Inflammatory and Coagulation Biomarkers in Patients with Sars-COV2 Infection Receiving COVID-19 Convalescent Plasma: The Bergamo Registry

INTRODUCTION: Passive immunization therapy with convalescent plasma has been successfully used in prior viral pandemics. For these reasons, from the beginning of the COVID-19 outbreak in March 2020, our hospital has been actively involved in the collection of COVID-19 convalescent plasma (CCP) and its administration to hospitalized COVID-19 patients. We set up a registry to collect prospectively clinical and laboratory data, and blood samples, from CCP donors and CCP recipients (IMMUNOCOVID registry, clinicaltrials.gov identifier #04614012, approved by the local Ethics Committee). In the present study, in a cohort of COVID-19 plasma recipients, we prospectively assessed the effect of CCP treatment on different clinical and laboratory parameters, including anti-SARS-CoV2 IgG antibody (Ab) levels, inflammatory and coagulation biomarkers.

METHODS: Hospitalized COVID-19 patients were treated with maximum 3 CCP units (200 ml/unit), each given every other day, and followed-up clinically for 30 days after first CCP infusion. Venous blood samples were collected on days 0 (D0), 3 (D3), and 5 (D5) before each CCP administration, and on day 7 (D7) after the first administration. The following laboratory measurements were performed: IgG anti-SARS-CoV2 Nucleocapsid protein (anti-N) and IgG anti-Spike protein (anti-S) Ab (quantitative assay); fibrinogen, D-dimer, C reactive protein (CRP), procalcitonin, LDH, Hb, blood cell counts, AST, ALT, creatinine, and GFR. Results are expressed as median and 5th-95th percentile range.

RESULTS: From May 2020 to April 2022, 334 (103F/231M) hospitalized COVID-19 patients received CCP treatment. The median age of the cohort was 67 (41-86) years; 89 were admitted to the intensive care unit (ICU) and 245 were in the medical general ward (non-ICU patients). Among this cohort, 255 patients received 3 CCP units, 47 patients 2 CCP units, and 32 only 1 CCP unit. The median time from hospital admission to CCP infusion was 2 days (0 - 70) and a total of 890 CCP units were infused with a median value of 153 AU/ml (100-400) anti-S IgG Ab. Treatment with CCP led to a significant (p<0.001) 7.1-fold increase in anti-S and 1.7-fold increase in anti-N Ab at day 7. By multivariate analysis, the percentage increase in anti-S Ab [i.e., delta = (D7-D0/D0)] was significantly (p<0.05) associated with younger age (beta=-0.181) and male gender (beta=-0.195), but not with disease severity (ICU vs non-ICU), with the highest increment occurring in males <60 years (9.8-fold). Regarding inflammatory and coagulation biomarkers, at enrollment, CRP, neutrophil count, LDH, procalcitonin, fibrinogen and D-dimer levels were all significantly elevated, while lymphocytes and Hb were significantly lower than the normal range. Compared to non-ICU patients, the ICU group, at D0, had higher levels (p<0.05) of inflammatory biomarkers and D-dimer, and significantly lower (p<0.05) lymphocyte count, Hb, and fibrinogen level.

In the subgroup of 255 patients who received 3 CCP infusions, in parallel to anti-SARS-CoV2 IgG increment, a significant (p<0.001) reduction in CRP, LDH, ferritin, procalcitonin, and fibrinogen levels occurred. This was particularly apparent in the non-ICU subgroup. Among the whole cohort of 334 patients, 66 had cancer (28 hematological tumors, 33 solid tumors, and 5 both hematological and solid tumors). The median age of this subgroup was 70 years (49-88), with 16 of them admitted to ICU. In this category of patients, a significant increase (p<0.01) of both anti-S (4.7-fold) and anti-N (1.3-fold) IgG occurred, not differently from the rest of patients.

Four out of 890 CCP infusions were associated with a mild adverse event with a resolution in 24 hours. Regarding overall mortality, 48 patients (14%) died after 30 days follow-up [15F/33M, median age 64 years (40-81)], 16 of them were in ICU.

CONCLUSIONS: In our study, CCP treatment leads to an increase in antibody levels in the recipients, particularly in males <60 years. This occurs also in subjects with cancer and those with severe COVID-19. Notably, the increase of humoral immune response is associated with a decrease in inflammatory parameters and fibrinogen levels. The low incidence of adverse events observed supports the safety of CCP administration.

No relevant conflicts of interest to declare.