Crisi comiziale generalizzata in giovane paziente proveniente dal Togo

Introduzione: La neurocisticercosi (NCC) è la più comune infezione elmintica del sistema nervoso centrale ed una delle principali cause di epilessia acquisita in paesi a risorse limitate. In Europa sono in aumento i casi di importazione. La diagnosi non è sempre agevole e la sua gestione richiede un approccio multidisciplinare. Obiettivo: Descriviamo un caso di verosimile NCC in una paziente recentemente immigrata che ha presentato crisi comiziale generalizzata. Caso clinico: paziente di 21 anni proveniente dal Togo, in Italia dal 2017, giunta a ricovero per primo episodio di crisi epilettica generalizzata. Non precedenti degni di nota. All’ingresso in Ospedale la paziente era apiretica, in buone condizioni cliniche, in assenza di deficit neurologici e segni meningei. Le indagini radiologiche (TC, RMN) hanno evidenziato la presenza di puntiformi calcificazioni in sede cortico-sottocorticale temporale biemisferica e corticale-parietale-posteriore con segni di edema vasogenico e captazione con aspetto “a anello” di dimensioni dai 4 ai 7 mm. L’EEG ha mostrato rara attività parossistica in regione frontale biemisferica. La visita oculistica non ha evidenziato anomalie. La TC total body e la RMN midollo spinale non hanno evidenziato segni di patologia o localizzazione extra-encefalica. Nella norma gli esami ematici. Tra le indagini microbiologiche: negative sierologie per Cisticerco (EITB), Echinococco, HIV, Toxoplasma, Borrelia, Ameba, CMV, VZV. L’esame coproparassitologico è risultato negativo. Nella norma l’analisi del liquor. Alla luce del quadro clinico- strumentale, applicando due diversi set di criteri diagnostici disponibili in letteratura, è stato possibile porre diagnosi di probabile NCC intraparenchimale. Data la natura calcifica delle lesioni cerebrali non è stato intrapreso trattamento antiparassitario, ma sola terapia antiepilettica (levetiracetam), in accordo con attuali raccomandazioni. La paziente è attualmente in follow-up clinico e strumentale e non ha presentato ulteriori crisi comiziali. Conclusione: Il caso descritto appare compatibile con NCC intraparenchimale con lesioni calcificate per le quali, accanto al trattamento antiepilettico, non viene suggerita terapia antiparassitaria. Indipendentemente dalla negatività delle indagini sierologiche (fino al 50% dei casi in presenza di forme inattive), la NCC deve essere considerata nella diagnosi differenziale, in soggetti provenienti da area endemica soprattutto a fronte di un quadro clinico, epidemiologico e neuroradiologico, compatibili

Impact of transmitted drug resistance in naïve-patients starting 2 NRTI plus a boosted protease-inhibitor (PI) or integrase-inhibitor (INSTI).

Background The role of transmitted drug resistance (TDR) in predicting outcomes of initial antiretroviral therapy including PI or INSTI has not been fully explored. Methods From the ARCA database we selected adult naïve HIV-1 infected patients starting first-line 3-drugs therapy including INSTI or PI, from 1/2008 to 6/2016, with baseline resistance genotype and at least 1 HIV-1 RNA during follow up. TDR was defined as the detection of at least one mutation among those included in the WHO-recommended SDRM list (Bennett 2009). The primary endopoints were: virological failure (VF, defined as an HIV-RNA, VL, > 200 copies/ml after week 24) and treatment failure (TF, defined as VF or treatment change for any reason). Survival analysis was used to investigate predictors of TF and VF. Results 1147 pts were analyzed: 1031 (89.9%) treated with PI and 116 (10.1%) with INSTI. Baseline characteristics are shown in table. In the PI-group baseline VL was higher while CD4+ cells count was lower than in INSTI. Overall TDR were 4.7% for NRTI, 4.4% NNRTI, 1.5% PI without significant differences between groups. During a median observation time of 57 wks (IQR 26-107) TF occurred in 771 treatments in PI-group, with an estimated probability at 48 wks of 36% (CI 34.5-37.5) and in 46 in INSTI-group with an estimated probability at 48 wks of 31% (26.2-35.8); during a median observation time of 55 wks (26-107) VF occurred in 161 treatments in PI-group, with an estimated probability at 48 wks of 12% (10.8-13.1) and in 11 in INSTI-group with an estimated probability at 48 wks of 12% (8.5-15.5). After adjusting for gender, nationality, TDF/FTC use and viral subtype, independent predictor of VF was AZT/3TC use (vs other backbones HR 3.8, CI 95% 2.2-6.3, p<0.001); adjusting for nationality and viral subtype, independent predictors of TF were geographic area (Southern vs Northern Italy, HR 0.8, 0.6-0.9, p=0.04), baseline VL (+ 1 log10 HR 1.1, 1.0-1.2, p=0.03) and AZT/3TC (versus other backbones HR 2.1, 1.5-2.8, p=<0.001). Third drug class was not associated with VF or TF. In the INSTI-group, but not in the PI-group, the presence of any NRTI TDR was predictor of VF (HR 7.1, 1.8-28.2, p=0.005) after adjusting for nadir CD4 cells count and TF (HR 2.7, 1.1-7.0, p=0.03). Among patients in the INSTI-group with VF, 3 presented NRTI TDR (2 M41L and 1 M184V). In the PI-group, adjusting for gender, nationality, geographic area, viral subtype, TDF/FTC use, baseline and nadir CD4 cells count, independent predictor of VF was AZT/3TC use (HR 3.4, 1.8-6.2, p<0.001); adjusting for nationality and viral subtype, independent predictor of TF was AZT/3TC use (vs other backbones HR 2.3, 1.7-3.1, p<0.001). Conclusions PI and INSTI based first-line regimens show high efficacy in the real practice; despite the low incidence of TDR, our data support the need of pre-treatment genotyping to optimize therapy in patients starting INSTI-therapy. Further studies are required to confirm our suggestions

Clinical and molecular characterization of COVID-19 hospitalized patients

Clinical and molecular characterization by Whole Exome Sequencing (WES) is reported in 35 COVID-19 patients attending the University Hospital in Siena, Italy, from April 7 to May 7, 2020. Eighty percent of patients required respiratory assistance, half of them being on mechanical ventilation. Fiftyone percent had hepatic involvement and hyposmia was ascertained in 3 patients. Searching for common genes by collapsing methods against 150 WES of controls of the Italian population failed to give straightforward statistically significant results with the exception of two genes. This result is not unexpected since we are facing the most challenging common disorder triggered by environmental factors with a strong underlying heritability (50%). The lesson learned from Autism-Spectrum-Disorders prompted us to re-analyse the cohort treating each patient as an independent case, following a Mendelian-like model. We identified for each patient an average of 2.5 pathogenic mutations involved in virus infection susceptibility and pinpointing to one or more rare disorder(s). To our knowledge, this is the first report on WES and COVID-19. Our results suggest a combined model for COVID-19 susceptibility with a number of common susceptibility genes which represent the favorite background in which additional host private mutations may determine disease progression

Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study

Background: Recently, loss-of-function variants in TLR7 were identified in two families in which COVID-19 segregates like an X-linked recessive disorder environmentally conditioned by SARS-CoV-2. We investigated whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients.Methods: This is a nested case-control study in which we compared male participants with extreme phenotype selected from the Italian GEN-COVID cohort of SARS-CoV-2-infected participants (&lt;60y, 79 severe cases versus 77 control cases). We applied the LASSO Logistic Regression analysis, considering only rare variants on young male subsets with extreme phenotype, picking up TLR7 as the most important susceptibility gene.Results: Overall, we found TLR7 deleterious variants in 2.1% of severely affected males and in none of the asymptomatic participants. The functional gene expression profile analysis demonstrated a reduction in TLR7-related gene expression in patients compared with controls demonstrating an impairment in type I and II IFN responses.Conclusion: Young males with TLR7 loss-of-function variants and severe COVID-19 represent a subset of male patients contributing to disease susceptibility in up to 2% of severe COVID-19

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

Genetic mechanisms of critical illness in Covid-19.

Host-mediated lung inflammation is present,1 and drives mortality,2 in critical illness caused by Covid-19. Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development.3 Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study(GWAS) in 2244 critically ill Covid-19 patients from 208 UK intensive care units (ICUs). We identify and replicate novel genome-wide significant associations, on chr12q24.13 (rs10735079, p=1.65 [Formula: see text] 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), on chr19p13.2 (rs2109069, p=2.3 [Formula: see text] 10-12) near the gene encoding tyrosine kinase 2 (TYK2), on chr19p13.3 (rs2109069, p=3.98 [Formula: see text] 10-12) within the gene encoding dipeptidyl peptidase 9 (DPP9), and on chr21q22.1 (rs2236757, p=4.99 [Formula: see text] 10-8) in the interferon receptor gene IFNAR2. We identify potential targets for repurposing of licensed medications: using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease; transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe Covid-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms, and mediators of inflammatory organ damage in Covid-19. Both mechanisms may be amenable to targeted treatment with existing drugs. Large-scale randomised clinical trials will be essential before any change to clinical practice

Pathogen-sugar interactions revealed by universal saturation transfer analysis

Many pathogens exploit host cell-surface glycans. However, precise analyses of glycan ligands binding with heavily modified pathogen proteins can be confounded by overlapping sugar signals and/or compounded with known experimental constraints. Universal saturation transfer analysis (uSTA) builds on existing nuclear magnetic resonance spectroscopy to provide an automated workflow for quantitating protein-ligand interactions. uSTA reveals that early-pandemic, B-origin-lineage severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike trimer binds sialoside sugars in an “end-on” manner. uSTA-guided modeling and a high-resolution cryo–electron microscopy structure implicate the spike N-terminal domain (NTD) and confirm end-on binding. This finding rationalizes the effect of NTD mutations that abolish sugar binding in SARS-CoV-2 variants of concern. Together with genetic variance analyses in early pandemic patient cohorts, this binding implicates a sialylated polylactosamine motif found on tetraantennary N-linked glycoproteins deep in the human lung as potentially relevant to virulence and/or zoonosis