Nasopharyngeal viral infection as a source of elevated fecal calprotectin: a diagnostic pitfall in intestinal inflammation

Fecal calprotectin is widely used as a non-invasive biomarker for intestinal inflammation, particularly in inflammatory bowel disease (IBD), the most common clinical context for its use, where misinterpretation can lead to unnecessary invasive procedures or inappropriate therapy escalation. However, its specificity has been questioned due to elevated levels observed in non-intestinal conditions. Here, we investigated whether nasopharyngeal viral infections contribute to elevated fecal calprotectin, thereby confounding its diagnostic interpretation. Bioinformatic analysis revealed high constitutive expression of calprotectin subunits (S100A8/A9) in squamous epithelia of the upper aerodigestive tract compared with distal gut mucosa. To assess gastrointestinal stability of epithelial-derived calprotectin, healthy volunteers ingested porcine calprotectin, which was subsequently detected in feces, demonstrating resistance to intestinal degradation. In a retrospective cohort, patients with non-SARS-CoV-2 respiratory viral infections displayed significantly higher fecal calprotectin levels than SARS-CoV-2 patients (447 µg/g vs. 82 µg/g, p < 0.001), despite limited gastrointestinal involvement. Nasopharyngeal calprotectin levels did not differ significantly between viral etiologies, but in COVID-19 patients, fecal calprotectin positively correlated with nasopharyngeal calprotectin (R = 0.43, p = 0.008) and viral load (R = 0.13, p = 0.026). These findings suggest that calprotectin released from proximal epithelial tissues during viral infection can persist through the gastrointestinal tract and influence fecal calprotectin levels, underscoring the importance of contextual interpretation of this biomarker and the value of incorporating virological assessment into diagnostic workflows.