Role of proteases and alpha-1-proteinase inhibitor in the development of respiratory failure in SARS-CoV-2 pneumonia in patients with type 2 diabetes

BACKGROUND: SARS-CoV-2 pneumonia in patients with type 2 diabetes mellitus (T2DM) is linked to severe disease and high mortality. The role of alpha-1 protease inhibitor (α1-PI) in regulating proteolytic activity in this population during COVID-19 remains poorly understood.

AIM: To evaluate the activity of alpha-1 protease inhibitor (α1-PI), elastase-like proteases (ELP), and trypsin-like proteases (TLP) in the plasma of patients with type 2 diabetes mellitus (T2DM) infected with SARS-CoV-2, and to develop a prognostic model for the risk of respiratory failure (RF).

MATERIALS AND METHODS: A prospective observational study included 172 participants divided into four groups: SARS-CoV-2 pneumonia without T2DM (n=70), T2DM without infection (n=32), T2DM with pneumonia (n=15), and healthy controls (n=30). Plasma levels of α1-PI, elastase- and trypsin-like proteases (ELP, TLP), ACE, PAR-4, CRP, glucose, C-peptide, and TBARS were measured. Data were analyzed using non-parametric tests, Spearman’s correlation, and binary logistic regression.

RESULTS: In patients without T2DM and severe pneumonia, α1-PI activity was reduced by 21% (23.7 IU/mL [15.1; 33.2] vs. 30.0 in controls; p=0.008), with moderate increases in ELP and TLP. In contrast, T2DM patients with COVID-19 showed a 41% rise in α1-PI (42.4 IU/mL [31.8; 53.4]; p=0.023) alongside marked activation of TLP (10.9-fold; p<0.001), ELP (4.3-fold; p<0.001), ACE (2.7-fold), and PAR-4. PAR-4 declined with worsening respiratory failure (RF), especially in T2DM (0.8 ng/mL in RF grade III vs. 6.8 without RF; p=0.010). Logistic regression showed that lower α1-PI increased pneumonia risk in non-T2DM individuals (OR=0.092; 95% CI 1.011–1.056; p=0.003), while higher α1-PI raised risk in T2DM (OR=1.033; 95% CI 0.849–0.997; p=0.040). A prognostic RF model (AUC=0.88) included ELP, TLP, T2DM status, and infection severity; α1-PI was excluded (p>0.05).

CONCLUSION: In patients with type 2 diabetes mellitus (T2DM) and COVID-19, a more pronounced protease activation and a dual response of α1-protease inhibitor (α1-PI) are observed, indicating an ineffective anti-inflammatory response. Decreased PAR-4 levels correlate with the severity of respiratory failure (RF). The prognostic model enables risk stratification for RF in T2DM patients.

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