Diarrhea caused by bacterial, viral, and/or parasitic infection represents a significant worldwide healthcare burden. Each year, there are two billion instances of diarrheal disease globally, resulting in nearly two million deaths.1 The World Health Organization estimates that diarrhea is the cause of or is a major contributor to approximately one-quarter of all post-neonatal childhood deaths.2 In the United States, an estimated 1.4 episodes of acute diarrhea occur per person each year.3 Though most cases of diarrheal disease are generally self-resolving and not life-threatening in immunocompetent individuals, certain bacterial and viral infections can result in serious clinical morbidity and even death.
On a high level, diarrheal infection can be classified into two categories based on the source of infection: healthcare-associated diarrhea and community-acquired diarrhea. Healthcare-associated diarrhea is a diarrheal infection acquired within the hospital or in connection with receiving medical care. Clostridium difficile is typically the cause of these infections, which are a major healthcare concern. Community-acquired diarrhea, on the other hand, are those infections caused by environmental enteric bacteria, viruses, or parasites. These infections can be caused by a number of different sources including contaminated food and water sources, and are typically milder in presentation than healthcare-associated diarrhea.
Healthcare-associated c.diff
Healthcare-associated diarrhea caused by C. difficile is a life-threatening disease that remains a major concern of healthcare providers. In fact, C. difficile infection (CDI) is the second leading cause of healthcare-associated infection (HAI) in the United States, behind only methicillin-resistant Staphylococcus aureus (MRSA) infection. In the United States, more than 250,000 CDI occur annually, resulting in 14,000 deaths and a total cost for treatment of $1 billion.4 Recent exposure to antimicrobials is the leading risk factor for development of CDI, as antimicrobials will deplete the normal flora of a patient’s gastrointestinal tract, leaving the patient susceptible to overpopulation with C. difficile if exposed to the bacterium.
Transmission of C. difficile spores to a patient frequently occurs via the hands of healthcare workers. Around half of affected patients first show symptoms of CDI during hospitalization, while the other half first show symptoms in long-term care facilities or are those who were recently cared for in a hospital or clinic.4 While there is no widespread antimicrobial resistance among C. difficile isolates currently, their ease of spread and associated clinical implications have continually frustrated healthcare providers and have placed a premium on preventative measures that can be taken to reduce prevalence of these infections.
Diagnostic tests for CDI have evolved over time to address the time-critical need for accurate detection. Until recently, cytotoxic culture was widely considered the gold standard for detection of CDI. This technically challenging test, however, is associated with very long turnaround times, sometimes upwards of 10 days. Antibody-mediated enzyme immunoassays (EIA) were the first widespread attempt to reduce the turnaround times for detection of CDI; however, these assays have not provided the sensitivity necessary to accurately detect CDI and replace cytotoxic culture as the preferred diagnostic.
Nucleic-acid amplification tests (NAATs) have migrated into a routine diagnostic adopted by many laboratories. These tests can provide the necessary sensitivity and specificity to accurately diagnose CDI with associated turnaround times short enough so that infection-control measures can be taken quicker to minimize chances of the infection spreading throughout a healthcare facility. These tests, however, are associated with greater costs than EIAs and cytotoxic culture, so their adoption has been somewhat slow to date. Testing algorithms that utilize EIA testing as a screening test with reflex testing of the positive samples by NAATs have been proposed as a means to provide rapid and accurate testing for CDI that is cost-efficient.5
Community-acquired diarrhea
Community-acquired diarrhea affects millions each year in the United States alone, second only to respiratory illness for prevalence and stated reason for physician visit. These infections are typically transmitted by contaminated food or water sources, but can also be transmitted person-to-person, as in the case of Norovirus. Typically, in healthy adults, these infections are self-limiting and antimicrobials are not required to clear them. Community-acquired diarrhea can, however, have greater clinical implications in the very young, the elderly, and the immunocompromised. Symptoms associated with these infections range from asymptomatic to mild symptoms including watery diarrhea with nausea to the most severe symptoms, which include diarrhea and nausea accompanied with fever/chills, abdominal cramps, hypotension, and in the case of shiga-toxin producing E. coli (STEC), the potentially fatal condition hemolytic uremic syndrome (HUS).
The current diagnostic challenge associated with detection of community-acquired diarrhea is twofold. Since clinical presentation of diarrheal disease does not narrow down the potentially responsible pathogen(s), physicians often end up taking the “shotgun” approach to diagnostic testing by ordering testing for a majority of stool pathogens. If physicians are able to characterize the patient’s history, it could greatly narrow the number of diagnostic tests necessary for a given patient. On the diagnostic end, stool culture and ova and parasite (O&P) remain the gold standard diagnostics. Though generally considered sensitive and specific, these procedures are labor-intensive, unpleasant for technicians, can take as long as five to seven days to produce definitive results in the case of stool cultures, and require a high degree of technical skill in the case of performing O&Ps.
Together, the excessive ordering of stool pathogen testing by physicians paired with less-than-ideal diagnostic options has led to what some consider significant inefficiencies in the clinical laboratory. As a result, medical technologists can spend unnecessary time working up negative stools, which can account for upwards of 95% of stools samples submitted for testing. Confirmation of a negative stool sample takes as little as one to two hours with a rapid diagnostic test, allowing laboratories to reallocate medical technologist time to other priorities.
Rapid diagnostics for stool pathogens
Since treatment decisions can vary depending on the identity of the infectious agent and the overall health of the patient, rapid identification of pathogenic bacteria, viruses, and parasites from a stool specimen is crucial. From a therapeutic standpoint, rapid testing for stool pathogens can improve patient management decisions and minimize the use of inappropriate or unnecessary antimicrobials. This is especially important when it comes to detection of STEC, where continued antimicrobial exposure may increase the risk of a patient developing HUS.6
From a public health standpoint, rapid diagnostics for stool pathogens can trigger outbreak investigations earlier for such pathogens as Salmonella and Vibrio. Rapid identification of contagious stool pathogens like Norovirus and Shigella can allow for the proper infection control measures to be taken within a hospital or outside of a hospital at such places as long-term care or daycare facilities to minimize the spread of infection. Rapid diagnostic results can also mitigate further downstream testing, such as colonoscopies, when the origin of diarrheal infection is yet to be determined due to the slow turnaround time of conventional diagnostic methods.
Rapid diagnostics for stool pathogens have only recently emerged as viable options for testing for community-acquired diarrhea. Antibody-mediated EIA methods have shown the ability to shorten turnaround times for such stool pathogens as STEC; however, these kits lack the multiplexing capabilities necessary to replace culture for routine screening and may still require 12-to-24-hour turnaround times. Multiplex molecular methods are very well suited as the diagnostic platform for stool pathogens, because these tests can target a majority of stool pathogens at one time. The sample-to-results automation and rapid turnaround times of these tests will result in improved workflow efficiencies in the clinical laboratory. The improved sensitivity of molecular-based tests over culture will also provide the accurate results necessary for earlier optimization of patient management, better infection control, and quicker public health response to potential outbreaks.
Diarrheal illness will continue to be a burden to healthcare providers worldwide. Rapid diagnostic tests for stool pathogens may provide a means to minimize the impact of this burden throughout the entire hospital.
References
- World Health Organization. Diarrhoeal Disease: Fact Sheet N°330 April 2013. http://www.who.int/mediacentre/factsheets/fs330/en/index.html. Accessed February 17, 2014.
- Bryce J, Boschi-Pinto C, Shibuya K, Black RE. WHO estimates of the causes of death in children. Lancet. 2005;365(9465):1147-1152.
- Herikstad H, Yang S, Van Gilder TJ, et al. A population-based estimate of the burden of diarrhoeal illness in the Unites States: FoodNet, 1996-1997. Epidemiol Infect. 2002;129(1): 9-17.
- Centers for Disease Control and Prevention, U.S. Department of Health and Human Services. Antibiotic Resistance Threats in the United States, 2013. http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf. Accessed February 17, 2014.
- Culbreath K, Ager E, Nemeyer RJ, Kerr A, Gilligan PH. Evolution of testing algorithms at a university hospital for detection of Clostridium difficile infections. J. Clin. Microbiol. 2012; 50(9):3073-3076.
- Panos GZ, Betsi GI, Falagas ME. Systematic review: are antibiotics detrimental or beneficial for the treatment of patients with Escherichia coli O157:H7 infection? Aliment. Pharmacol. Ther. 2006;24(5):731-42.
