Syndromic tests expand the medical laboratory’s growing stewardship role

Medical laboratories stand at the nexus of most clinical decision making. From common respiratory and gastrointestinal (GI) ailments to rare genetic and infectious diseases and cancers, medical laboratories deliver an ever-increasing range of diagnostic information so treating healthcare providers can address each patient’s needs accordingly.

With this extraordinary diagnostic capability comes a greater dependence on laboratories to guide care and an ever-increasing pressure for accurate answers. This dependence increases the responsibility for stewardship by medical laboratories; in other words, with great power comes great responsibility.

Beyond antimicrobial stewardship

The first calls for antimicrobial stewardship rang out 25 years ago.¹ Today’s syndromic tests, which simultaneously identify a variety of pathogens that can cause indistinguishable symptoms, such as a fever, runny nose or persistent diarrhea, are game changers in this effort.² Syndromic tests are multiplex molecular assays. These advanced microbiology technologies discern the cause of that runny nose or diarrhea, identifying not only if the pathogen is viral, bacterial or parasitic, but also the precise pathogen at work. Consider covid versus influenza. Both can present with similar symptoms but are caused by different viral agents for which different antivirals are available.

It is well understood that medical labs enable antimicrobial stewardship. But today, information that can be generated only at the bench positions laboratories as stewards of health system resources and patient care quality as well.

Syndromic testing for GI pathogens aligns with healthcare goals of providing the right test and the right treatment to the right patient at the right time. To understand their powerful impact on healthcare, let’s consider the enormous global impact of “stomach bugs.”

Newer assays help squash the stomach bug

GI infections are often referred to as the “stomach flu” but have no relationship to the influenza virus family. In the United States, enteric or GI infections are incredibly common. Per 2019 data, digestive diseases prompted an estimated 19 million emergency department visits, were the underlying cause of nearly 300,000 deaths, and were a contributing or “other” cause of an additional 472,000 deaths. Among these deaths, age-adjusted mortality rates were higher for men versus women, and higher among Black versus White individuals.³

Those most at risk of serious illness or death from GI infections include infants and children, immunocompromised individuals, the elderly, people in long-term care facilities and travelers.  The symptoms are often vexingly nonspecific and overlapping, and they can be caused by a wide variety and class of pathogens, including bacteria, viruses, and parasites.

Nearly indistinguishable on examination, GI Infections also are burdensome to diagnose using traditional stool cultures. They take several days or longer, are labor intensive, look for far fewer pathogens, and delay informed patient management decisions. 

Fortunately, advanced molecular diagnostic tests such as syndromic GI panels now offer actionable diagnostic insights in as little as one hour.

And it is reasonable that the workflow is preferable. 200 uL of stool resuspended in Cary-Blair medium, loaded into a diagnostic instrument, with a simple scan-run-results-in-an-hour protocol that looks for 16 pathogens, is easier and far more pleasant for lab personnel than growing bacteria in stool samples over several days.

Labs can guide physicians to the right tests

Syndromic GI panels can test for 16 or more pathogens in one test. But they also come in smaller, targeted panels, seeking the most actionable subset of these pathogens for lower-risk patients.  

Medical laboratories are well positioned to work in consultation with ordering doctors to ensure and demand that the science they employ asks the right questions and delivers the right answers — a critical and growing stewardship responsibility.

In the 1940s, Dr. Theodore Woodward coined the expression, “When you hear hoofbeats, think of horses, not zebras.”  Today’s syndromic panels enable the simultaneous search for both, and more. But for average-risk, otherwise healthy individuals, the diagnostic journey should begin with smaller, lower cost assays.  

When a small, target panel makes sense

Consider the case of a young adult in good underlying health presenting to the emergency room after several days of diarrhea, fatigue, and weight loss. He is ideally suited to the speed and capabilities of a smaller, more targeted GI panel. In this theoretical discussion, let’s say he tests positive for norovirus. He requires supportive care such as rest and hydration, and specific instructions and precautions to prevent the spread at home to family members, or others in the community. No antibiotics should be prescribed, and an inpatient stay is promptly deemed unnecessary.

Alternatively, negative test results of the five (depending on the panel) most common, actionable pathogens, along with further observation, may lead his care providers to make the informed decision that further diagnostic investigation is warranted for this patient. 

When a more comprehensive panel makes sense

Now consider a similar young adult with an established diagnosis of Crohn’s disease, a chronic inflammatory bowel disease that causes symptoms such as diarrhea, cramping, abdominal pain, weight loss, and fatigue. He presents to the emergency department with the same symptoms as the individual above. Is it an acute flair-up of his otherwise well-controlled Crohn’s?  Is he one of the estimated nine million people in America who has a foodborne disease?⁴ And if so, which one? While he could need a battery of scoping procedures and inpatient care to address an acute flair up of Crohn’s, a full syndromic panel alone could reveal the source of the problem. In this case, let’s assume the patient is diagnosed with E. Coli.

Armed with this information from the laboratory, the specialist can order the appropriate inpatient or outpatient care and avoid unnecessary medications, additional tests and scanning or scoping procedures.

Risks of incomplete tests or false negative results

The wide range of pathogens involved in GI infections has a complementary range of treatment protocols, ranging from fluids and bed rest at home to isolation, and hospital-based care.  The consequences of misdiagnosis can be severe, including inappropriate therapy, worsened illness and post-infectious sequelae, unnecessary side effects, and antibiotic resistance and outbreaks.

Patients receiving the wrong therapy can suffer higher relapse rates, carry a potentially infectious illness for longer than necessary, suffer complications of the wrong treatment, and develop hemolytic uremic syndrome (HUS)⁵, which can require intravenous fluids and supplements, blood transfusions, and even dialysis to restore normal body function. Misdiagnosis can also lead to more severe illness and post-infectious sequelae such as superinfections, major disruptions to the patient’s gut equilibrium, Guillen-Barre syndrome, C. difficile, rashes, isolation, and other complications.^6,7,8

STEC (Shiga-like toxin-producing E. coli) offers an example of how misdiagnosis or a false negative result can cause real patient harm. STEC differentiation is very important for clinical management. People become infected with STEC by eating contaminated foods such as raw or undercooked meat, milk and vegetables and it can cause damage to the colon and kidneys. ^9,10 

STEC is defined by the production of Shiga toxin 1 (stx1) or Shiga toxin 2 (stx2).¹¹ There are more than 400 serotypes of STEC, of which 0157 is the most common.¹² Although STEC is a bacterial infection, antibiotics should not be used to treat it. They cause the STEC bacteria to dump these toxins which should be avoided in all cases.

Knowing STEC 0157 is present offers substantial prognostic value, especially for infants and children and others who are at high risk for HUS development.¹³ It also should trigger additional patient monitoring and prompt precautions to prevent transmission to other patients, hospital staff, family, and other close contacts.  STEC can be deftly managed, but a false negative, or no awareness of the STEC infection, runs counter to the laboratory’s stewardship mandate.  

The risk of false positives

Just as not identifying a pathogen or a false negative result can hide the actual problem and lead to the wrong treatment, so too can a false positive. False positives are troubling to medical laboratories and especially to the care providers and patients. A false positive may delay the diagnosis of the actual problem allowing a condition to worsen or prompt unnecessary medical interventions. Norovirus offers an illustrative case in point.

Norovirus is, to be blunt, wildly contagious. It spreads easily and quickly, and although one person may first be infected by a food source, that person will spread billions of norovirus particles, shedding them to food, water, and surfaces they touch. It takes just a few tiny norovirus particles to make others sick.^14,15 Even ubiquitous hand sanitizers and many cleaning products do not work well against norovirus.¹⁶

When norovirus is falsely diagnosed it can set in motion a range of unnecessary costs and time-consuming activities in a hospital or long-term care setting. These activities may include isolation protocols or contact precautions for the patient, including the use of personal protective equipment (PPE) gear by treating personnel, which must be donned, removed and then discarded every time patient contact is required. Additionally, changes to room assignments, terminal cleaning – including UV light¹⁷ – for any rooms that patient has occupied, laundry and food service protocols, staff health monitoring, visitor monitoring or prohibition, and more may be initiated.¹⁸

Not to be discounted, two or more false positives among patients or staff in close proximity could lead to an erroneous reportable event. While individual norovirus diagnoses are not reportable, outbreaks are, and the Centers for Disease Control and Prevention (CDC) and health officials consider two or more similar illnesses resulting from a common exposure that is laboratory-confirmed an outbreak.¹⁹

Aside from these preventive measures, ongoing false positives, particularly in a known situation²⁰ may also require the cost and delays associated with additional diagnostic testing to confirm results using another method, including sending samples outside for testing.  

As molecular diagnostic science continues its rapid and exciting pace of change, medical laboratories that embrace and invest in newer ways of diagnosing disease will see ever-greater opportunities to provide consultative support. Medical laboratories and the quality of their test results must be trusted by their healthcare partners, and in turn, labs must be able to trust the accuracy, precision, sensitivity, and specificity of the tests they run to build on their growing stewardship role in the healthcare ecosystem. 

References

1. Charani E, Holmes A. Antibiotic Stewardship-Twenty Years in the Making. Antibiotics (Basel). 2019;8(1):7. doi:10.3390/antibiotics8010007.
2. Dumkow LE, Worden LJ, Rao SN. Syndromic diagnostic testing: a new way to approach patient care in the treatment of infectious diseases. J Antimicrob Chemother. 2021;76(Suppl 3):iii4-iii11. doi:10.1093/jac/dkab245.
3. Stong C. National databases analysis: Digestive disease burden increasing across US. Gastroenterology Advisor. January 31, 2025. Accessed February 27, 2025. https://www.gastroenterologyadvisor.com/news/digestive-disease-burden-increasing-in-us/.
4. The Interagency Food Safety Analytics Collaboration. Foodborne illness source attribution estimates for Salmonella, Escherichia coli O157, and Listeria monocytogenes — United States, 2021. CDC. Published 2021. Accessed February 27, 2025. https://www.cdc.gov/ifsac/media/pdfs/P19-2021-report-TriAgency-508.pdf. 
5. Guerrant RL, Van Gilder T, Steiner TS, et al. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis. 2001;32(3):331-51. doi:10.1086/318514.
6. Center for Disease Control. Antibiotic Resistance Threats in the United States, 2013. Createspace; 2014.
7. Owens RC Jr, Ambrose PG. Antimicrobial safety: focus on fluoroquinolones. Clin Infect Dis. 2005;41 Suppl 2:S144-57. doi:10.1086/428055. 
8. Antimicrobial resistance: global report on surveillance. Who.int. April 1, 2014. Accessed February 28, 2025. https://www.who.int/publications/i/item/9789241564748.
9. E. coli. Who.int. February 7, 2018. Accessed February 28, 2025. https://www.who.int/news-room/fact-sheets/detail/e-coli.
10. Kaper JB, Nataro JP, Mobley HL. Pathogenic Escherichia coli. Nat Rev Microbiol. 2004;2(2):123-40. doi:10.1038/nrmicro818.
11. Cdph.ca.gov. Accessed February 28, 2025. https://www.cdph.ca.gov/Programs/CID/DCDC/CDPH%20Document%20Library/STECHUSEpiSummary2013-2019.pdf.
12. Croxen MA, Law RJ, Scholz R, Keeney KM, Wlodarska M, Finlay BB. Recent advances in understanding enteric pathogenic Escherichia coli. Clin Microbiol Rev. 2013;26(4):822-80. doi:10.1128/CMR.00022-13.
13. Hemolytic uremic syndrome (HUS). Health.ny.gov. Updated June 2024. Accessed February 28, 2025. https://www.health.ny.gov/diseases/communicable/e_coli/hus.htm. 
14. CDC. How Norovirus spreads. Norovirus. April 24, 2024. Accessed February 28, 2025. https://www.cdc.gov/norovirus/causes/index.html.
15. CDC. About. Norovirus. April 24, 2024. Accessed February 28, 2025. https://www.cdc.gov/norovirus/about/index.html. 
16. CDC. How to prevent. Norovirus. January 13, 2025. Accessed February 28, 2025. https://www.cdc.gov/norovirus/prevention/index.html. 
17. Ramos CCR, Roque JLA, Sarmiento DB, et al. Use of ultraviolet-C in environmental sterilization in hospitals: A systematic review on efficacy and safety. Int J Health Sci (Qassim). 2020;14(6):52-65.
18. CDC. II. Summary of recommendations. Infection Control. March 21, 2024. Accessed February 28, 2025. https://www.cdc.gov/infection-control/hcp/norovirus-guidelines/summary-recommendations.html.
19. CDC. Norovirus outbreaks. Norovirus. January 2, 2025. Accessed February 28, 2025. https://www.cdc.gov/norovirus/outbreak-basics/index.html. 
20. Class 2 device recall BIOFIRE FilmArray gastrointestinal (GI) panel. February 15, 2024. Accessed February 28, 2025. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfres/res.cfm?id=205002.