Gastrointestinal Infections and the Importance of Laboratory Testing

Infectious gastroenteritis affects hundreds of millions of people across the globe every year. Among the common causes are viruses, bacteria and parasites and infections are usually contracted by ingestion of contaminated food, water or through contact with infected individuals. In the US, it is estimated that foodborne pathogens alone affect about 48 million people, leading to 128,000 hospital admissions and 3,000 deaths per year (1,2). The economic burden of foodborne illnesses is estimated to cost approximately $15.6 billion annually (1).

Timely and precise identification of causative agents of gastroenteritis is essential for patient care, public health, and disease monitoring. While some infections resolve without medical intervention, cases of persistent diarrhea and severe illness can lead to life-threatening complications and require pathogen-specific therapeutic interventions. Accurate diagnosis not only improves patient outcomes but also prevents unnecessary antibiotic use in cases with viral etiology or when antibiotics are contraindicated. As gastrointestinal infections easily spread in the community, outbreaks can occur, which further highlights the importance of diagnostic testing for public health. In recent years, molecular diagnostic methods have started to replace conventional culture approaches for detection of gastrointestinal pathogens due to their increased sensitivity and rapid turnaround times, both of which have significant impact on informing treatment decisions.

Causes of GI infections

The most common cause of infectious gastroenteritis are viral infections, with norovirus being the most prevalent pathogen, followed by rotavirus, astrovirus, sapovirus and enteric adenoviruses which are also prevalent in the US (3-5). However, in severe cases of infectious diarrhea, bacterial etiology is more frequently detected (6). Enteropathogenic bacteria include Salmonella, Escherichia coli (E. coli), Campylobacter, Shigella, Yersinia and Aeromonas among others (3-5). In cases with prolonged or chronic diarrhea, common etiology includes parasites such as Giardia, Entamoeba histolytica, Cryptosporidium, and Cyclospora (3-5,7). Patients at risk of severe or persistent infections include young children, the elderly, pregnant women, hospitalized patients, people in long-term care facilities, immunocompromised individuals, and travelers from regions with poor hygiene standards (8,9). For example, young children are at particular risk of developing complications from GI infections with rotavirus being noted as the main causative agent of diarrhea in children under 5 years old (10). Similarly, immunocompromised, pregnant women and the elderly are at higher risk of developing life-threatening complications due to infectious gastroenteritis (8). Moreover, in hospitals and long-term care facilities, nosocomial GI infections can be easily acquired and spread from person-to -person, for example infections caused by Clostridioides difficile, one of the leading causes of antibiotic use-associated diarrhea (11).

Challenges in the diagnosis of GI infection

Most cases of infectious gastroenteritis are self-limiting and resolve spontaneously but, individuals with persistent or severe symptoms require specific treatment including antibiotics or other therapeutics to prevent complications. While clinical presentation of infectious gastroenteritis can vary from mild illness to severe disease, and certain pathogens may be associated with specific symptoms (e.g., bloody diarrhea), the clinical symptoms alone are not sufficient to determine the cause of infection and laboratory testing is often required to inform treatment decisions (12).

Diagnostic testing for GI infections is a complex task that involves overcoming various challenges related to the diverse range of causative pathogens and the inherent limitations of the available diagnostic tests. Prior to the introduction of molecular diagnostic testing, the standard diagnostic approach involved use of many different types of tests with variable sensitivity and specificity, including routine stool culture, antigen detection-based tests, or ova and parasite examinations which many labs still use today. The main limitations of these diagnostic approaches are complex ordering practices, limited coverage of prevalent pathogens which require special culturing conditions or non-standard microscopy evaluations, and most importantly, long time to result of up to (3-4) days, which has limited clinical utility (13-15). In practice, this has led to patients often receiving empiric treatment prior to obtaining test results. A significant challenge is also underdiagnosis of pathogens not included in the standard ordering practices, such as Cyclospora or Campylobacter upsaliensis (16,17), for example, or pathogens with challenging culture conditions requiring >7 days, such as Yersinia18. Detection of parasites, which mainly relied on microscopic evaluation, required highly skilled laboratory personnel and, while recommendations include evaluation of several stool samples to increase sensitivity of pathogen detection, these specimens are rarely received by the laboratories (19-22). More recently, molecular diagnostic methods such as, multiplex real-time polymerase chain reaction (PCR)-based tests, have started to replace conventional methods for diagnostic testing of gastrointestinal infections.

Advantages of molecular testing

The main advantage of molecular diagnostics are high sensitivity, specificity, and short time-to-results compared to traditional methods like culture and microscopy (23-26). Multiplex PCR tests can simultaneously detect viral, bacterial, and parasitic pathogens in a single sample, including co-infections, thus helping clinicians make better informed treatment decisions that enable improved patient outcomes and contribute to antimicrobial stewardship (23-26). In patients suffering from non-infectious causes of gastroenteritis, molecular diagnostics offers a fast-track to conducting differential diagnosis. Molecular testing can also aid in reducing healthcare costs where rapid and accurate diagnosis leads to more efficient resource utilization, adjusted hospitalization numbers, and shorter hospital stays (23-27). Finally, as many gastrointestinal pathogens belong to nationally notifiable diseases due to their potential for causing outbreaks, molecular testing plays an important role in quick identification of pathogens involved in outbreaks and informing public health action aimed at limiting the spread of infections in the communities (28).

REFERENCES

1. CDC. CDC and Food Safety. 2023; https://www.cdc.gov/foodsafety/cdc-and-food-safety.html#:~:text=CDC estimates that each year,than $15.6 billion each year., 2023.
2. CDC. Estimates of Foodborne Illness in the United States. 2018; https://www.cdc.gov/foodborneburden/index.html, 2023.
3. Scallan E, Hoekstra RM, Angulo FJ, et al. Foodborne illness acquired in the United States--major pathogens. Emerg Infect Dis. 2011;17(1):7-15.
4. Delahoy MJ, Shah HJ, Weller DL, et al. Preliminary Incidence and Trends of Infections Caused by Pathogens Transmitted Commonly Through Food - Foodborne Diseases Active Surveillance Network, 10 U.S. Sites, 2022. MMWR Morb Mortal Wkly Rep. 2023;72(26):701-706.
5. CDC. Estimated annual number of episodes of illnesses caused by 31 pathogens transmitted commonly by food, United States. 2006; https://www.cdc.gov/foodborneburden/pdfs/scallan-estimated-illnesses-foodborne-pathogens.pdf, 2023.
6. Sattar SBA, Singh S. Bacterial Gastroenteritis. In: StatPearls. Treasure Island (FL): StatPearls Publishing Copyright © 2023, StatPearls Publishing LLC.; 2023.
7. Kaiser L, Surawicz CM. Infectious causes of chronic diarrhoea. Best Pract Res Clin Gastroenterol. 2012;26(5):563-571.
8. Foodsafety.gov. People at Risk of Food Poisoning. 2023; https://www.foodsafety.gov/people-at-risk#:~:text=People at risk include:,to illness or medical treatment.
9. Connor B. Travelers’ Diarrhea - CDC Yellow Book 2024. 2024; https://wwwnc.cdc.gov/travel/yellowbook/2024/preparing/travelers-diarrhea.
10. CDC. Rotavirus. 2021; https://www.cdc.gov/rotavirus/index.html#:~:text=Rotavirus commonly causes severe, watery,your child with rotavirus vaccine.&text=The most common symptoms of,, and/or abdominal pain., 2023.
11. Sandhu BK, McBride SM. .Clostridioides difficile. Trends Microbiol. 2018;26(12):1049-1050.
12. Burd EM, Hinrichs BH. Gastrointestinal Infections. In: Leonard DGB, ed. Molecular Pathology in Clinical Practice. Cham: Springer International Publishing; 2016:707-734.
13. Kellner T, Parsons B, Chui L, et al. Comparative Evaluation of Enteric Bacterial Culture and a Molecular Multiplex Syndromic Panel in Children with Acute Gastroenteritis. J Clin Microbiol. 2019;57(6).
14. Buss JE, Cresse M, Doyle S, Buchan BW, Craft DW, Young S. Campylobacter culture fails to correctly detect Campylobacter in 30% of positive patient stool specimens compared to non-cultural methods. Eur J Clin Microbiol Infect Dis. 2019;38(6):1087-1093.
15. Van Lint P, De Witte E, De Henau H, et al. Evaluation of a real-time multiplex PCR for the simultaneous detection of Campylobacter jejuni, Salmonella spp., Shigella spp./EIEC, and Yersinia enterocolitica in fecal samples. Eur J Clin Microbiol Infect Dis. 2015;34(3):535-542.
16. Anderson NW, Tarr PI. Multiplex Nucleic Acid Amplification Testing to Diagnose Gut Infections: Challenges, Opportunities, and Result Interpretation. Gastroenterol Clin North Am. 2018;47(4):793-812.
17. Li J, Cui Z, Qi M, Zhang L. Advances in Cyclosporiasis Diagnosis and Therapeutic Intervention. Front Cell Infect Microbiol. 2020;10:43.
18. Savin C, Leclercq A, Carniel E. Evaluation of a single procedure allowing the isolation of enteropathogenic Yersinia along with other bacterial enteropathogens from human stools. PLoS One. 2012;7(7):e41176.
19. Richard RL, Yusof H. Advancements in Parasite Diagnosis and Challenges in the Management of Parasitic Infections: A Mini Review. 2018; Singapore.
20. Hotez PJ. Neglected parasitic infections and poverty in the United States. PLoS Negl Trop Dis. 2014;8(9):e3012.
21. Lynn MK, Morrissey JA, Conserve DF. Soil-Transmitted Helminths in the USA: a Review of Five Common Parasites and Future Directions for Avenues of Enhanced Epidemiologic Inquiry. Curr Trop Med Rep. 2021;8(1):32-42.
22. Polage CR, Stoddard GJ, Rolfs RT, Petti CA. Physician use of parasite tests in the United States from 1997 to 2006 and in a Utah Cryptosporidium outbreak in 2007. J Clin Microbiol. 2011;49(2):591-596.
23. Ramanan P, Bryson AL, Binnicker MJ, Pritt BS, Patel R. Syndromic Panel-Based Testing in Clinical Microbiology. Clin Microbiol Rev. 2018;31(1).
24. Zhang H, Morrison S, Tang YW. Multiplex polymerase chain reaction tests for detection of pathogens associated with gastroenteritis. Clin Lab Med. 2015;35(2):461-486.
25. Binnicker MJ. Multiplex Molecular Panels for Diagnosis of Gastrointestinal Infection: Performance, Result Interpretation, and Cost-Effectiveness. J Clin Microbiol. 2015;53(12):3723-3728.
26. Montasser K, Osman HA, Abozaid H, Khalil HS, Hatem Amer W, Sabry AMM. Multiplex PCR: Aid to more-timely and directed therapeutic intervention for patients with infectious gastroenteritis. Medicine (Baltimore). 2022;101(41):e31022.
27. Teh R, Tee W, Tan E, et al. Review of the role of gastrointestinal multiplex polymerase chain reaction in the management of diarrheal illness. J Gastroenterol Hepatol. 2021;36(12):3286-3297.
28. Switaj TL, Winter KJ, Christensen SR. Diagnosis and Management of Foodborne Illness. Am Fam Physician. 2015;92(5):358-365.