The question of whether to treat a patient with a positive Clostridioides difficile (C. diff) antigen test and a negative toxin test highlights a common diagnostic challenge. C. difficile is a bacterium that can cause severe diarrhea and colitis, particularly in people who have recently taken antibiotics. Diagnosis relies on detecting the bacteria and the toxins it produces, which cause the disease. The ambiguity arises because the two types of tests do not always agree, suggesting the organism is present but not actively causing disease. Understanding this test pattern is central to distinguishing between harmless colonization and an active infection.
Understanding the Diagnostic Tests
Identifying C. difficile infection (CDI) often involves a multi-step testing approach on a stool sample. This strategy combines a highly sensitive test to screen for the organism with a more specific test to confirm toxin production. The initial test, the Glutamate Dehydrogenase (GDH) antigen assay, detects an enzyme found in all C. difficile bacteria, regardless of whether they produce toxin. A positive GDH result simply indicates the organism is present in the patient’s gut.
Because GDH is present in both toxin-producing and non-toxin-producing strains, the test is highly sensitive for ruling out the bacteria if negative. However, its low specificity means a positive result cannot confirm an active infection. To determine if the bacteria is producing disease-causing agents, a separate test is needed to detect the actual C. difficile toxins A and B. This toxin test, often an Enzyme Immunoassay (EIA), directly looks for the substances that cause inflammation and diarrhea.
The toxin EIA test has high specificity, meaning a positive result strongly indicates an active infection. However, its limitation is relatively low sensitivity; toxins degrade quickly, and the test may fail to detect low levels of toxin even in a symptomatic patient. This difference creates the diagnostic dilemma of a positive GDH antigen and a negative toxin result. Some laboratories use a third test, a Nucleic Acid Amplification Test (NAAT) like PCR, to resolve discordant results by checking for the toxin genes. NAATs are highly sensitive but can also detect colonization.
Colonization Versus Active Infection
A positive GDH antigen and a negative toxin test strongly suggests C. difficile colonization rather than an active infection. Colonization occurs when the bacteria reside in the gut without causing clinical symptoms like diarrhea. The GDH test is positive because the organism is present, but the toxin test is negative because toxins are either not being produced or are at levels too low to be detected.
Colonization is common, found in approximately 3% of healthy adults and up to half of hospitalized patients. The distinction between colonization and a true infection is based on the presence of symptoms, particularly diarrhea. A patient with a positive GDH/negative toxin result who is asymptomatic is considered colonized and typically does not require antibiotic treatment.
In some cases, this discordant result can occur in a patient with a genuine, low-level infection. This may happen if toxin production is intermittent, or if the stool sample was not processed quickly enough, allowing the unstable toxin to degrade before testing. The GDH test confirms the organism’s presence, but the negative toxin result may be a false negative due to the limitations of the toxin assay.
When Treatment is Necessary
Management for a positive antigen, negative toxin result is primarily dictated by the patient’s clinical presentation, not the test result alone. Treatment is mandatory only for a symptomatic infection, known as C. difficile infection (CDI). The defining clinical criterion for treatment is the presence of three or more unformed stools in 24 hours that cannot be explained by other causes, such as laxative use.
If a patient has this discordant test result but is asymptomatic, antibiotic treatment is generally not indicated. Treating colonization can lead to unnecessary antibiotic exposure, potentially contributing to antibiotic resistance and increasing the risk of a future, symptomatic C. difficile infection. Clinical guidelines reserve treatment for patients with active disease.
However, if a patient is experiencing significant diarrhea and other symptoms like abdominal pain or fever, clinical suspicion for CDI often overrides the negative toxin result. The discordant result may be interpreted as an early infection or a false negative from the toxin assay. The overall clinical picture takes precedence, and the patient may be treated with specific antibiotics aimed at C. difficile, such as oral vancomycin or fidaxomicin. Discontinuing the inciting antibiotic, if possible, is a standard first step in management.