When Refractory Rhinosinusitis Should Trigger Diagnostic Reassessment: A Red-Flag- and Phenotype-Guided Review of Rare and Uncommon Mimics

Chronic rhinosinusitis (CRS) is common, but several rare diseases, rare sinonasal manifestations of systemic disorders, and uncommon local mimics can present as apparently refractory CRS. For terminology, this review uses the European epidemiological threshold of no more than 5 affected persons per 10,000 population for a rare disease, while conditions that do not consistently meet that threshold are described as uncommon mimics or rare sinonasal manifestations. The clinical problem is therefore not to test every patient for every rare disorder, but to recognise when routine CRS no longer explains the phenotype. This narrative review focuses on eosinophilic granulomatosis with polyangiitis (EGPA), granulomatosis with polyangiitis (GPA), primary ciliary dyskinesia (PCD), cystic fibrosis, humoral immune dysfunction, sarcoidosis, immunoglobulin G4-related disease, acute invasive fungal rhinosinusitis, sinonasal malignancy, and rhinolithiasis because they can mimic CRS yet require materially different investigation or treatment. A refractory course is not itself a diagnosis: symptoms should first be linked to objective sinonasal inflammation and treatment delivery assessed. Unilateral bleeding or a mass, tissue necrosis, facial numbness, visual or cranial neuropathy, destructive crusting, marked eosinophilia with adult-onset asthma, early-life wet cough with laterality abnormality, or recurrent bacterial respiratory infection should redirect investigation. Tests are most useful when interpreted conditionally, i.e., negative antineutrophil cytoplasmic antibody does not exclude localised vasculitis; nasal biopsy has limited sensitivity; low nasal nitric oxide is an adjunct rather than a stand-alone PCD diagnosis; and serum angiotensin-converting enzyme or immunoglobulin G4 cannot establish a tissue diagnosis. Cross-sectional imaging defines anatomy and extension but rarely determines aetiology without endoscopy and appropriately handled tissue. Biologic non-response should also trigger diagnostic reassessment before treatment escalation. The proposed red-flag framework is a pragmatic expert synthesis, not a validated diagnostic prediction rule, and is intended to facilitate earlier recognition of consequential mimics while reducing indiscriminate testing and serial empirical therapy.