectious agents, in particular C. difficile and noroviruses, is desirable to limit transmission to other hospitalized patients [7,10].

Nosocomial infectious associated with  antibiotics

Clostridium defficile

The most important enteropathogens causing nosocomial diarrhea are C. difficile, which accounts for 25% of all cases of AAD and practically all cases of pseudomembranous colitis. C. difficile is an anaerobic spore-forming Gram-positive bacillus, received its specific name due to previously occurring difficulties in cultivation [13]. In studies of 30 - ies of the last century, its presence has been demonstrated in the gastrointestinal tract in 50 % or more of healthy newborns (but not adults). Therefore, it was considered a commensal long time. Currently, an infection caused by C. difficile, is one of the most common hospital-acquired (nosocomial) infections. Infection with C. difficile comes from an exogenous source, route of infection - fecal-oral [7]. By the end of the forth week of stay in hospital half of the patients infected with C. difficile [16]. This pathogen spores are widely distributed in the hospital environment (facilities, equipment, personnel and carriage in patients) and can be stored up to 40 days after discharge of the patient [16]. Thus, for the development of diarrhea caused by C. difficile, requires a combination of two conditions - changes in the composition of normal intestinal flora, promoting colonization of C. difficile, and pathogen infection from an exogenous source. Although there are over 400 strains of C. difficile, disease causing only strains producing toxins [17] that after endocytosis by epithelial cells of colon damage actin of cytoskeleton, causing cell death. A toxin A breaks the link cells of the colonic mucosa with the basement membrane and damages villous epithelium. Toxin B induces apoptosis, and its cytotoxic effect is expressed in more than 1000 times stronger than toxin A. Both toxins stimulate macrophages and monocytes that by interleukin -8 promotes tissue infiltration by neutrophils [17]. Severity of clinical manifestations depends on risk factors from the patient, and especially from its immunoreactivity. Patients with low levels of immunoglobulin G (IgG) to the toxin A has more severe disease, while those with high levels of immunoglobulin usually recover spontaneously [17]. CDI is usually associated with prior antibiotic treatment, but may be due to other factors that disorder the intestinal microflora [7,12].

CDI is diagnosed on clinical symptoms (such as diarrhea) and the presence of laboratory confirmation of the presence of toxin - producing strain of C. difficile in stool. Currently, diagnosis of CDI use enzyme immunoassay (EIA) that detects toxins A and B (rapid tests), immunoassays (common antigen), and nucleic acid amplification method, which aims to detect the genes encoding C. difficile toxins A and B. It isn’t need to determine the resistance C. difficile  to antibiotic clinically, but it can be performed in epidemiological surveillance  [15].

Diagnosis CDI is some difficulty due to the inability of many laboratories to do adequate testing. Identification of CDI in the feces should be considered in all patients with suspected AAD. In practice, diagnostic tests to identify the CDI should be used in all patients with a history of diarrhea and prior antibiotic (within the preceding three months, or if the diarrhea appeared after 3 days of hospitalization). The risk group include patients aged over 65 years, chronic comorbidities, and patients with negative test results on other types of intestinal infection [11].

In many countries, the level of awareness about this infection  is insufficient. Low vigilance medical staff in relation to this infection can lead to incomplete or incorrect diagnosis. As a result : 1) the treatment is delayed or not assigned a higher risk of serious illness and complications. 2) Infection control measures are delayed, which could lead to an activation of infection. 3) The incidence is underestimated. 4) It is increased the prescriptions for unnecessary and costly diagnostic tests [12].

Specific therapy of C. difficile- AAD  shows sick elderly, patients with comorbidities, patients in whom it is impossible to cancel an antimicrobial agent, while maintaining diarrhea, despite the abolition of the antibiotic caused it, if there is evidence of colitis (fever, leukocytosis, the results of endoscopy) [7].

First-line therapy comprising metronidazole, whose efficiency is higher than 90% at a dose of 500 mg PO 3 - 4 times a day for 10 - 14 days. [7] Vancomycin is also effective, which is the drug of choice in pregnancy, the ineffectiveness or intolerance to metronidazole, and is used in a dose of 125 - 500 mg orally 4 times a day 10 - 14 days [7].

Klebsiella oxytoca

Pathogenic strains of Klebsiella oxytoca produce a toxin that inhibits DNA synthesis [9]. Such strains cause 50%–80% of all cases of C. difficile negative, hemorrhagic colitis after antibiotics but are probably not a significant cause of nonbloody AAD [9]. For example, a prospective study of hospitalized patients with AAD identified cytotoxic K. oxytoca in 3 of 18 (16,7%) patients with bloody diarrhea but none of 89 patients with nonbloody diarrhea [6]. More recently, a laboratory study identified cytotoxic K. oxytoca in only 2,3% of 429 stool specimens ubmitted for C. difficile testing. This data confirming that K. oxytoca is relatively rare in routine stool samples [18]. Most patients are adults. The disease is presented with acute onset of abdominal pain, bloody diarrhea, and leukocytosis after exposure to penicillins or other antibiotics [9]. Diagnosis is supported by recovery of pure or predominant K. oxytoca from stool or colon aspirate. Few wild-type strains produce toxins and tests for toxin-producing K. oxytoca are not available clinically [6, 18]. Symptoms resolve upon antibiotic discontinuation, and therapy directed at K. oxytoca is not necessary [9].

Clostridium perfringens

Enterotoxin-producing type A C. perfringens is an established cause of food poisoning and rarely cause of AAD [5,8]. The majority of data supporting a role for C. perfringens in AAD come from cross-sectional studies showing a higher prevalence and bacterial counts of C. perfringens in symptomatic patients vs controls, and from outbreaks of nosocomial diarrhea associated with C. perfringens and no other pathogens [8]. Nevertheless  large studies suggest that only 1%–3% of diarrheal samples have C. perfringens as a potential cause; occasional studies report up to 8% as positive [5,7]. The median duration is 7 days, 1 in 5 patients have ≥10 stools per day, and patients treated by metronidazole. Pseudomembranes have not been reported [8]. Diagnostic testing is not widely available and <5% of wild-type C. perfringens strains are toxigenic, making culture impractical [17]. A research immunoassay has been developed to detect the enterotoxin (CPEnt) and polymerase chain reaction (PCR)  has  been used [5,17].

Others

Staphylococcus aureus is a cause of AAD rarely (0,2%–4%), especially with methicillin-resistant strains that produce toxins [5]. Salmonella species are a rare cause of AAD and pseudomembranous colitis [4]. Salmonella also rarely cause AMA and pseudomembranous colitis [4]. Role of Candida spp. (and in particular, Candida albicans) proved indirectly by its detection in the stool of patients with ADA (more than 10⁵ colony forming units (CFU) per 1 g of intestinal content) and based on the regression of AMA symptoms after nystatin application, but many investigators questioned the reliability this evidence [19].

Infectious Causes not Associated With Antibiotics

Norovirus is the predominant cause of infectious gastroenteritis in the community, accounting for up to 90% of outbreaks and 5%–30%  hospitalizations of patients with diarrhea [6,20]. In hospitals, norovirus is an important cause of outbreaks but the extent of sporadic infections is unknown [10]. The median duration of symptoms was 3 days and vomiting was absent in almost half of cases [20]. Otavirus, astrovirus, and adenovirus can spread nosocomially in young children [21]. Enterotoxigenic Bacteroides fragilis is an emerging cause of diarrhea in community settings, but its role in nosocomial diarrhea is unknown [15].

Infectious diarrhea in immunocompromised patients is often longer and more severe, but asymptomatic carriage is also common [5]. In addition to C. difficile, cytomegalovirus and gastrointestinal viruses (eg, rotavirus, adenovirus, norovirus) can cause significant morbidity in transplant patients [5,6,14]. Finally, parasites and bacteria that are typically associated with community-acquired diarrhea (eg, Giardia, Cryptosporidium, Strongyloides, Campylobacter) have been reported in transplant patients with hospital-onset diarrhea and should probably be considered when risk factors are present [5,6].

Non-infectious causes of nosocomial diarrhea

Drug-induced diarrhea can be inflammatory and non-inflammatory and caused by an effect on the intestine or the microbiota [4, 6, 11]. More than 700 drugs have diarrhea as a side effect and 15%–40% of patients on enteral feeding develop diarrhea [11,13]. As a result, edications and enteral feeding account for the majority of cases of diarrhea in hospitalized patients, especially intensive care unit, transplant, and cancer patients [4, 12, 14]. Antibiotics are estimated to be responsible for 5- 25% of drug-induced diarrhea but other medications also induce diarrhea commonly (Table 1) [5, 6, 11]. Rates are particularly high with antineoplastic agents and immunosuppressants; iatrogenic diarrhea due to laxative overdose is also common (Table 1) [6, 11]. Some medications contain sorbitol or other carbohydrates as excipients that can cause osmotic diarrhea [11, 13]. Enteral feeding is a potential cause of diarrhea that may be reduced by continuous infusion and adjustment of the formula and fiber content, but diarrhea persists in 10%–15% of patients [13].

A wide array of chronic conditions such as lactose intolerance, inflammatory bowel disease, irritable bowel syndrome, and diabetic enteropathy can contribute to diarrhea in hospitals. Colonic ischemia is an important cause of acute bloody diarrhea and abdominal pain that can present in hospitalized patients, especially vascular surgery and elderly patients [6].  In critically ill patients, hypoalbuminemia has been associated with diarrhea but it is unclear if this is a primary cause or a marker of the severity of illness and malnutrition [1]. Autoimmune reactions are a common cause loose stools during transplantation of hematopoietic stem cells [14].

The frequency and causes of diarrhea vary significantly among hospitalized patient groups. Patients hospitalized for short periods with few exposures have relatively low rates of diarrhea (≤5%). Patients with longer lengths of stay and more intense treatments, such as intensive care, transplantation, and cancer chemotherapy, have higher rates of diarrhea, ranging from15% to 80% (Table 2) [1, 5, 6, 12, 14]. In these groups, it can be difficult to determine the specific cause of symptoms but some etiologies are more  likely  than others  (Table 2).

The first step in evaluating a patient with suspected nosocomial diarrhea is to verify the presence of diarrhea and assess the onset, duration, and severity of symptoms. The frequency, consistency, and volume of stools should be determined and any signs or symptoms of dehydration, infection, or sepsis should be noted. Severe abdominal cramping suggests an inflammatory process but is not specific for infection. Vomiting is also nonspecific but should prompt consideration of norovirus. Bloody stools occur rarely in AAD (or CDI) with the exception of K. oxytoca hemorrhagic colitis. For severity assessment, a number of factors have been examined as predictors of severe CDI but there are no validated criteria for CDI or non–C. difficile diarrhea [6, 7]. A separate grading system is used for chemotherapy-induced diarrhea [22]. Clostridium difficile infection should be excluded in all patients with clinically significant diarrhea regardless of antibiotic exposure [7]. The medical history should be reviewed for preexisting conditions that may contribute to diarrhea (eg, inflammatory bowel disease), and iatrogenic causes like laxative overdose should be excluded. If diarrhea persists and laxatives or CDI are not responsible, additional evaluation may be indicated, depending on the presence or absence of blood in the stool, the host immune status, and the severity of symptoms. Medications should be reviewed to identify potential causes of drug-induced diarrhea (Table 1) [6, 22]. If the patient is receiving enteral nutrition, the rate and site of infusion and formula should be evaluated for optimization [13]. Norovirus testing by reverse transcriptase PCR should be considered in immunocompetent patients when vomiting is present, immunocompromised patients with persistent symptoms, and potential outbreaks when multiple patients or staff have similar symptoms on the same ward [20]. Testing for fecal white blood cells is insensitive and nonspecific and should not be  performed routinely. Testing for other infectious causes has a low yield except possibly in transplant patients [6]. In these patients, active cytomegalovirus infection and other gastrointestinal viruses such as norovirus, adenovirus, and rotavirus should be excluded but most cases are due to medications or graft-vs-host disease [6, 14]. In human immunodeficiency virus–infected patients or transplant patients with risk factors for community-acquired bacteria or parasites or a history of diarrhea prior to admission, stool culture and tests for parasites may be considered but should not be performed routinely.  Colonic ischemia should be excluded in patients with bloody diarrhea [6]. Testing is generally not available for enterotoxin-producing strains of C. perfringens, K. oxytoca, and S.aureus, most strains do not produce toxins.

In patients with normal immunity with mild diarrhea phased approach [6, 13]. Cancel laxatives, in the presence of CDI prescribe appropriate therapy [7]. Medications that are commonly associated with diarrhea should be discontinued and enteral nutrition, if present, should be optimized [3, 19]. Antidiarrheal agents  may be useful in selected C. difficile–negative cases. Immunocompromised patients and patients with severe diarrhea require frequent monitoring and earlier, more aggressive intervention. Guidelines are available for management of chemotherapy-induced diarrhea [22]. All patients with CDI or norovirus infection should be isolated as early as possible.

Probiotics have been shown to be effective in preventing pediatric AAD and treating childhood infectious gastroenteritis, but their safety and efficacy in hospitalized adults are unproven [3, 13]. In particular, caution should be used with probiotics in patients with compromised immunity or intestinal mucosa [7, 9]. In these patients, there is an increased risk of gut translocation of probiotic organisms, and rare cases of bacteremia, fungemia, and mortality due to probiotic strains have been reported [9]. This is an active area of research that will continue to evolve.

Nosocomial diarrhea is a common and underappreciated complication of hospitalization that is generally not caused by C. difficile. Most cases are noninfectious but surprisingly little is known about the other causes of nosocomial diarrhea, especially in intensive care unit, transplant, and cancer patients. Medications cause the majority of diarrhea via side effects, toxicity, and disruption of the intestinal microbiome, which in the future may be ameliorated by changes in management, prebiotics, or probiotics. There is a significant need for systematic prospective studies to define the epidemiology and impact of diarrhea in hospitalized patients and high-risk subgroups. In particular, the incidence of norovirus and other potential infectious causes needs to be clarified with studies. More data are also needed regarding changes in the microbiome introduced by hospitalization and common treatments and the role of the microbiome in diarrhea pathogenesis and complications.

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