Metabolic alterations unravel the materno fetal immune responses with disease severity in pregnant women infected with SARS-CoV-2 (preprint)

Background: Pregnancy being immune compromised state, COVID-19 disease poses a high risk of premature delivery and threat to fetus. Plasma metabolome regulates immune cellular responses and we aimed to analyze the plasma secretome, metabolome, and immune cells in COVID-19-positive pregnant mothers and cord blood. Methods: COVID-19 RT-PCR positive pregnant females (n=112) asymptomatic (n=82), or with mild (n=21) or moderate (n=9) disease and control healthy pregnant (n=10) females were included. Mothers blood and cord blood (n=80) was analyzed for untargeted metabolome profiling and plasma cytokines by high-resolution mass spectrometry (MS) and multiplex cytokine bead array. Immune scan in mothers was done using flow cytometry. Results: In asymptomatic SARS-CoV-2 infection, the amino acid metabolic pathways such as glycine, serine, L-lactate, and threonine metabolism was upregulated, riboflavin and tyrosine metabolism, downregulated. In mild to moderate disease, the pyruvate and NAD+ metabolism (energy metabolic pathways) were mostly altered. In addition to raised TNF-alpha, IFN-alpha, IFN-gamma, IL-6 cytokine storm, IL-9 was increased in both mothers and neonates. Pyruvate and NAD+ metabolic pathways along with IL-9 and IFN-gamma had an impact on non-classical monocytes, increased CD4 T cells and B cells but depleted CD8+ T cells. Cord blood mimicked the mothers metabolomic profiles by showing altered valine, leucine, isoleucine, glycine, serine, threonine in asymptomatic and NAD+ and riboflavin metabolism in mild and moderate disease subjects. Conclusions: Our results demonstrate a graduated immune-metabolomic interplay in mother and fetus in pregnant females with different degrees of severity of COVID-19 disease. IL-9 and IFN- gamma regulated pyruvate, lactate TCA metabolism, and riboflavin metabolism with context to disease severity are hallmarks of this materno-fetal metabolome.

Sustained expression of inflammatory monocytes and activated T cells in COVID-19 patients and recovered convalescent plasma donors (preprint)

Intense monocyte activation and infiltration into the target tissues is the main mechanism of lung injury in SARS CoV2 infection. A reduction in the degree and nature of such cellular responses is expected following recovery. We aimed to investigate the immune responses in severe Covid-19 patients and recovered patients. MethodsSevere COVID-19 patients (n=34) at Lok Nayak Hospital, New Delhi and COVID-19 recovered patients (n=15) from mild disease and considered for convalescent plasma (COPLA) donation at Institute of Liver and Biliary Sciences (ILBS), New Delhi were recruited. We performed a multiplex cytokine bead assay in plasma and detailed multicolour flow cytometric analysis in peripheral blood of both groups and outcomes were compared in both groups and with healthy controls (n=10). ResultsA significant increase in inflammatory markers [MIP1-a, MIP3a, MCP1, MIF, MMP12, ITAC, VEGF-A, and leptin] was observed in severe patients. Non-survivors additionally showed increased IL-6 levels. Despite the sustained expression of MIPs, the recovered patients showed a surge in MCSF and IL-18 levels. Both the groups had increased CCR2, CX3CR1 positive monocytes, low CD8 T cells, APRIL and BAFFR+ve B cells compared with healthy subjects. In conclusion, patients who have recovered and considered for COPLA donations still have compromised immunity with sustained expression of inflammatory monocytes and activated T cells.

Efficacy of Convalescent Plasma Therapy compared to Fresh Frozen Plasma in Severely ill COVID-19 Patients: A Pilot Randomized Controlled Trial (preprint)

Background: The role of convalescent plasma (COPLA) for the treatment of severely ill Corona Virus Disease-2019 is under investigation. We compared the efficacy and safety of convalescent plasma with fresh frozen plasma (FFP) in severe COVID-19 patients. Methods and findings: This was an open-label, single-centre phase II RCT on 29 patients with severe COVID-19 from India. One group received COPLA with standard medical care (SMC) (n=14), and another group received FFP with SMC (n=15). A total of 29 patients were randomized in the two treatment groups. Eleven out of 14 (78.5%) patients remained free of ventilation at day seven in the intervention arm while the proportion was 14 out of 15 (93.3 %) in the control arm (p= 0.258). The median reductions in RR per min at 48-hours in COPLA-group and FFP group were -6.5 and -3 respectively [p=0.004] and at day seven were -14.5 and -10 respectively (p=0.008). The median improvements in percentage O2 saturation at 48-hours were 6.5 and 2 respectively [p=0.001] and at day seven were 10 and 7.5 respectively (p=0.026). In the COPLA-group, the median improvement in PaO2/FiO2 was significantly superior to FFP at 48-hours [41.94 and 231.15, p=0.009], and also at day-7 [5.55 and 77.01 p<0.001]. We did not find significant differences in hospitalization duration between the groups (0.08). Conclusion: COPLA therapy resulted in rapid improvement in respiratory parameters and shortened time to clinical recovery, although no significant reduction in mortality was observed in this pilot trial. We need larger trials to draw conclusive evidence on the use of Convalescent plasma in COVID-19.