Inflammation as Prognostic Hallmark of Clinical Outcome in Patients with SARS-CoV-2 Infection

The COVID-19 pandemic, caused by SARS-CoV-2, presents a broad clinical spectrum ranging from asymptomatic infection to severe interstitial pneumonia and multiple organ dysfunction syndrome driven by dysregulated inflammation. Early identification of hospitalized patients at high risk of severe outcomes and death is crucial to tailor management during pandemic waves. The study aims to characterize clinical and laboratory features of hospitalized COVID-19 patients and to determine which inflammatory biomarkers and lymphocyte subsets predict in-hospital mortality, comparing survivors and non-survivors and estimating independent risk factors.

Prior studies have linked systemic inflammation and immune dysregulation to COVID-19 severity and mortality. Elevated CRP, PCT, ferritin, D-dimers, fibrinogen, and cytokines (notably IL-6 and IL-10) have been associated with severe disease, while lymphopenia and reduced T-cell subsets correlate with poor outcomes. Evidence on PCT as a prognostic marker is mixed, with some studies showing strong associations and others refuting its independent value. CRP often rises early and correlates with severity; composite ratios (CRP/albumin, CRP/lymphocyte) may improve prognostic accuracy. LDH elevation reflects tissue injury and has been repeatedly associated with adverse outcomes. Reductions in CD3+, CD4+, and CD8+ T cells, and high neutrophil-to-lymphocyte ratios, predict severity, need for intubation, and mortality. IL-6 is frequently reported as an independent predictor of mortality and organ involvement and may be less affected by corticosteroid therapy. Age and comorbidities (hypertension, obesity, diabetes, cardiac disease) consistently emerge as strong risk factors for death.

Design: Retrospective cohort study at the public "F. Perinei" Murgia Hospital (Altamura, Italy). Ethics approval obtained (Azienda Ospedaliero Universitaria Consorziale Policlinico, Bari, 0015987; 17 February 2022). Period: March–June 2021. Participants: 150 hospitalized, RT-PCR–confirmed COVID-19 patients, divided by outcome into survivors (n=100) and non-survivors (n=50). Diagnostics: SARS-CoV-2 confirmation by RT-PCR (NeoPlex kit on KingFisher system). Amplification: RT at 50°C 30 min; 95°C 15 min; 40 cycles (95°C 15 s, 60°C 60 s). Positive if Ct ≤ 38. Laboratory measurements (within 24 h of admission): - Hematology: total lymphocytes using automated analyzer (Pentra ABX HORIBA). - Inflammatory biomarkers: LDH and CRP (Olympus AU680, Beckman Coulter), PCT (Liaison, DiaSorin), IL-6 and ferritin (ADVIA Centaur XP, Siemens), D-dimer and fibrinogen (ACL TOP 500, Werfen). - Lymphocyte immunophenotyping: Flow cytometry (AQUIOS CL, Beckman Coulter) with TETRA-1 panel (CD45, CD3, CD4, CD8); analysis via Aquios system software v2.2.0. Clinical data: Demographics, days from symptom onset, comorbidities, treatments, respiratory support, ICU admission. Treatments during hospitalization (descriptive): Empirical antimicrobials in moderate/severe cases; remdesivir in 12%; corticosteroids in moderate/severe; hyperimmune plasma in 6%. Statistical analysis: Categorical variables as counts (%); continuous variables as mean with 95% CI or median (IQR). Comparisons by Student’s t-test (normal) or Mann–Whitney U (non-normal). Categorical comparisons by χ2. ROC analyses (Wilson/Brown method). Multinomial binary logistic regression for mortality predictors; results as odds ratios (OR) with 95% CI. Two-sided p<0.05 considered significant. Software: MedCalc and GraphPad Prism 8.2.

- Cohort: 150 patients; survivors 100, non-survivors 50. Median age 70 y; non-survivors older than survivors (79 vs 65 y; p<0.0001). 84% had ≥1 comorbidity: hypertension 55.3%, obesity 35.3%, diabetes 24%, chronic cardiac disease 22.6%, neurological 16%, pulmonary 8%, kidney 7.3%, malignancy 4.6%. - Care: ICU admission in 22%. On admission, respiratory support: CPAP 68%, Venturi mask 16.7%, simple face mask 12%. - Hematology/Immunology (median [IQR] unless stated): • Lymphocytes (×10^3/µL): 0.70 (0.50–0.90) non-survivors vs 1.0 (0.70–1.4) survivors; p<0.0001. • CD3 (cells/µL): 304 (194–491) vs 556 (358–836); p<0.0001. • CD4 (cells/µL): 184 (113–272) vs 353 (207–548); p<0.0001. • CD8 (cells/µL): 83 (49–139) vs 172 (97–265); p<0.0001. • CD4/CD8 ratio: similar (2.00 vs 1.97); p=0.9539. • Platelets (×10^3/µL): 200 (160–258) vs 254 (197–318); p=0.0013. - Inflammation-related biomarkers: • IL-6 (pg/mL): 20 (11–57) non-survivors vs 9 (3–19) survivors; p<0.0001. • LDH (U/L): 489 (359–557) vs 318 (257–398); p<0.0001. • CRP (mg/L): 128 (68–170) vs 51 (16–80); p<0.0001. • PCT (ng/mL): 0.21 (0.10–0.51) vs 0.05 (0.02–0.12); p<0.0001. • D-dimers (ng/mL): 1490 (997–3604) vs 1041 (652–1692); p=0.0114. • Ferritin (ng/mL): 1111 (618–1561) vs 655 (349–1013); p=0.0018. • Fibrinogen (g/L): no significant difference (544 vs 523; p=0.4193). - Multivariable logistic regression (independent risk factors for in-hospital mortality): • Age: OR 1.14 per year (95% CI 1.07–1.22; p=0.0001). • Number of comorbidities: OR 1.84 per additional comorbidity (95% CI 1.11–3.05; p=0.0178). • IL-6 >20 pg/mL: OR 1.03 (95% CI 1.00–1.06) borderline. • LDH >489 U/L: OR 1.01 (95% CI 1.00–1.01) borderline. - ROC analyses: • T-cell subsets: AUC CD3+=0.769 (0.690–0.848), CD4+=0.752 (0.670–0.833), CD8+=0.741 (0.655–0.827); all p<0.001. • IL-6 AUC=0.735 (0.651–0.818); LDH AUC=0.784 (0.703–0.864); age AUC=0.805 (0.736–0.873); comorbidities AUC=0.709 (0.622–0.800).

Findings support that heightened systemic inflammation and profound lymphocytopenia characterize hospitalized COVID-19 patients with fatal outcomes. Non-survivors exhibited markedly elevated IL-6, LDH, CRP, and PCT alongside significantly reduced total lymphocyte counts and CD3+, CD4+, and CD8+ T-cell subsets, whereas CD4/CD8 ratios remained largely unchanged. Age and comorbidity burden independently predicted in-hospital mortality, emphasizing host vulnerability as a dominant driver of outcomes. The results align with literature that associates CRP and LDH with tissue injury and poor prognosis, PCT with severe disease (potentially reflecting bacterial co-infection, prolonged ventilation, or STAT3/ACE2 pathway activation), and IL-6 with cytokine storm and multiorgan involvement. The consistent depletion of T-cell subsets underscores immune exhaustion/migration rather than direct lymphocyte infection and supports the prognostic utility of early lymphocyte profiling. Overall, integrating inflammatory biomarkers with clinical factors (age, comorbidities) can improve risk stratification of hospitalized patients.

In hospitalized COVID-19 patients, inflammatory biomarkers (IL-6, LDH, CRP, PCT) are significantly elevated and T-lymphocyte counts (CD3+, CD4+, CD8+) are significantly reduced in non-survivors compared to survivors. Age and comorbidity burden are independent predictors of in-hospital mortality, while LDH and IL-6 show borderline independent associations. These data reinforce inflammation and lymphocytopenia as hallmarks of poor prognosis and highlight the value of early laboratory profiling for risk assessment. Future work should validate these findings in larger, multicenter cohorts and develop practical scoring systems combining clinical and laboratory parameters to guide triage and targeted interventions.

Monocentric, retrospective design and a limited enrollment window (March–June 2021) may affect generalizability. Potential confounding by treatment heterogeneity and evolving standards of care during the study period cannot be excluded. Some biomarkers with significant univariate differences did not retain significance in multivariable models. External validation in larger, diverse populations is needed.