Epidemiological Characteristics, Pathogenesis and Clinical Implications of Sinusitis in the Era of COVID-19: A Narrative Review

There is an emerging burden of chronic sinusitis during the COVID-19 era, manifesting in different forms. Understanding the association between COVID-19 and sinusitis is essential to inform healthcare practice and management. This narrative review was conducted to highlight evidence on links between COVID-19 and sinusitis, including epidemiology, pathogenesis, clinical implications, and risk factors for complications such as acute invasive fungal rhinosinusitis (AIFR).

Association between chronic rhinosinusitis (CRS) and COVID-19: Studies show mixed results. A Korean nested case-control study (Lee et al.) found higher SARS-CoV-2 infection rates in CRS patients (AOR 1.22; 95% CI 1.04–1.42) and more severe outcomes (AOR 1.71; 95% CI 1.09–2.71). A cohort study (Wang et al.) reported no significant association with severe illness, but CRS was assessed via self-reported interviews and fatal cases were excluded. A retrospective study (Sbeih et al.) found increased hospitalization risk in COVID-19 patients with CRS (AOR 3.19; 95% CI 1.12–10.68) without increased mortality, ICU admission, or mechanical ventilation. Case-control and cohort data (Workman et al.; Miller et al.) suggest CRS patients do not have higher infection rates, and oral corticosteroid use in CRS was not associated with increased COVID-19 infection. Pathogenesis linking CRS and COVID-19: CRS is associated with increased sepsis, pneumonia, and mortality, potentially via reduced nitric oxide production and acting as a microbial reservoir. Immune dysfunctions in CRS include specific antibody deficiency and epithelial barrier dysfunction, increasing susceptibility to infections. Mechanisms proposed for increased SARS-CoV-2 infectivity/severity in CRS include higher co-infection rates (2.9 times more likely), impaired mucociliary clearance, loss of ciliated cells, goblet cell hyperplasia, basal cell proliferation, and increased expression of TMPRSS2 and ACE2 in nasal epithelium. Type 2 inflammation in CRS can modulate ACE2/TMPRSS2 expression, and interferon-driven upregulation of ACE2 may enhance susceptibility. Reports suggest IL-4/IL-13 inhibition (dupilumab) may reduce COVID-19 severity in CRS. CRS symptoms during COVID-19: Using SNOT-22, a cross-sectional study (Akhlaghi et al.) found no significant differences in otologic, nasal, emotional, and sleep domains between COVID-19 patients with and without CRS; COVID-19 did not appear to alter CRS manifestations. No difference in COVID-19 severity between CRS with vs without nasal polyps. SNOT scores decreased over one year among CRS patients (40.1 vs 46.3; p<0.01). Olfactory loss in COVID-19: WHO reports indicate olfactory dysfunction in 5%–85% of COVID-19 patients. Sudden anosmia without nasal congestion has been noted as an early symptom; some countries advised isolation for sudden olfactory loss, though self-report-based detection was unreliable. Olfactory loss is usually reversible within weeks, but may persist for months or be permanent in some cases. Proposed mechanisms include infection of sustentacular/supporting cells with ACE2 overexpression, olfactory cleft obstruction and epithelial edema, and NRP1-mediated injury enhancing spike binding. Endothelial injury to olfactory mucosa is supported, but does not fully explain features such as presence of viral particles in olfactory bulbs, neuroimaging changes, variable duration, and inverse association with disease severity; NRP1 expression in olfactory neurons and progenitors may contribute and delay recovery via neuronal damage and axonal transport to olfactory bulbs. Fungal sinusitis and AIFR in COVID-19: AIFR is characterized by acute fungal tissue invasion within days to <4 weeks, often with vascular invasion and thrombosis, presenting with fever, facial pain, nasal congestion, and potential orbital/intracranial extension causing visual attenuation, proptosis, and neurologic deficits. Pre-COVID studies reported steady AIFR cases; multiple centers observed substantial increases during the pandemic. A systematic review of 14 reports identified 206 AIFR cases associated with COVID-19, mostly in India, Egypt, and North America. A large Indian series (Sen et al., n=2826) reported rhino-sinusal mucormycosis in 24.6% and rhino-orbital in 48.9%. Reviews reported similar sinusitis prevalence (~24.6%). Intracranial involvement, including cavernous sinus involvement, was frequently reported; one review estimated 36/132 cases. Ethmoid sinus involvement was common (reports up to 90–100%), and pansinusitis was frequent. Risk factors for COVID-19-associated AIFR: Diabetes mellitus (DM) consistently emerged as the most common comorbidity pre- and intra-pandemic; prevalence among AIFR patients historically ~48%, with hematologic malignancies ~39%. In COVID-19-associated AIFR, systematic reviews reported DM in 73.3% and steroid use in ~65% of patients; hypertension was also common, whereas hematologic malignancies were less frequent than pre-pandemic series. Studies showed associations between higher HbA1c, steroid duration, and AIFR risk. Steroid-induced hyperglycemia and diabetic ketoacidosis likely contribute. COVID-19-related immune dysregulation may increase fungal susceptibility. Elevated serum ferritin and iron dysregulation were associated with mucormycosis risk and worse outcomes in several studies (e.g., mean ferritin ~662 ng/mL; higher in non-survivors). Combined risk factors (uncontrolled DM plus steroid exposure) conferred highest risk in multiple observational studies.

A comprehensive literature search was conducted across Scopus, PubMed, and Google Scholar, supplemented by manual searching. Keywords were developed using MeSH terms and included: "sinusitis", "invasive", "COVID-19", "risk factors", "fungal", "rhinosinusitis", and "pathogenesis". Searches used individual and combined keywords. Inclusion criteria were peer-reviewed, full-text, English-language publications; non-English and non–peer-reviewed articles were excluded. The initial search retrieved 285 articles; after applying inclusion/exclusion criteria, 96 papers were included addressing epidemiological characteristics, pathogenesis, and associations between sinusitis and COVID-19.

- CRS and COVID-19: - Higher infection risk and severity among CRS patients in a Korean nationwide study: infection AOR 1.22 (95% CI 1.04–1.42); severe outcomes AOR 1.71 (95% CI 1.09–2.71). - Increased hospitalization risk in COVID-19 patients with CRS: AOR 3.19 (95% CI 1.12–10.68); estimated hospitalization risk 3.46 times higher than without CRS; no increase in mortality, ICU admission, or mechanical ventilation. - No increased infection risk associated with CRS in matched cohorts; no increased infection risk with oral corticosteroid use among CRS patients. - Pathogenesis linking CRS to COVID-19: - CRS associated with reduced nitric oxide, potential microbial reservoir status, and immune dysfunction (antibody deficiency, epithelial barrier dysfunction), potentially increasing infection and severity risk. - Increased ACE2/TMPRSS2 expression in nasal epithelium and impaired mucociliary clearance in CRS may facilitate SARS-CoV-2 entry and retention; type 2 inflammation and interferon signaling may upregulate ACE2. - Reports of reduced COVID-19 severity with IL-4/IL-13 inhibition (dupilumab) in CRS with nasal polyps. - CRS symptoms during COVID-19: - SNOT-22-based study found no differences in symptom domains between COVID-19 patients with vs without CRS; SNOT scores decreased over time among CRS patients (40.1 vs 46.3; p<0.01); no severity difference between CRS with vs without nasal polyps. - Olfactory dysfunction: - Prevalence ranges widely (5%–85%); often sudden without nasal congestion; self-reported screening has limitations; most recover within weeks, but some have prolonged or permanent loss. - Mechanisms include supporting cell infection with ACE2 overexpression, olfactory cleft obstruction/edema, and NRP1-mediated entry; endothelial injury to olfactory mucosa documented; neuronal involvement may explain delayed recovery and imaging findings. - AIFR and COVID-19: - Marked rise in AIFR and mucormycosis during the pandemic; systematic review identified 206 AIFR cases linked to COVID-19 across 14 reports, predominantly from India and Egypt. - Large Indian series (n=2826) found rhino-sinusal mucormycosis in 24.6% (second most common site after rhino-orbital, 48.9%). - Intracranial/cavernous sinus involvement reported frequently (e.g., 36/132 cases in review); ethmoid sinus involvement up to 90–100% in some series; pansinusitis common. - Risk factors for COVID-19-associated AIFR: - DM most prevalent (up to 73.3% in a systematic review); steroid exposure common (~65%); hypertension frequent; hematologic malignancies less common than pre-COVID reports. - Associations between higher HbA1c, longer steroid duration, and AIFR risk; steroid-induced hyperglycemia/diabetic ketoacidosis noted. - Elevated ferritin and iron indices associated with mucormycosis risk and severity (e.g., mean ferritin ~662 ng/mL; higher in non-survivors).

The review synthesizes evidence that CRS may adversely influence COVID-19 by increasing susceptibility to infection and risk of severe outcomes, though findings are inconsistent across studies, likely due to methodological differences (e.g., self-reported CRS, exclusion of fatal cases). Proposed mechanisms—including impaired sinonasal epithelial defenses, altered mucociliary function, and increased ACE2/TMPRSS2 expression under type 2 inflammatory conditions—provide biologic plausibility for increased SARS-CoV-2 entry and persistence in CRS. Despite concerns, oral corticosteroid use for CRS did not correlate with higher infection rates in available cohorts. Olfactory dysfunction is a prominent, often early, COVID-19 manifestation; while usually reversible, a subset experiences prolonged or possibly permanent loss. Mechanistic data implicate supporting cell infection, epithelial edema, endothelial injury, and NRP1-mediated viral entry with potential neuronal/progenitor cell involvement, offering explanations for clinical variability and recovery timelines. A dramatic increase in AIFR/mucormycosis has been observed during the pandemic, especially in regions with high DM prevalence and extensive steroid use. COVID-19-associated immune dysregulation, uncontrolled diabetes, steroid-induced hyperglycemia, and iron dysregulation (hyperferritinemia) likely act synergistically to predispose to invasive fungal disease, including rhino-sinusal and rhino-orbito-cerebral forms with frequent orbital and intracranial extension. Early recognition and urgent management remain critical due to high morbidity and mortality. Overall, while CRS may negatively impact COVID-19 outcomes and COVID-19 may predispose to olfactory dysfunction and AIFR, heterogeneity in study designs necessitates further robust investigations to clarify causality and quantify risks.

This narrative review highlights that CRS may be associated with worse COVID-19 outcomes, though results are conflicting and require further study. COVID-19 frequently causes olfactory dysfunction, typically transient but sometimes prolonged or permanent. Evidence also indicates a strong association between COVID-19 and AIFR, with severe morbidity due to common underlying immunocompromising conditions. The most frequent risk factors for COVID-19-associated AIFR include uncontrolled diabetes, steroid exposure, hypertension, and markers of iron overload, with COVID-19-related immune dysregulation further increasing susceptibility. Future research should employ standardized CRS definitions, adjust for confounders (e.g., comorbidities, steroid dosing), and prospectively assess incidence and outcomes of AIFR to inform prevention and management strategies.

- Many included studies were observational, with potential confounding and selection bias. - Some cohorts assessed CRS via self-reported methods and excluded fatal cases, potentially underestimating associations with severe outcomes. - A substantial portion of the evidence on AIFR comprises case reports and small case series, limiting precise incidence estimates and generalizability. - Olfactory dysfunction data often rely on self-report, which may misestimate prevalence compared to objective testing. - Considerable variability in steroid regimens and clinical practices across settings complicates risk attribution. - Heterogeneity in populations, comorbidities (e.g., baseline diabetes prevalence), and health system factors may influence observed associations.