Background Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. Methods A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival. Results In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6–24.0, P = 0.52) and 22.4% (97.5% CI: 17.2–28.3, P < 0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline. Conclusions Tocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline. Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092).
Hepcidin, the iron hormone, is produced by the liver in response to iron and inflammation. Its synthesis during inflammation is triggered by cytokines, but the details of iron activation are obscure. We tested the role of Kupffer cells and macrophages by studying iron-loaded or inflamed mice with selective inactivation of Kupffer cells or the in vitro effect of conditioned human macrophages on hepcidin expression. Hepcidin messenger RNA (mRNA) expression was studied by Northern blot and reverse transcriptase polymerase chain reaction analysis in mice that were treated with 40 mg/kg gadolinium (
Classic hereditary hemochromatosis (HH)is a common genetic disorder of iron metabolism caused by a mutation in the HFE gene. Whereas the prevalence of the mutation is very high, the clinical penetrance of the disease is low, suggesting that the HFE mutation is a necessary but not sufficient cause of clinical HH. Several candidate modifier genes have been proposed in mice and humans, including haptoglobin. Haptoglobin is the plasma protein with the highest binding affinity for hemoglobin. It delivers free plasma hemoglobin to the reticuloendothelial system, thus reducing loss of hemoglobin through the glomeruli and allowing hemeiron recycling. IntroductionClassic hereditary hemochromatosis (HH) is a common genetic disorder of iron metabolism characterized by a gradual but progressive expansion of the plasma iron compartment. Affected patients develop toxic iron overload and tissue damage including liver cirrhosis, hepatocarcinoma, and heart disease. Most patients with HH are homozygous for a missense mutation (C282Y) that disrupts the conformation of HFE, an atypical major histocompatibility class I molecule. 1 Similar to human patients, mice lacking the Hfe protein or producing a mutated protein analogous to the human C282Y protein develop increased hepatic iron levels and elevated transferrin saturation. 2,3 Whereas C282Y is among the most prevalent human mutations, the clinical penetrance of the disease is low, suggesting that the HFE C282Y mutation is a necessary but not sufficient cause of clinical HH. 4 Variable penetrance may be due to epigenetic, environmental, and genetic factors. 5 Also, in mice there is a marked difference in hepatic iron loading between C57BL/6 and DBA/2 Hfe Ϫ/Ϫ strains, indicating that other genes modify the murine HH phenotype. 6,7 Several candidate modifier genes have been proposed in mice and humans, 8-10 including haptoglobin (Hp). Hp is the plasma protein with the highest binding affinity for hemoglobin (K d Ϸ 1 pM). 11 It binds free hemoglobin and delivers it to the reticuloendothelial system by CD163 receptor-mediated endocytosis. 12 Thus, Hp is believed to reduce loss of hemoglobin through the glomeruli and to allow heme-iron recycling.Hp is synthesized as a single polypeptide, which is cleaved into ␣-and -chains. The mammalian isoform Hp1-1 is a homodimer of 2 Hp molecules linked by a single disulfide bond through their respective ␣-chains. In humans, a variant with a longer ␣-chain is also present. Individuals homozygous for the longer allele show a multimeric Hp phenotype designated Hp2-2. Hp2-1 refers to the molecular phenotype (both Hp dimers and multimers) seen in humans heterozygous for the 2 variant alleles. Complexes of hemoglobin and multimeric Hp (the 2-2 phenotype) exhibit higher functional affinity for CD163 than do complexes of hemoglobin and dimeric Hp (the 1-1 phenotype).In healthy men, the Hp2-2 type is associated with higher serum iron and ferritin levels than the Hp2-1 and Hp1-1 types. Moreover, in healthy men carrying the Hp2-2 type, a fraction of Hphemo...
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