| Biomarker | Sample Type | Detection Methods | Protection / Notes | References |
| Secretory IgA (sIgA) – Virus-specific IgA in mucosal secretions | Nasal swab eluate, nasal wash, saliva; BAL fluid for lung mucosa | ELISA; CLIA | Neutralizes virus at the entry site, preventing or reducing infection in the upper airway and thereby also lowering risk of severe disease (by limiting viral spread). High mucosal sIgA correlates with reduced infection risk. | |
| Pro-inflammatory cytokines – (e.g., IL-6, IL-8, IL-1β, IFN-γ) in respiratory secretions | Nasal or nasopharyngeal secretions (swab or wash), sputum, or BAL fluid; (also measured in serum for systemic inflammation) | ELISA; multiplex cytokine assays (e.g., Luminex); RT-qPCR for mRNA in mucosal cells (gene expression) | Early robust production (e.g., nasal IL-6/IL-1β/IL-8) in the airway is associated with controlled infection and milder disease. By contrast, if they spill into blood at high levels (especially IL-6), it reflects uncontrolled inflammation (cytokine storm; poor prognosis). | |
| Nasal tissue-resident memory T cells (TRM) – CD8⁺ and CD4⁺ TRM in nasal mucosa | Nasal mucosal tissue or curettage sample (e.g., inferior turbinate swab or brush) | Flow cytometry (phenotyping: e.g., CD69⁺ CD103⁺ on CD8⁺/CD4⁺ T cells); immunohistochemistry on nasal tissue biopsies | Nasal TRMs provide an immediate local immune response, killing infected cells at the infection site. Their presence is linked to faster virus clearance and protection from symptomatic COVID-19. Parenteral vaccination alone induces few nasal TRM; they appear mainly after infection or with hybrid immunity. | |
| Lung TRMs – CD8⁺ and CD4⁺ TRM in lung parenchyma | Lung biopsy or resected tissue; BAL fluid (for alveolar TRM) | Flow cytometry on lung tissue digests (TRM markers such as CD69, CD103); immunohistochemistry on lung sections | TRMs in the lungs provide rapid, local responses upon re-exposure, curbing viral replication in lung tissue. Presence of a robust lung TRM pool correlates with efficient viral clearance, milder symptoms, and long-term protection against severe disease. Patients who develop strong polyfunctional TRM after infection tend to have better outcomes in subsequent exposures. | |
| MAIT cells (Mucosal-Associated Invariant T cells) – innate-like T cells abundant in mucosa | Peripheral blood (common for assessment); also present in mucosal sites (nasal tissue, BAL, lung) | Flow cytometry (e.g., CD3⁺Vα7.2⁺CD161^ phenotype); MR1-tetramer staining (specific identification) | MAIT cell activation status can indicate mucosal immune engagement; activated MAIT cells in mucosa help orchestrate dendritic cells and Tfh cell responses, supporting antiviral immunity. Strong MAIT activation correlates with better mucosal defense, whereas in severe disease MAIT cells become exhausted and lose function. | |
| Interferon-λ (Type III IFNs; e.g. IFN-λ1/λ2/λ3) – antiviral cytokines at mucosal surfaces | Nasal swab fluid, nasopharyngeal aspirate, or BAL fluid (local secretions); blood serum (for spill-over systemic IFN-λ) | ELISA (high-sensitivity kits); multiplex cytokine assay (e.g., Bio-Plex); RT-qPCR for IFN-λ mRNA in swabbed epithelial cells | IFN-λ is often low-level, but crucial for early mucosal antiviral defense, inducing ISGs with minimal systemic inflammation. Robust endogenous IFN-λ response limits virus spread and inflammation, protecting against severe outcomes. Detectable levels are found in moderate COVID-19, whereas many severe cases have undetectable or declining IFN-λ in serum. | |
| SARS-CoV-2-specific IgG – IgG antibodies transudated into mucosa from blood | Nasal swab extract or nasal wash fluid; saliva or oral fluid (gingival transudate); bronchoalveolar lavage (for lung mucosa IgG) | ELISA; CLIA | Indicates established immune memory. Mucosal IgG can neutralize virus in the lower airways; higher IgG (in serum and nose) is linked to protection in the lungs (preventing pneumonia and severe COVID-19). However, IgG is less effective than IgA in preventing initial infection in the upper airway. | |
| Lymphoid chemokines – (e.g., CXCL13, CCL19, CCL21) promote tertiary lymphoid tissue formation | BAL fluid or lung tissue biopsy (for local levels); blood plasma/serum (especially CXCL13 systemically) | ELISA; multiplex immunoassay; RT-qPCR for mRNA in tissue samples | High local concentrations in lungs help recruit immune cells and facilitate iBALT formation (protective), whereas very high plasma CXCL13 indicates severe disease and poorer prognosis. CXCL13 is often measured in plasma as a biomarker of germinal center activity in COVID-19. | |
| BAFF / APRIL cytokine levels – B cell helper cytokines for activation and IgA class switching | Blood serum/plasma (systemic); can be measured in mucosal fluids (e.g. BAL) | ELISA or multiplex bead-based immunoassay; serum cytokine analyzers | Promote mucosal B-cell maturation and IgA production, aiding early neutralization of virus at mucosal surfaces. Protective role is indirect; systemic levels rise in severe infection, so their role in protection is not fully clear. |