Effects of tocilizumab versus hemoadsorption combined with tocilizumab in patients with SARS-CoV-2 pneumonia: Preliminary results.

OBJECTIVE: To assess the variations of Interleukin-6 (IL-6) in patients with SARS-CoV-2 infection treated with Tocilizumab (TCZ) alone or in association with hemoadsorption (HA). DESIGN: Retrospective. SETTING: An Intensive Care Unit (ICU) admitting mechanically ventilated patients with SARS-CoV-2 pneumonia. PATIENTS: Four adult patients. INTERVENTIONS: We compared the blood values of IL-6, C-reactive protein (CRP) and of other biochemical variables including the PaO2/FiO2 in two patients who received TCZ alone and in other 2 in whom it was associated with the HA (TCZ-HA) due to the presence of impending or established organ failures other than the lung. All variables were measured before, during and after the treatment. MAIN RESULTS: In all patients, the IL-6 increased during the treatment; after its termination, its values sharply decreased only in those treated also with HA; conversely, the CRP decreased in all patients; the PaO2/FiO2 increased in three patients and remained stable in the remaining one. Both the TCZ and the HA were well tolerated; all patients were weaned from the mechanical ventilation and discharged from the hospital. LIMITATIONS: Although the limited number of patients does not allow to draw firm conclusions, the increase of the IL-6 of can be ascribed to its displacement from cellular and soluble receptors, whereas its decrease is likely due to the scavenging effect exerted by the HA. Although the association TCZ-HA could be valuable in the treatment of the Cytokine Release Storm (CRS) associated with the SARS-CoV-2, the HA could be more effective as it neutralizes a wider panel of inflammatory mediators.

Kinetics of Immunoglobulins in Septic Shock Patients Treated With an IgM- and IgA-Enriched Intravenous Preparation: An Observational Study.

Objective: To assess the variations of the blood levels of immunoglobulins (Ig) in septic shock patients treated with an Ig preparation enriched in IgM and IgA (eIg). Design: The blood levels of Ig in survivors (S) and non-survivors (NS) of a group of septic shock patients were measured before the initial administration (D0) and 1 (D1), 4 (D4), and 7 (D7) days thereafter. The SAPS II score, the capillary permeability, the primary site of infection, the antibiotic appropriateness, and the outcome at 28 days were also assessed. Results: In the interval D0-D7, the IgM increased significantly only in the S while remained stable in NS; the IgA significantly increased in both groups; the IgG did not vary significantly in both groups. At D4, the capillary permeability significantly decreased in S but not in NS. Conclusions: The kinetics of the different classes of Ig after eIg were different between S and NS. This could be related either to (a) different capillary permeability in the two groups or to (b) higher Ig consumption in NS. Further studies to confirm the benefits of eIg in the treatment of sepsis syndrome and to define the specific target population and the correct eIg dose are warranted.

Correction to: Effects of the timing of administration of IgM- and IgA-enriched intravenous polyclonal immunoglobulins on the outcome of septic shock patients.

Following publication of the original article [1], we have been notified that the tagging of the author name was done incorrectly in the XML version of the paper. The correct given name is Michele Claudio, and the family name is Vassallo.

Effects of the timing of administration of IgM- and IgA-enriched intravenous polyclonal immunoglobulins on the outcome of septic shock patients.

BACKGROUND: The administration of endovenous immunoglobulins in patients with septic shock could be beneficial and preparations enriched with IgA and IgM (ivIgGAM) seem to be more effective than those containing only IgG. In a previous study Berlot et al. demonstrated that early administration of ivIgGAM was associated with lower mortality rate. We studied a larger population of similar patients aiming either to confirm or not this finding considering also the subgroup of patients with septic shock by multidrug-resistant (MDR) pathogens. METHODS: Adult patients with septic shock in intensive care unit (ICU) treated with ivIgGAM from August 1999 to December 2016 were retrospectively examined. Collected data included the demographic characteristics of the patients, the diagnosis at admission, SOFA, SAPS II and Murray Lung Injury Score (LIS), characteristics of the primary infection, the adequacy of antimicrobial therapy, the delay of administration of ivIgGAM from the ICU admission and the outcome at the ICU discharge. Parametric and nonparametric tests and logistic regression were used for statistic analysis. RESULTS: During the study period 107 (30%) of the 355 patients died in ICU. Survivors received the ivIgGAM earlier than nonsurvivors (median delay 12 vs 14 h), had significantly lower SAPS II, SOFA and LIS at admission and a lower rate of MDR- and fungal-related septic shock. The appropriateness of the administration of antibiotics was similar in survivors and nonsurvivors (84 vs 79%, respectively, p: n.s). The delay in the administration of ivIgGAM from the admission was associated with in-ICU mortality (odds ratio per 1-h increase = 1.0055, 95% CI 1.003-1.009, p < 0.001), independently of SAPS II, LIS, cultures positive for MDR pathogens or fungi and onset of septic shock. Only 46 patients (14%) had septic shock due to MDR pathogens; 21 of them (46%) died in ICU. Survivors had significantly lower SAPS II, SOFA at admission and delay in administration of ivIgGAM than nonsurvivors (median delay 18 vs 66 h). Even in this subgroup the delay in the administration of ivIgGAM from the admission was associated with an increased risk of in-ICU mortality (odds ratio 1.007, 95% CI 1.0006-1.014, p = 0.048), independently of SAPS II. CONCLUSIONS: Earlier administration of ivIgGAM was associated with decreased risk of in-ICU mortality both in patients with septic shock caused by any pathogens and in patients with MDR-related septic shock.

Relaxometric and modelling studies of the binding of a lipophilic Gd-AAZTA complex to fatted and defatted human serum albumin.

A new lipophilic gadolinium chelate consisting of a long aliphatic chain bound to the AAZTA coordination cage (Gd-AAZTAC17) has been synthesised. It possesses two coordinated water molecules (q=2) in fast exchange with the solvent (tau298(M) = 67 ns), which yields a relaxivity of 10.2 mM(-1) s(-1). At concentrations greater than 0.1 mM, it forms micelles (average diameter 5.5 nm) characterised by a relaxivity of approximately 30 mM(-1) s(-1) at 20 MHz and 298 K. The latter value appears to be "quenched" by magnetic interactions among the Gd(III) ions on the surface of the micelle that cause a decrease in the electronic relaxation time. A relaxivity of 41 mM(-1) s(-1) was recorded for this micellar system when 98 % of the Gd(III) ions were replaced by diamagnetic Y(III). Gd-AAZTAC17 exhibits a better affinity for fatted human serum albumin (HSA) than for defatted HSA, whereas the relaxivities of the supramolecular adducts are reversed. The relaxivity shown by Gd-AAZTAC17/defatted HSA ({r b(1) (20 MHz, 298 K)=84 mM(-1) s(-1)) is by far the highest relaxivity reported so far for non-covalent paramagnetic adducts with slow-moving substrates. As shown by molecular docking calculations, the gadolinium complex enters a hydrophobic pocket present in fatted HSA more extensively than the corresponding adduct with defatted HSA. Interestingly, no marked difference was observed in either the relaxation enhancement or the binding affinity between fatted and defatted HSA when the binding titrations were carried out at a Gd-AAZTAC17 concentration higher than its critical micellar concentration (cmc). This behaviour has been attributed to the formation of an association between the negatively charged micelle of the lipophilic metal complexes and the positive residues on the surface of the protein.