Background Although immune modulation is a promising therapeutic avenue in coronavirus disease 2019 (COVID-19), the most relevant targets remain to be found. COVID-19 has peculiar characteristics and outcomes, suggesting a unique immunopathogenesis. Methods Thirty-six immunocompetent non-COVID-19 and 27 COVID-19 patients with severe pneumonia were prospectively enrolled in a single center, most requiring intensive care. Clinical and biological characteristics (including T cell phenotype and function and plasma concentrations of 30 cytokines) and outcomes were compared. Results At similar baseline respiratory severity, COVID-19 patients required mechanical ventilation for significantly longer than non-COVID-19 patients (15 [7–22] vs. 4 (0–15) days; p = 0.0049). COVID-19 patients had lower levels of most classical inflammatory cytokines (G-CSF, CCL20, IL-1β, IL-2, IL-6, IL-8, IL-15, TNF-α, TGF-β), but higher plasma concentrations of CXCL10, GM-CSF and CCL5, compared to non-COVID-19 patients. COVID-19 patients displayed similar T-cell exhaustion to non-COVID-19 patients, but with a more unbalanced inflammatory/anti-inflammatory cytokine response (IL-6/IL-10 and TNF-α/IL-10 ratios). Principal component analysis identified two main patterns, with a clear distinction between non-COVID-19 and COVID-19 patients. Multivariate regression analysis confirmed that GM-CSF, CXCL10 and IL-10 levels were independently associated with the duration of mechanical ventilation. Conclusion We identified a unique cytokine response, with higher plasma GM-CSF and CXCL10 in COVID-19 patients that were independently associated with the longer duration of mechanical ventilation. These cytokines could represent the dysregulated immune response in severe COVID-19, as well as promising therapeutic targets. ClinicalTrials.gov: NCT03505281.

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Summary -Human and bovine milks were used as serum substitute for cell cultures. Two whey fractions termed LBS65 and LELm prepared by different steps were routinely used for culturing hybridomas in our laboratory. They stimulated 3H-thymidine incorporation into hybridoma, but a minimum of 1% of fetal calf serum (FCS) was required when the cells were propagated in the long-term. ln this investigation, the chemical composition of LBS65 and LELm was studied in parallel to FCS composition. LBS65 and FCS had a total protein level of about 40 g/l, while LELm contained them at a concentration of 11 g/l. The amino acid content of FCS and LBS65 was very similar (about 4 000 urnol/l), whereas it was lower in LELm (about 300 umorl). Although the values of nitrogen cornpounds were different in LBS65 and LELm, these 2 whey fractions behaved similarly to a substitute of FCS. Whey fractions were low in sodium, and high in calcium compared to FCS. The cholesterol level was lower and triglycerides were higher in whey than in FCS. The ratio of unsaturated! saturated fatty acids varied from 1 whey fraction to another. It differed from the FCS ratio. FCS and whey fractions contained small amounts of steroid or peptide hormones. However, progesterone, 17-0H-progesterone, ACTH and cAMP concentrations were higher in the whey fraction than in FCS. Whey fractions are a complex medium containing various compounds able to promote cell growth. However, sorne unknown compounds present in FCS and absent in milk fractions are required in long-term cell culturing.bovine milk 1 whey 1 whey hormone 1 whey amino acid

COVID-19 pneumonia has specific features and outcomes that suggests a unique immunopathogenesis. Severe forms of COVID-19 appear to be more frequent in obese patients, but an association with metabolic disorders is not established. Here, we focused on lipoprotein metabolism in patients hospitalized for severe pneumonia, depending on COVID-19 status. Thirty-four non-COVID-19 and 27 COVID-19 patients with severe pneumonia were enrolled. Most of them required intensive care. Plasma lipid levels, lipoprotein metabolism, and clinical and biological (including plasma cytokines) features were assessed. Despite similar initial metabolic comorbidities and respiratory severity, COVID-19 patients displayed a lower acute phase response but higher plasmatic concentrations of non-esterified fatty acids (NEFAs). NEFA profiling was characterised by higher level of polyunsaturated NEFAs (mainly linoleic and arachidonic acids) in COVID-19 patients. Multivariable analysis showed that among severe pneumonia, COVID-19-associated pneumonia was associated with higher NEFAs, lower apolipoprotein E and lower high-density lipoprotein cholesterol concentrations, independently of body mass index, sequential organ failure (SOFA) score, and C-reactive protein levels. NEFAs and PUFAs concentrations were negatively correlated with the number of ventilator-free days. Among hospitalized patients with severe pneumonia, COVID-19 is independently associated with higher NEFAs (mainly linoleic and arachidonic acids) and lower apolipoprotein E and HDL concentrations. These features might act as mediators in COVID-19 pathogenesis and emerge as new therapeutic targets. Further investigations are required to define the role of NEFAs in the pathogenesis and the dysregulated immune response associated with COVID-19.Trial registration: NCT04435223.

A dairy by-product was used in cell line cultures as a replacement for fetal calf serum (FCS). Various fractions were prepared from whey. All fractions have the ability to stimulate DNA synthesis in human and mouse 3T3 fibroblast and hybridoma cultures.They also allow hybridoma proliferation in the long term using only 0.5 % FCS. In these latter experiments, heated and ultrafiltered fractions were more effective than iO % fetal calf serum.

An amendment to this paper has been published and can be accessed via the original article.

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