Definition of the Immune Parameters Related to COVID-19 Severity

A relevant portion of patients with disease caused by the severe acute respiratory syndrome coronavirus 2 (COVID-19) experience negative outcome, and several laboratory tests have been proposed to predict disease severity. Among others, dramatic changes in peripheral blood cells have been described. We developed and validated a laboratory score solely based on blood cell parameters to predict survival in hospitalized COVID-19 patients. We retrospectively analyzed 1,619 blood cell count from 226 consecutively hospitalized COVID-19 patients to select parameters for inclusion in a laboratory score predicting severity of disease and survival. The score was derived from lymphocyte- and granulocyte-associated parameters and validated on a separate cohort of 140 consecutive COVID-19 patients. Using ROC curve analysis, a best cutoff for score of 30.6 was derived, which was associated to an overall 82.0% sensitivity (95% CI: 78–84) and 82.5% specificity (95% CI: 80–84) for detecting outcome. The scoring trend effectively separated survivor and non-survivor groups, starting 2 weeks before the end of the hospitalization period. Patients’ score time points were also classified into mild, moderate, severe, and critical according to the symptomatic oxygen therapy administered. Fluctuations of the score should be recorded to highlight a favorable or unfortunate trend of the disease. The predictive score was found to reflect and anticipate the disease gravity, defined by the type of the oxygen support used, giving a proof of its clinical relevance. It offers a fast and reliable tool for supporting clinical decisions and, most important, triage in terms of not only prioritization but also allocation of limited medical resources, especially in the period when therapies are still symptomatic and many are under development. In fact, a prolonged and progressive increase of the score can suggest impaired chances of survival and/or an urgent need for intensive care unit admission

Clinical and genetic determinants of nevirapine plasma trough concentration

Background: Only few data are available on the influence of CYP2B6 and CYP3A4/A5 polymorphisms on nevirapine plasma concentrations in the Caucasian population. Our aim was to assess the impact of CYP2B6 and CYP3A4/A5 polymorphisms on nevirapine plasma concentrations consecutively collected. Methods: We retrospectively analyzed clinical data of all HIV-positive patients who were followed at the Infectious Diseases Unit, DIBIC Luigi Sacco, University of Milan between January 2000 and December 2015. All patients with at least one nevirapine plasma trough concentration (NVP C min ) determination were tested for CYP2B6 c.516 G>T, CYP3A4*22C>T and CYP3A5*3 A>G polymorphisms. Univariate and multivariate regression analyses were carried out considering NVP C min as the dependent variable and genetic polymorphisms and clinical characteristics as independent variables. Results: A total of 143 patients were evaluated. Most of them were males (61.5%) and Caucasian (92.3%). Overall, NVP C min varied from 1571 to 14,189  ng/mL (median  =  5063  ng/mL, interquartile range  =  3915–6854). The median NVP C min significantly differed in patients with different CYP2B6 genotypes, but did not vary in those with different CYP3A phenotypes. In the final general linear model, factors significantly associated with a higher NVP C min were each extra unit of T alleles of CYP2B6 rs3745274 (β  =  0.328, 95% confidence interval  =  0.172–0.484; p   <  0.0001), older age (β  =  0.362, 95% confidence interval  =  0.193–0.532; p   <  0.0001) and hepatitis C virus coinfection (β  =  0.161, 95% confidence interval  =  0.006–0.315; p   <  0.041). Conclusion: Our study, conducted in a prevalent Caucasian population, highlighted the importance of CYP2B6 genetic variants in influencing nevirapine plasma trough concentration. Furthermore, older age and hepatitis C virus coinfection significantly increase exposure to nevirapine

Is a pharmacogenomic panel useful to estimate the risk of oxaliplatin-related neurotoxicity in colorectal cancer patients?

Oxaliplatin-induced peripheral neurotoxicity (OXPN) is a dose-limiting toxicity in colorectal cancer (CRC) patients. Single nucleotide polymorphisms (SNPs) in genes involved in drug transport may lead to higher intracellular oxaliplatin accumulation in the dorsal root ganglia and thus increased risk of OXPN. In this study, a panel of 5 SNPs, namely ABCC2 (-24C > T/rs717620 and c.4544 G > A/rs8187710), ABCG2 (c.421 C > A/rs2231142), ABCB1 (c.3435 C > T/rs1045642) and SLC31A1 (c.-36 + 2451 T > G/rs10981694), was evaluated to assess their association with grade 2-3 OXPN in metastatic CRC patients. SNPs were considered according to a dominant model (heterozygous + homozygous). Germline DNA was available from 120 patients who received oxaliplatin between 2010 and 2016. An external cohort of 80 patients was used to validate our results. At the univariable logistic analyses, there were no significant associations between SNPs and incidence of OXPN. Taking into account the strength of observed association between OXPN and the SNPs, a clinical risk score was developed as linear predictor from a multivariable logistic model including all the SNPs together. This score was significantly associated with grade 2-3 OXPN (p = 0.036), but the external calibration was not satisfactory due to relevant discrepancies between the two series. Our data suggest that the concomitant evaluation of multiple SNPs in oxaliplatin transporters is an exploratory strategy that may deserve further investigation for treatment customization in CRC patients