Background Interleukin-6 (IL-6) was proposed to be associated with the severity of coronavirus disease 2019 (COVID-19). The present study aimed to explore the kinetics of IL-6 levels, validate this association in COVID-19 patients, and report preliminary data on the efficacy of IL-6 receptor blockade. Methods We conducted a retrospective single-institutional study of 901 consecutive confirmed cases. Serum IL-6 concentrations were tested on admission and/or during hospital stay. Tocilizumab was given to 16 patients with elevated IL-6 concentration. Results 366 patients were defined as common cases, 411 patients as severe, and 124 patients as critical according to the Chinese guideline on diagnosis and treatment of COVID-19. The median concentration of IL-6 was < 1.5 pg/ml (IQR < 1.50–2.15), 1.85 pg/ml (IQR < 1.50–5.21), and 21.55 pg/ml (IQR 6.47–94.66) for the common, severe, and critical groups respectively (P < 0.001). The follow-up kinetics revealed serum IL-6 remained high in critical patients even when cured. An IL-6 concentration higher than 37.65 pg/ml was predictive of in-hospital death (AUC 0.97 [95% CI 0.95–0.99], P < 0.001) with a sensitivity of 91.7% and a specificity of 95.7%. In the 16 patients who received tocilizumab, IL-6 concentrations were significantly increased after administration, and survival outcome was not significantly different from that of propensity-score matched counterparts (n = 53, P = 0.12). Conclusion Serum IL-6 should be included in diagnostic work-up to stratify disease severity, but the benefit of tocilizumab needs further confirmation. Trial registration retrospectively registered.

Epidemiological investigations have shown that fetuses with intrauterine growth retardation (IUGR) are susceptible to adult metabolic syndrome. Clinical investigations and experiments have demonstrated that caffeine is a definite inducer of IUGR, as children who ingest caffeine-containing food or drinks are highly susceptible to adult obesity and hypertension. Our goals for this study were to investigate the effect of prenatal caffeine ingestion on the functional development of the fetal hippocampus and the hypothalamic-pituitary-adrenal (HPA) axis and to clarify an intrauterine HPA axis-associated neuroendocrine alteration induced by caffeine. Pregnant Wistar rats were intragastrically administered 20, 60, and 180 mg/kg·d caffeine from gestational days 11–20. The results show that prenatal caffeine ingestion significantly decreased the expression of fetal hypothalamus corticotrophin-releasing hormone. The fetal adrenal cortex changed into slight and the expression of fetal adrenal steroid acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc), as well as the level of fetal adrenal endogenous corticosterone (CORT), were all significantly decreased after caffeine treatment. Moreover, caffeine ingestion significantly increased the levels of maternal and fetal blood CORT and decreased the expression of placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2). Additionally, both in vivo and in vitro studies show that caffeine can downregulate the expression of fetal hippocampal 11β-HSD-2, promote the expression of 11β-hydroxysteroid dehydrogenase 1 and glucocorticoid receptor (GR), and enhance DNA methylation within the hippocampal 11β-HSD-2 promoter. These results suggest that prenatal caffeine ingestion inhibits the development of the fetal HPA axis, which may be associated with the fetal overexposure to maternal glucocorticoid and activated glucocorticoid metabolism in the fetal hippocampus. These results will be beneficial in elucidating the developmental toxicity of caffeine and in exploring the fetal origin of adult HPA axis dysfunction and metabolic syndrome susceptibility for offspring with IUGR induced by caffeine.

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The aim of the present study was to evaluate the role of placental apoptosis in mediating the reproductive and developmental toxicity of caffeine in rodents. Female Kunming mice were treated with caffeine (60, 120 and 240 mg/kg per day) before and during pregnancy. The conception rate, maternal bodyweight gain, placental weight and indices of fetal developmental, including the rate of intrauterine growth retardation (IUGR; i.e. the actual number of fetuses exhibiting IUGR as a percentage of the total number of fetuses), were determined on gestational day (GD) 18. Female Wistar rats were treated with caffeine (20, 60 and 180 mg/kg per day) from GD11 to GD20. The IUGR rate, maternal plasma angiotensin (Ang) II and prolactin concentrations, placental pathology, expression of angiotensin AT(1) and AT(2) receptors and apoptosis-related proteins were measured on GD20. In mice, caffeine treatment dose-dependently reduced the total conception rate, delayed conception and decreased maternal bodyweight gain, placental weight, fetal bodyweight and fetal body and tail lengths, whereas the IUGR rate was increased. In rats, caffeine treatment dose-dependently decreased placental weight and fetal bodyweight and increased the IUGR rate. Abnormal placental structures and decreased maternal plasma prolactin concentrations were observed following 180 mg/kg per day caffeine treatment, which resulted in increases in renin-angiotensin system (RAS) activity, including maternal plasma AngII concentrations and placental AT(1B) and AT(2) receptor expression, and Bax and p53 expression, but decreases in placental Bcl-2 expression. On the basis of the results of the present study, it appears that caffeine ingestion has detrimental effects on the reproductive system and fetal development in rodents that are associated with chronic activation of the maternal and placental RAS, and induction of p53-dependent placental apoptosis.