Rebecca H. Sunenshine
Eileen L. Yee
Introduction
Diarrhea has been variably defined in a number of ways (e.g., ≥6 watery stools over 36 hours, ≥3 unformed stools over 24 hours for ≥2 consecutive days, or ≥8 unformed stools over 48 hours) and is a common condition among patients within healthcare facilities and among home healthcare patients [1]. Many, if not most, episodes of diarrhea that occur in hospitalized patients are related to therapeutic interventions. For example, drug side effects are a common cause of diarrhea, nausea, and vomiting. The increased osmotic load of enteral tube feedings on the large intestine is a common cause of diarrhea among patients in some long-term care settings. However, despite the frequency of such noninfectious etiologies, episodes of infectious gastroenteritis account for a significant proportion of all patients in healthcare settings who develop diarrhea with or without nausea and vomiting.
When evaluating one or more patients who develop gastrointestinal symptoms following admission to a healthcare facility, several clues point to an infectious etiology. These include not only associated findings, such as fever or elevated white blood cell (WBC) count, but also the disease course and spread within a population with specific risk factors. For example, antimicrobial agents are not only among the most common drugs responsible for diarrhea without an apparent infectious etiology (i.e., antibiotic-associated diarrhea) but also are the most common risk factor for disease caused by Clostridium difficile [2]. Thus, C. difficile in particular should be sought to explain either individual patients or clusters of patients who develop diarrhea following receipt of antimicrobial agents for unrelated conditions. Likewise, clusters of patients who develop diarrhea, nausea, and vomiting lasting only a few days, accompanied by symptomatic healthcare workers should lead to seeking a viral etiology, especially norovirus [3]. The most important aspect of pathogens responsible for infectious gastroenteritis is their ability to be rapidly transmitted in healthcare settings among patients who often are highly susceptible. Such outbreaks can be devastating and lead to significant increased costs, patient morbidity, and, in some instances, mortality.
The focus and scope of this chapter are the three most important infectious etiologies of gastroenteritis acquired in healthcare setting: C. difficile, norovirus, and rotavirus. Although there is no evidence that parasitic causes of gastroenteritis pose a significant threat for healthcare transmission, other bacterial agents, such as Salmonella and Shigella spp. are infrequently transmitted in such settings [4,5,6,7,8]. In the case of nontyphi Salmonella spp., Chapter 21 addresses food-borne transmission of infectious agents of gastroenteritis. However, there now are several concerning reports of nonfood-borne transmission in healthcare facilities of multidrug resistant, nontyphi Salmonella spp. [4,6]. These organisms act like other multidrug-resistant gram-negative bacteria, which are often transmitted via the hands of healthcare workers (HCWs) and are responsible for a variety of infections of sites ranging from the urinary tract to bloodstream; under such circumstances, patients and healthcare workers only occasionally develop gastrointestinal infection. Partly due
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to their very low infectious dose, Shigella spp. remain an important cause of infectious gastroenteritis in day care settings where child-to-child transmission occurs and can involve staff [9,10]. However, for reasons not entirely clear but likely include overall better infection control practices, outbreaks of shigellosis have been relatively infrequent in healthcare settings.
Clostridium Difficile
Epidemiology
Multiple risk factors for CDAD are cited in the literature, most notably prior antimicrobial use; with more than 90% of healthcare-associated C. difficile infections occuring after or during antimicrobial therapy [2,28]. Almost all antimicrobial agents, with the exception of aminoglycosides, have been associated with the development of CDAD. However, data suggest that broad-spectrum antimicrobial agents, which have a greater influence on the normal intestinal flora, are more likely to be associated with CDAD [2]. Results of several recent studies indicate that fluoroquinolones have emerged as the most important antimicrobial risk factor in CDAD outbreaks, superseding other antimicrobial agents, including clindamycin and β-lactam/β-lactamase inhibitors [19,29,30]. Receipt of multiple antimicrobial agents and longer courses of antimicrobials also are risk factors [2].
At least three studies have identified the following additional risk factors for healthcare-associated CDAD: age >65, severity of underlying illness, presence of a nasogastric tube, antiulcer medications, and duration of hospital stay [2]. Conflicting evidence exists regarding the contribution of stomach acid–suppressing medications, such as proton-pump inhibitors and histamine-2 blockers in the development of CDAD [29,31,32].
Specific populations appear to be at greater risk for developing CDAD than the general population. The majority of CDAD occurs in healthcare facilities [16] as do the majority of CDAD outbreaks [33,34]. This is likely due to the concentration in these facilities of affected patients who serve as reservoirs for infectious spores. These can be transmitted among patients via the fecal/oral route, often following contamination of the patient-care environment and/or the HCW's hands. Among hospitalized patients, medical patients are at significantly higher risk of CDAD than are surgical patients [21,31]. In addition, C. difficile is the most common infectious cause of acute diarrheal illness in long-term care facilities (LTCF) [35,36]. In nonoutbreak settings, the prevalence of C. difficile colonization in LTCF ranges from 4–20% [36] compared to a rate of <3% reported in healthy adults [20,28]. The LTCF population is associated with several other known CDAD risk factors including increased antimicrobial use, older age, and increased use of stomach acid–suppressing medications. These additional risk factors make determining which factors contribute most to the increased CDAD risk in LTCFs difficult.
Neonates represent another population with increased C. difficile colonization with rates ranging from 5–70% [28]. Ironically, despite these high carriage rates, neonates are much less likely to develop CDAD than are adults. Based on observations in rabbits, this is thought to be due to the
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lack of receptors to toxin A in the immature enterocytes of neonates [37].
Two events appear as prerequisites in the pathogenesis of CDAD: The colon's normal flora must be disrupted, as with antimicrobials, and C. difficile must be ingested, although not necessarily in that order [28]. Only toxigenic strains of C. difficile produce clinical disease, but toxin production does not guarantee symptomatic progression [16]. Other host factors can influence the clinical presentation, such as pre-existing colonization with C. difficile and the presence of humoral immunity. It has been suggested that colonization with C. difficile can actually protect against the development of symptomatic disease [38] which could be due to the development of immunity. Kyne et al. demonstrated that patients who became asymptomatic carriers had significantly greater antibody responses to toxin A than those who developed HA-CDAD [39]. This pathogen–host interaction, in which new exposure to the organism confers greater risk of developing disease than chronic colonization highlights the importance of exogenous over endogenous sources of infection in HA-CDAD.
Clinical Presentation
The incubation period between new exposure or, more specifically, ingestion of C. difficile and the manifestation of disease has not been well established. One study of serial stool cultures for C. difficile performed in hospitalized patients suggested that this interval is in most instances less than 7 days [38]. In a recent study of cancer outpatients however, the median interval between discharge from an inpatient healthcare facility where exposure was likely to have occurred and CDAD diagnosis was 20.3 days, ranging from 2–60 days [40]. This suggests a longer incubation period than had been previously thought. Distinct from the interval between exposure and symptom onset is the duration of increased susceptibility following exposure to an antimicrobial. Although symptoms can develop immediately after beginning antimicrobial therapy, their onset can be delayed up to 6–8 weeks after therapy is completed [16]. This reflects the alteration in bowel flora that can persist for several weeks following completion of some forms of antimicrobial therapy; during this time, a patient remains at increased risk for the development of CDAD whenever exposure to C. difficile occurs.
The clinical presentation of C. difficile is a continuum that includes asymptomatic carriage, diarrhea, colitis, PMC, and fulminant colitis [16]. It most commonly presents as mild to moderate nonbloody diarrhea, sometimes accompanied by low abdominal cramping. Systemic symptoms are typically absent, and physical exam is remarkable only for mild abdominal tenderness. Colitis, in contrast, tends to present with more severe symptoms, including profuse watery diarrhea, abdominal pain, and distention. Fever, nausea, and dehydration often are present. Occult blood can occur in the stool, but hematochezia is rare. Colonoscopy reveals a characteristic membrane with adherent yellow plaques usually in the distal colon, although occasionally it can be confined to the proximal colon and can be missed on exam.
Patients with severe colitis are at an increased risk of developing paralytic ileus and toxic megacolon [16], which can lead to a paradoxical decrease in diarrhea. Such severe cases can also present as fulminant colitis with acute abdomen and systemic symptoms such as fever and tachycardia. The presence of any of these complications requires an immediate surgical consult. A review of 11 patients with toxic megacolon revealed that 64% required corrective surgery, and once the patients underwent surgery for complications of CDAD, the mortality rate rose from 32% to 50% [41].
Recurrence is one of the most frustrating and challenging complications of CDAD. There is no universal agreement on a clinical definition of CDAD reinfection versus relapse. One strategy defines relapse as recurrent symptoms occurring within 2 months following CDAD diagnosis and a reinfection as symptoms that develop after 2 months [42,43,44]. However, studies of patients who have “relapsed” within 2 months of a previous CDAD episode indicate that 48–56% of such patients are actually reinfected with a different strain of C. difficile[43,44]. Whether caused by a reinfection versus true relapse, 12–24% of patients develop a second episode of CDAD within 2 months of the initial diagnosis. If a patient has two or more prior episodes of CDAD, the risk of additional recurrences increases to 50–65% [41]. These statistics highlight the importance of the prevention strategies discussed later.
Diagnosis
A variety of methods to detect C. difficile exists from tissue culture assays to enzyme immunoassays, each of which has advantages and disadvantages (Table 33-1). Most clinical laboratories use enzyme immunoassays that have a rapid turnaround time and require less technical expertise than tissue culture does. Although the negative predictive value hinges on the sensitivity of the particular
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assay, in most instances one negative result is enough to rule out CDAD. Nonetheless, a high clinical suspicion can warrant repeat testing. Due to its cost and turnaround time of approximately 72 hours, anaerobic bacterial culture is the method employed least by hospitals to diagnose CDAD [45]. This method's accuracy also varies considerably by institution due to the use of nonstandardized methods and culture media. The primary advantage of anaerobic culture is that it lends itself to molecular typing of strains, which can be useful in an outbreak setting. (Table 33-1).
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TABLE 33-1 |
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Treatment
Discontinuation of the inciting antibiotic is the most important step in the initial treatment of CDAD [43]. In addition, 10 days of appropriate oral antimicrobial therapy is recommended [46,47]. In a large study of 189 patients with CDAD, 97% of them responded to initial antibiotic therapy [48]. Although this study was based on treatment predominantly with oral vancomycin, several older studies comparing oral metronidazole to oral vancomycin for the treatment of CDAD indicate that metronidazole has been, at least historically, as effective and less expensive than oral vancomycin [49,50]. In addition, the use of metronidazole avoids the increased risk of promoting vancomycin resistance that could result from the widespread use of oral vancomycin. For these reasons, most experts have recommended metronidazole as the first-line antimicrobial therapy for CDAD [46,51]. A recent prospective observational study reported a 78% response rate to therapy with metronidazole [52], which is significantly lower than previously published response rates to both oral vancomycin and metronidazole. Coupled with the emergence of a more virulent strain, this study has led to a slightly different treatment strategy. For the majority of CDAD patients, metronidazole remains appropriate first-line treatment provided that the clinician is vigilant about following the patient for response to therapy [47]. However, alternative first-line therapy, such as oral or intraluminal vancomycin, should be considered for patients who present with moderate or severe disease.
In addition, it is important to realize that mild disease caused by C. difficile can quickly progress to moderate or severe disease and that these distinctions are not always easy to make. Specific symptoms that suggest moderate disease severity include fever, profuse diarrhea, abdominal pain, and leukocytosis [46]. Severe disease is said to occur when complications of colitis arise, such as sepsis, volume depletion, electrolyte imbalance, hypotension, peritonitis, paralytic ileus, or toxic megacolon. Other authors include a white blood cell (WBC) of >20,000 cells/millimeter (mm)3 and elevated creatinine as indicators of severe disease [47,53]. Because of possible disease progression despite appropriate therapy, the treating clinician should follow a patient treated for CDAD closely for symptom improvement within 1–2 days of initial therapy [47]. Fever should subside within 24–48 hours, and diarrhea should resolve within 2–5 days [47,48]. If the disease progresses after initiation of treatment, additional or alternative therapeutic options should be considered, including a surgical consult for any signs of toxic megacolon, peritonitis, or sepsis (Table 33-2). However, in the absence of clinical deterioration, a slow clinical response should not lead to the conclusion that a patient has failed treatment before 6–7 days of therapy [54]. Finally, therapeutic response should be based purely on clinical signs and symptoms; performance of a repeat toxin assay as a “test of cure” should be discouraged because patients can remain colonized with toxin-producing strains following recovery [55].
Prevention and Infection Control Strategies
Two approaches to reducing C. difficile rates have been described: (1) interruption of horizontal spread of the
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organism within healthcare facilities and (2) reduction of the individual's risk of acquiring the disease once exposed to the organism [1]. Because prior antimicrobial use is associated with the vast majority of patients who develop HA-CDAD, restriction of antimicrobial use is potentially an important infection control strategy to reduce patient risk. However, with the exception of clindamycin [56,57] and cephalosporin restrictions [58,59], there remain relatively few reports demonstrating success by reducing the use of a specific class of agents to control CDAD. Vancomycin has been studied for the eradication of asymptomatic colonization in patients; however, its effects are not sustained, and patients can be at increased risk for prolonged carriage after treatment is discontinued. For this reason, experts do not recommend the treatment of patients colonized with C. difficile as an infection control strategy [1]. Significant intraluminal levels of metronidazole are achieved only in the presence of diarrhea, which renders the drug ineffective for patients with asymptomatic colonization [43].
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TABLE 33-2 |
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Spread of C. difficile in healthcare facilities has been well documented in the literature; spread occurs primarily via infected humans (both symptomatic and asymptomatic) and contamination of the patient-care environment [1,60]. The most effective means of decreasing horizontal spread of C. difficile has been the combination of vigilant hand hygiene and isolation precautions. The literature contains both direct and indirect evidence for contamination of HCWs' hands in endemic and outbreak settings. The 1994 Hospital Infection Control Practices Advisory Committee (HICPAC) guideline for isolation precautions in hospitals recommends contact precautions for symptomatic patients which includes placing them in a private room or cohorting them with other symptomatic patients, as well as using gowns and gloves upon entering the patient's room [61]. One hospital reported a 60% decrease of CDAD after instituting a more stringent infection control program including increased enforcement of contact precautions, a monthly educational program, triclosan-containing hand soap, and increased environmental cleaning [62].
It is recognized that alcohol is not effective in killing C. difficile spores [63]. This information has led infection control personnel to be concerned that the recent increased incidence of CDAD is due to the rise in the use of alcohol-based hand rubs (ABHR) in healthcare facilities. To investigate this hypothesis, Boyce et al. evaluated the trends of ABHR use and the percentage of positive C. difficile toxin assays from 2000 to 2003 in a 500-bed tertiary care hospital [64]. These authors calculated a 10fold rise in the use of ABHRs while the percentage of all hand-hygiene episodes performed using soap and water decreased from 90% in 2001 to 15% at the end of 2003. During that period, the proportion of positive C. difficile toxin assays also decreased from 10.3% in 2000 to 7.4% in 2003. These data suggest that factors other than increased use of alcohol-based hand-hygiene products are responsible for the recent rise in HA-CDAD. Despite this, if a hospital is experiencing an outbreak, it is prudent for HCWs to hand wash exclusively with soap and water after glove removal in the care of known CDAD patients [63].
Environmental contamination due to C. difficile is exacerbated by the persistence of spores that can be highly resistant to routine disinfection and survive on dry surfaces for up to 6 months [65,66]. The rate of surface contamination increases in proportion to the C. difficile status, severity of diarrhea, and incontinence of patients in the area [1]. Although asymptomatic carriers of C. difficile can serve as reservoirs for disease transmission within healthcare facilities, epidemiologic studies suggest that they appear less contagious than do symptomatic patients. Furthermore, the degree of environmental contamination surrounding asymptomatic carriers is lower than that of surrounding patients with symptomatic disease. Patient-care items such as reusable electronic rectal thermometers have been implicated in outbreaks; and dedication of single-use items to individual patients can eliminate this source of contamination [1,33]. “High-touch” surfaces in patients' bathrooms (e.g., light switches) also have been implicated in outbreaks and should be targeted for enhanced environmental cleaning.
No well-controlled trials of disinfectant use in environmental control strategies for C. difficile have been conducted; however, the use of both unbuffered and phosphate-buffered hypochlorite solutions (bleach) has been shown to effectively decrease rates of C. difficile contamination, and some studies suggest that cleaning with bleach can lower CDAD rates [65,67,68,69]. Moreover, these studies suggest that environmental contamination is highest and therefore the likelihood of success of environmental cleaning strategies is greatest when CDAD rates are at their highest. Although there are no Environmental Protection Agency (EPA)–registered disinfectants with a claim for C. difficile spore inactivation, the CDC/HICPAC Guideline
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for Environmental Infection Control in Healthcare Facilities recommends “meticulous cleaning followed by disinfection using hypocholorite-based germicides as appropriate” [65]. When used as part of a cleaning strategy to reduce environmental contamination with C. difficile spores, household bleach should be diluted 1:10 to make a final working concentration of sodium-hypochlorite of at least 5,000 parts per million. The bleach solution should be prepared daily. After applying the solution to visibly clean surfaces, it should be allowed to remain moist for at least a 10-minute contact time and then be wiped off to prevent buildup of hypochlorite residual. Unfortunately, sodium-hypochlorite solutions at this concentration can cause respiratory irritation and will cause many surfaces to deteriorate; these solutions can “pit” stainless steel and aluminum and discolor several other materials. Many medical devices, especially electronics, are incompatible with chlorine-based cleaners, highlighting the need to develop other methods to reliably eradicate C. difficile spores in healthcare settings. Conducting an infection control risk assessment to identify practices and procedures that facilitate fecal contamination of environmental surfaces is one approach to minimizing contamination, thereby making the problem more manageable.
Surveillance
In light of recent reports of increasing rates and severity of CDAD in the United States, Canada, and parts of Europe, all associated with a more virulent strain of C. difficile, the surveillance for CDAD should be conducted in all healthcare facilities providing care to patients at increased risk for disease. Although there are currently no widely accepted surveillance definitions for CDAD, simply tracking the number of patients with new positive C. difficile laboratory tests over time could lead to earlier detection of either outbreaks or increasing disease trends. If an increase is noted, consideration should be given to tracking outcomes. Evidence suggests that if increased severe outcomes are noted, measures to more rapidly diagnose CDAD and escalate therapy (e.g., empowering nonphysician personnel to order tests, alerting clinicians to patients with signs of early severe disease) could reduce these severe outcomes [47].
Other principles of surveillance for HA-CDAD include considering the disease to be community acquired in patients who are symptomatic at the time of admission or in those who become symptomatic within a short period (e.g., ≤48 hours) following admission. However, because there is increasing recognition that patients exposed to C. difficile while hospitalized can develop symptoms within 1–2 months following discharge [40], consideration should be given to including such recently discharged patients with community-onset CDAD in an institution's definition of HA-CDAD. Finally, because the risk of being exposed to and acquiring C. difficile increases in proportion to the duration of hospitalization, rates of CDAD should be expressed as cases per 10,000 patient-days.
Outbreak Management
Whether an outbreak or an increasing trend in HA-CDAD rates is noted, specific steps should be undertaken. First, isolation precautions for CDAD patients should be reinforced by paying particular attention to placing them in single rooms or cohorting them with other CDAD patients and ensuring that CDAD patients do not share bathroom facilities with non-CDAD patients. The appropriate and consistent use of barrier precautions as part of contact precautions should be reinforced, and personnel should be instructed to wash their hands with soap and water after removal of gloves while leaving the CDAD patient room.
Policies and practices surrounding the reuse of patient care equipment for both CDAD and non-CDAD patients should be reevaluated. As noted, for example, reusable electronic rectal thermometers should be replaced throughout the facility with single-use, dedicated-use, or nonrectal thermometers, and the cleaning and reprocessing of all bedside commodes should be reviewed. If sodium hypochlorite was not already part of the institution's cleaning and disinfection strategy for CDAD patients, it should be introduced in recognition of the limitations outlined earlier. If bleach cleaning is already used, the frequency of cleaning in CDAD patients' rooms should be increased if possible with priority given to regular terminal cleaning. If increased rates continue despite these measures, additional attention should be given to the appropriateness of antimicrobial prescribing. Several institutions reporting successful control of the epidemic strain have achieved this success only after both enhancing infection control measures and reducing overall antimicrobial prescribing including fluoroquionlones [19,70].
Rotavirus
Rotaviruses are RNA virus members of the family Reoviridae. They were discovered in 1973 by Bishop and colleagues, who performed electron microscopy on duodenal biopsies from children hospitalized in Australia during an outbreak of acute gastroenteritis. These viruses were named for their characteristic “wheel-like” appearance; they are the most common cause of severe gastroenteritis among children less than 5 years old and have caused outbreaks in daycare centers among young children and occasionally in nursing homes for the elderly. The rotavirus genome consists of 11 segments of double-stranded RNA; 6 of these encode for structural proteins and 5 for nonstructural proteins enclosed in a triple-layer, nonenveloped, icosahedral capsid that is 70 nm in diameter. The seven major groups of rotavirus are identified as Groups A through G. Human infections are primarily caused by Groups A, B, and C. Within these groups, specific serotypes are further classified
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by their outer viral capsid protein (VP), known as VP7 (a glycoprotein, or G-protein) and VP4 (a protease-activated protein, or P-protein). VP7 and VP4 also are the proteins targeted for vaccine development because they induce neutralizing antibodies. Another important structural protein is VP6, which determines the group specificity (A though G), and provides the basis for commercial immunoassay testing.
Epidemiology
The highest incidence of rotavirus infections is reported in children between the ages of 6 to 23 months. By the age of 5, most children will have been infected with it. The first rotavirus infection usually is the most severe and subsequent infections tend to be milder due to stimulated immunity. In the United States, community-acquired rotavirus infections are estimated to cause 2.7 millions diarrheal episodes, approximately 410,000 physician visits, 205,000–272,000 emergency department visits, 55,000–70,000 hospitalizations, and approximately 20–60 deaths each year [71,72].
Rotavirus infections have a predictable winter peak in incidence in the temperate climate of the continental United States. In the Southwest, rotavirus lasts from October to December whereas in the Northeast, it occurs from March to May [73]. However, in tropical climates, rotavirus infections tend to occur throughout the year.
Primary transmission of rotavirus is through the fecal-oral route. Spread also occurs through person-to-person contact and contamination of fomites, environmental surfaces, water, and food. Transmission through either large droplets or airborne particles has been hypothesized on the basis of viral RNA detected in air samples collected from rooms of hospitalized children. Infected persons can shed large quantities (107 to 1012/gram) of virus in their stools with a duration of 4 days; however, there have been reports of immunosuppressed patients shedding rotavirus for up to one month even after resolution of symptoms [74]. The typical incubation period for rotavirus infection ranges from 1–3 days after an infectious dose as small as 10 virions [75].
Although the highest incidence of rotavirus infections occurs in young children, sporadic rotavirus infections have also occurred among the elderly and adults in close contact with infected children. Infections in neonates may occur; however, they often are asymptomatic because neonates are likely to be initially protected by maternal antibodies [76]. Rotavirus outbreaks have been well documented in hospitals, neonatal intensive care units, pediatric oncology wards, day care centers, and nursing homes [76,77,78,79]. Although it can be difficult to differentiate between infections acquired in hospitals versus in the community but responsible for hospitalization, approximately 55,000–70,000 hospitalizations per year are associated with rotavirus infection [80,81]. Healthcare-associated rotavirus infections can increase length of hospital stay from 2 to 6 days, directly impacting health care costs [76,82]. Contaminated fomites (i.e., toys) and asymptomatic HCWs carrying rotovirus are speculated to play a role in transmitting healthcare-associated rotavirus.
The survival of rotavirus on hands and environmental surfaces ranges from a few days on hands to 2 weeks on inanimate objects. Rotavirus has been found on the hands of more than 70% of HCWs involved in the care of children with community-acquired rotavirus infection and on the hands of 20% of HCWs not in direct contact with these children [76]. Patient risk factors for healthcare-associated rotavirus infection include prolonged hospital stay, exposure to hospital visitors with gastroenteritis (i.e., infected sibling) and underlying conditions such as prematurity, low birth weight, compromised immunity, and malnutrition [76,81]. Institutional factors associated with outbreaks include failure to isolate patients and implement contact precautions, poor hand hygiene, and use of inadequate disinfection procedures.
Both in the United States and across the globe, serotypes G1, G2, G3, G4, and P[8] account for more than 90% of the circulating rotaviruses. Surveillance for rotavirus strains in the United Stats is conducted by the National Rotavirus Strain Surveillance System at the CDC, which was established in 1996 among 11 voluntary hospital laboratories [83].
Clinical Presentation
Persons infected with rotavirus generally present with acute vomiting followed by watery, nonbloody, and profuse diarrhea with or without fever [84]. Because the disease process is more severe as a first infection, children tend to have episodes that are more severe. Although many adults also are susceptible to rotavirus, they tend to be either asymptomatic or have milder infections. Elderly and immunocompromised persons can also be more vulnerable to complications of dehydration resulting from rotavirus infection.
Diagnosis and Treatment
Laboratory confirmation is achieved by the detection of viral antigen in the stool or an increase in antibody titers in paired sera. Most hospitals use a commercial, monoclonal antibody, enzyme immunoassay (EIA) for stool testing of group A rotaviruses. Further laboratory testing for other rotavirus groups, such as group C, is limited to research laboratories.
Currently, no specific antiretroviral therapy is available for rotavirus illnesses. Supportive therapy is the mainstay of treatment using oral rehydration fluids or intravenous fluids [85]. Passive immunoglobulin therapy, such as hyperimmune bovine colostrum or intravenous gamma globulin, has been used and should be considered for
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immunocompromised patients with severe gastroenteritis; however, this treatment remains experimental.
Prevention and Control
In early 2006, the Advisory Committee on Immunization Practices (ACIP) recommended routine use of the recently FDA-approved rotavirus vaccine, RotaTeq® (Merck, Blue Bell, Pennsylvania), to prevent rotavirus gastroenteritis in children. Use of trade names and commercial sources is for identification only and does not imply endorsement by the Centers for Disease Control and Prevention or the U.S. Department of Health and Human Services. RotaTeq® vaccine is a live, oral vaccine prepared from five bovine-human reassortment rotaviruses (G1, G2, G3, G4, and P[8]). The recommended administration schedule is at 2, 4, and 6 months of life. Vaccine safety and efficacy studies have included more than 60,000 children worldwide. This vaccine is 74% effective in preventing G1–G4 rotavirus infections of any severity through the first rotavirus season following vaccination (95% confidence interval, 66.8 to 77.9%) and 98% effective in preventing severe G1–G4 rotavirus gastroenteritis (95% confidence interval, 88.3 to 100.0%) [86]. Another rotavirus vaccine, Rotarix®(GlaxoSmithKline Biologics, Rixensart, Begium), which is an attenuated human rotavirus strain of serotype G1P[8], also has been developed but has not yet been licensed. Both vaccines were tested in large clinical trials of more than 60,000 to ensure safety; no evidence was found that either vaccine was associated with intussusception. Breast-feeding could have some effect in preventing rotavirus infections in infants, but more research is needed. The use of probiotics, such as Lactobacillus, has been reported but lacks substantial evidence for effectiveness.
Control measures during outbreaks of rotavirus have consisted of isolating or cohorting ill patients, using contact precautions to prevent secondary transmission, cleaning and disinfecting contaminated surfaces and fomites (i.e., toys, diaper-changing areas, and medical devices), strictly enforcing work restrictions for symptomatic HCWs until 24–48 hours following symptom resolution, encouraging proper hand-hygiene practices, educating staff regarding rotavirus infection, and restricting patients and visitors with gastroenteritis from entering playrooms. The most effective environmental control strategy to inactivate rotavirus is cleaning and disinfecting surfaces [65]. General categories of hard surface disinfectant chemicals that are effective against rotavirus include, but are not limited to, preparations with a high alcohol content (i.e., quarternary ammonium or phenolic preparations with 79–95% ethanol) and chlorine-based products that contain at least 800 parts per million sodium hypochlorite (e.g., a 1:50 dilution of household bleach) [65,74,87]. Also, products with EPA—registered label claims for effectiveness against rotavirus can be used. Heating to temperatures of more than 60°C (i.e., heat pasteurization) is also effective rotavirus inactivation.
Norovirus
Noroviruses are single-stranded RNA viruses from the Calicivirdae family; they were discovered in 1972 by Kapikian and colleagues from stools collected in 1968 during an outbreak of gastroenteritis in an elementary school in Norwalk, Ohio. Formally referred to as “Norwalklike viruses” or “small, round-structured viruses,” noroviruses are nonenveloped, icosahedral, and small (27 nm in diameter). They are genetically diverse and have been identified in both humans and animals. Noroviruses have been classified into several different genogroups, GI to GV, which can be further divided into more than 25 genetic clusters through sequencing. Only strains within genogroup GI, GII, and GIV are known to affect humans.
Epidemiology
In the United States, norovirus infections are estimated to cause 23 million illnesses a year. Infection can occur year-round but has been referred to as the “winter-vomiting” disease because of its winter predilection and number of patients who present with vomiting.
Noroviruses can be transmitted by multiple routes, such as contaminated food/water and environmental surfaces/fomites, and direct contact, and airborne vomitus droplets [88,89]. The ability of noroviruses to cause infection in persons exposed to less than 100 viral particles with an incubation period of less than 2 days spread through multiple routes persists in the environment on both porous and nonporous surfaces and its relative resistance to inactivation with common cleaning agents, such as quaternary ammonium and phenolic compounds, allow this virus to cause widespread outbreaks with high attack rates.
Norovirus outbreaks have been frequently reported in LTCFs, hospitals, camps, cruise ships, and other areas where crowding occurs [3,90,91]. In 1982, Kaplan and colleagues created a set of criteria for identifying suspected norovirus outbreaks without laboratory confirmation based on clinical and epidemiologic observations because laboratory tests were still being developed at that time [92]. These criteria include vomiting reported in more than 50% of affected persons, median incubation period of 24–48 hours, median duration of illness lasting from 12–60 hours, and no other bacterial or parasitic agents identified in stool specimen. Reevaluation of the Kaplan criteria indicated a sensitivity of 68% and specificity of more than 99% in identifying norovirus outbreaks, proving it to be a useful diagnostic tool, especially since laboratory tests are not widely available [93]. Few documented healthcare-associated outbreaks of norovirus have been reported in the United States; however, data from other regions that conduct surveillance for these events, such as Europe and Australia, indicate that norovirus is the most common agent causing healthcare-associated outbreaks of acute gastroenteritis.
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Surveillance data from the United Kingdom and Wales oxduring 1990–1995 suggest that 39% of all norovirus outbreaks occurred in hospitals and 37% in LTCFs [94]. The economic impact of these healthcare-associated outbreaks was estimated to have direct costs of $184 million dollars annually [94]. Other than the strong association between close proximity to other patients with active vomiting and an increased risk for norovirus infection, risk factors for healthcare-associated outbreaks remain unclear [95]. In the United States, the predominant genotypes responsible for both community- and healthcare-associated infections are GII (79%) followed by GI (19%) [96].
Clinical Presentation
The incubation period for norovirus infection ranges from 24–48 hours with a median of 33 hours. Infected persons generally present with acute onset, explosive vomiting, and nonbloody diarrhea with or without fever. Recent studies suggest a genetic component to susceptibility of persons to norovirus infection because volunteer studies have demonstrated a proportion of volunteers infected with norovirus who remain asymptomatic [97]. Other symptoms can include abdominal cramps, nausea, and occasionally a low-grade fever; however, illness usually is self-limiting and should resolve in 3–7 days. Dehydration, especially in those who are very young or elderly, can require prompt medical attention. Because of the large genetic diversity of noroviruses and the lack of protective cross-immunity induced by different strains reinfections with norovirus are frequent with no observable long-term immunity.
Diagnosis and Treatment
Diagnosis of individual patients or outbreaks of norovirus infection require that stool (preferred) and/or vomitus samples be collected and sent to a state health department or research laboratory for detection of viral RNA using the reverse-transcription (RT) polymerase chain reaction (PCR), or RT-PCR. Samples can then be sequenced at standardized regions of the viral genome to allow for typing of isolates; comparison of such genotypes could unmask related and unrelated events during an outbreak. In addition, the Kaplan criteria can be used while awaiting laboratory results or in the absence of available testing. At present, no antiretroviral medications are available to treat norovirus infections. Management involves providing supportive care, including rest and rehydration with oral or intravenous fluids [85].
Prevention and Control
No vaccines are currently available to prevent norovirus infection. Although noroviruses are common and highly contagious and require only a small inoculum for infection, the risk of infection can be reduced by frequent and appropriate hand hygiene, avoidance of potentially contaminated food and/or water, and adequate disinfection of contaminated environmental surfaces and/or fomites [63,65].
Strategies successfully used in the past to manage healthcare-associated norovirus outbreaks include the early detection and/or suspicion of norovirus infections; control measures, such as isolating or cohorting patients using contact precautions; and, in some instances of ongoing widespread outbreaks, closure of wards or units to new admissions. Because nonenveloped viruses such as norovirus can require a higher concentration of alcohol for inactivation than is commonly available in some ABHRs [63] if outbreaks occur and persist while using the ABHR, it is prudent to perform hand washing with soap and water.
Other interventions to reduce secondary transmission include educating of HCWs and patients regarding the risks related to and prevention of norovirus transmission, reinforcing appropriate hand-hygiene measures, and promptly cleaning and containing body fluid spills. Disinfecting of contaminated surfaces/fomites with chlorine-based products (e.g., a 1:50 dilution of household bleach) or EPA—registered disinfectants with label claims for norovirus or its test surrogate (feline calcivirus [FCV]) also should be used [65]. If outbreaks continue despite this level of disinfection employing an even higher level disinfection with a 1:10 dilution of household bleach as recommended for C. difficle outbreaks could be beneficial. Ill HCWs involved in direct patient care and handling of hospital food should refrain from working until 24–48 hours after symptoms resolve [98]. Use of proper personal equipment such as gowns, masks, and gloves when cleaning up body fluid spills and disinfecting contaminated surfaces/fomites is recommended [65].
Acknowledgment
The authors wish to thank Lynne Sehulster, Ph.D., for her review of the manuscript with regard to environmental disinfection strategies and Marc-Alain Widdowson, VetMB, MA, MSc for his review of the manuscript with regard to rotavirus and norovirus epidemiology, clinical presentation, diagnosis, and control.
References
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