Escalated complement activation during hospitalization is associated with higher risk of 60-day mortality in SARS-CoV-2-infected patients.

BACKGROUND: The complement system, an upstream recognition system of innate immunity, is activated upon SARS-CoV-2 infection. To gain a deeper understanding of the extent and duration of this activation, we investigated complement activation profiles during the acute phase of COVID-19, its persistence post-recovery and dynamic changes in relation to disease severity. METHODS: Serial blood samples were obtained from two cohorts of hospitalized COVID-19 patients (n = 457). Systemic complement activation products reflecting classical/lectin (C4d), alternative (C3bBbP), common (C3bc) and terminal pathway (TCC and C5a) were measured during hospitalization (admission, days 3-5 and days 7-10), at 3 months and after 1 year. Levels of activation and temporal profiles during hospitalization were related to disease severity defined as respiratory failure (PO2/FiO2 ratio <26.6 kPa) and/or admission to intensive care unit, 60-day total mortality and pulmonary pathology after 3 months. FINDINGS: During hospitalization, TCC, C4d, C3bc, C3bBbP and C5a were significantly elevated compared to healthy controls. Severely ill patients had significantly higher levels of TCC and C4d (p < 0.001), compared to patients with moderate COVID-19. Escalated levels of TCC and C4d during hospitalization were associated with a higher risk of 60-day mortality (p < 0.001), and C4d levels were additionally associated with chest CT changes at 3 months (p < 0.001). At 3 months and 1 year, we observed consistently elevated levels of most complement activation products compared to controls. CONCLUSION: Hospitalized COVID-19 patients display prominent and long-lasting systemic complement activation. Optimal targeting of the system may be achieved through enhanced risk stratification and closer monitoring of in-hospital changes of complement activation products.

High viral loads combined with inflammatory markers predict disease severity in hospitalized COVID-19 patients: Results from the NOR-Solidarity trial.

OBJECTIVES: To investigate temporal changes in the association between SARS-CoV2 viral load (VL) and markers of inflammation during hospitalization, as well as the ability of these markers alone or in combination to predict severe outcomes. METHODS: Serial oropharyngeal and blood samples were obtained from hospitalized COVID-19 patients (n = 160). Levels of inflammatory markers and oropharyngeal VL were measured during hospitalization (admission, days 3-5, and days 7-10) and related to severe outcomes (respiratory failure/intensive care unit admission). RESULTS: Elevated admission levels of IL (interleukin)-6, IL-33, IL-8, monocyte chemoattractant protein-1 (MCP-1), interferon-γ-induced protein 10 (IP-10), IL-1ß, and IL-1Ra were associated with severe outcomes during hospitalization. Although no inflammatory markers correlated with VL at baseline, there was a significant correlation between VL and levels of IP-10 and MCP-1 at days 3-5, accompanied by IL-8 and IL-6 at days 7-10. Finally, there was a seemingly additive effect of IP-10, MCP-1, and IL-6 in predicting severe outcomes when combined with high VL at baseline. CONCLUSIONS: An increasing number of inflammatory markers were associated with VL during the first 10 days of hospitalization, and several of these markers were associated with severe outcomes, in particular when combined with elevated VL. Future studies should assess the potential for combining antiviral and immunomodulatory treatment, preferably guided by viral and inflammatory biomarkers, for the selection of high-risk patients.

CT abnormalities 3 and 12 months after hospitalization for COVID-19 and association with disease severity: A prospective cohort study.

OBJECTIVES: To investigate changes in chest CT between 3 and 12 months and associations with disease severity in patients hospitalized for COVID-19 during the first wave in 2020. MATERIALS AND METHODS: Longitudinal cohort study of patients hospitalized for COVID-19 in 2020. Chest CT was performed 3 and 12 months after admission. CT images were evaluated using a CT severity score (CSS) (0-12 scale) and recoded to an abbreviated version (0-3 scale). We analyzed determinants of the abbreviated CSS with multivariable mixed effects ordinal regression. RESULTS: 242 patients completed CT at 3 months, and 124 (mean age 62.3±13.3, 78 men) also at 12 months. Between 3 and 12 months (n = 124) CSS (0-12 scale) for ground-glass opacities (GGO) decreased from median 3 (25th-75th percentile: 0-12) at 3 months to 0.5 (0-12) at 12 months (p<0.001), but increased for parenchymal bands (p<0.001). In multivariable analysis of GGO, the odds ratio for more severe abbreviated CSS (0-3 scale) at 12 months was 0.11 (95%CI 0.11 0.05 to 0.21, p<0.001) compared to 3 months, for WHO severity category 5-7 (high-flow oxygen/non-invasive ventilation/ventilator) versus 3 (non-oxygen use) 37.16 (1.18 to 43.47, p = 0.032), and for age ≥60 compared to <60 years 4.8 (1.33 to 17.6, p = 0.016). Mosaicism was reduced at 12 compared to 3 months, OR 0.33 (95%CI 0.16 to 0.66, p = 0.002). CONCLUSIONS: GGO and mosaicism decreased, while parenchymal bands increased from 3 to 12 months. Persistent GGO were associated with initial COVID-19 severity and age ≥60 years.