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SARS-CoV-2 can attack the central nervous system in the early stages of infection. Headache, anosmia, and dysgeusia are common symptoms. Disturbance of consciousness and seizures can occur as complications in case of severe COVID-19. We described the case of a COVID-19 patient admitted for interstitial pneumonia and seizures. MRI showed newly diagnosed demyelinating lesions. High-dose steroid treatment allowed neurological and respiratory recovery. We speculated a delayed immune response induced by SARS-CoV-2. The virus may lead to a SIRS-like immune disorder or play a role of infective trigger. Prompt invasive treatment should be adopted to avoid hypoxic neurotoxicity and prevent CNS injuries.

Infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB) and Pseudomonas aeruginosa are leading causes of morbidity and mortality after lung transplantation (LuTx). We reviewed the pharmacology, clinical evidence, and safety of five agents potentially active against MDR-GNB in LuTx recipients (LUTR): ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, imipenem/relebactam, and cefiderocol. Literature from the last 10 years was reviewed for data on activity spectrum, efficacy in LUTR and adverse events. Ceftolozane/tazobactam and ceftazidime/avibactam were the most studied, providing high cure rates for difficult-to-treat Pseudomonas (DTR-PA) and Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales, respectively. Meropenem/vaborbactam offers reliable coverage of KPC strains, while imipenem/relebactam is an interesting option for imipenem-non-susceptible Pseudomonas spp. Cefiderocol exhibits the broadest in vitro spectrum, including metallo-β-lactamase producers. Across agents, pharmacokinetic variability, augmented renal clearance, and extracorporeal support can compromise target attainment; prolonged or continuous infusion is preferred. Collectively, these antibiotics expand the therapeutic armamentarium against MDR-GNB in LUTR, allowing pathogen-directed, toxicity-sparing regimens. Nonetheless, prospective LuTx-focused studies are needed to optimise their use in such a peculiar setting.

Background During prolonged FDC therapy, the emergence of FDC non-susceptibility in CRAB has been reported. Here, we report a transmission cluster of FDC-non-susceptible CRAB in four patients, all naïve to FDC treatment, characterized by a premature stop codon and amino acid deletion in the PirA protein. Methods CRAB strains obtained from patients admitted in a single medicine ward of the IRCCS Fondazione Ospedale Maggiore Policlinico between March and July 2024 were analyzed by WGS and antimicrobial susceptibility testing. Phylogenetic analysis was used to assess their genetic relatedness. Results Between March and July 2024, an outbreak of 33 CRAB was observed among hospitalized patients in a single ward at IRCCS. Genomic analysis, available in 29 cases, revealed that 24 isolates belonged to ST208/1806, 4 to ST369, and one to ST195/1816 (according to the Oxford scheme). FDC susceptibility was affected only in the four ST369 isolates (Kirby-Bauer disk diffusion diameter: 13 mm; UMIC ® method MIC: 4 mg/L), all characterized by a premature stop codon followed by a 52 amino acid deletion located between the amino acids 377 and 428 of the siderophore-drug receptor PirA. No other relevant mutations were detected in the iron-uptake genes. Core-genome ML tree including ST369 reference strains revealed that the four ST369 isolates were highly related and formed a distinct cluster (SNP distance: 3 [IQR: 1–6]). Of note, the four isolates were collected from four FDC-naïve individuals, two experiencing a CRAB-mediated infection. Conclusions Our findings alert about the circulation of clones carrying modified siderophore-drug receptors without evidence of previous FDC treatment and support the importance of testing FDC susceptibility appropriately before its administration.

Background The pandemic of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), had a significant impact worldwide. Vaccines against COVID-19 appear as a tool able to curb out mortality and reduce the circulation of the virus. Little is known so far about the clinical characteristics of individuals who developed SARS-CoV-2 infection after having received the vaccination, as well as the temporal relationship between vaccine administration and symptoms onset. Methods Retrospective cohort study among the 3219 healthcare workers (HCWs) of the Fondazione IRCCS Ospedale Maggiore Policlinico of Milano who received a full immunization with the BNT162b2 vaccine and who developed SARS-CoV-2 infection (documented through positive RT-PCR on nasopharyngeal swab) in March–April 2021. Results Overall, we have identified 15 HCWs with SARS-CoV-2 infection after vaccination, 7 (46.7%) of them were male and the mean age was 38.4 years (SD 14). In 4 of them, the presence of SARS-CoV-2 anti-nucleocapsid (anti-N) antibodies was assessed before vaccination and resulted positive in 1 case. In all HCWs the presence of SARS-CoV-2 anti-spike (anti-S1) antibodies was assessed, on average 42.2 days after the completion of vaccination, with a mean value of 2055 U/mL (SD 1927.3). SARS-CoV-2 infection was ascertained on average 56.2 days after vaccination. The mean cycle threshold (Ct) of SARS-CoV-2 PCR was 26.4, the lineage was characterized in 9 HCWs. None of the HCWs reported a primary or secondary immunodeficiency. Regarding symptoms, they were reported only by 7 (46.7%) HCWs and appeared on average 55 days after the second dose of vaccination. Of those who reported symptoms, one (14.3%) had fever, 7 (100%) rhinitis/conjunctivitis, 4 (57.1%) taste and smell alterations, none had respiratory symptoms, 4 headache/arthralgia (57.1%) and 1 gastrointestinal symptom (14.3%). All symptoms disappeared in a few days and no other unclassified symptoms were reported. Conclusions Infections occurring after vaccination with the BNT162b2 vaccine are mostly asymptomatic and are not associated with the serum titre of anti-S1 antibodies. We did not find a predominance of specific viral variants, with several lineages represented.

Coagulopathy and immune dysregulation have been identified as important causes of adverse outcomes in coronavirus disease (COVID-19). Mid-region proadrenomedullin (MR-proADM) is associated with endothelial damage and has recently been proposed as a prognostic factor in COVID-19. In non-COVID-19 immunocompromised patients, low in vitro interferon gamma (IFNγ) production correlates with infection risk and mortality. This prospective, monocentric, observational study included adult patients consecutively admitted with radiologic evidence of COVID-19 pneumonia and respiratory failure. MR-proADM and in vitro IFNγ production were measured at T0 (day 1 from admission) and T1 (day 7 from enrollment). One hundred patients were enrolled. Thirty-six percent were females, median age 65 (Q1–Q3 54.5–75) years, and 58% had ≥1 comorbidity. Only 16 patients had received COVID-19 vaccination before hospitalization. At admission, the median PaO2:FiO2 ratio was 241 (157–309) mmHg. In-hospital mortality was 13%. MR-proADM levels differed significantly between deceased and survivors both at T0 (1.41 (1.12–1.77) nmol/L vs. 0.79 (0.63–1.03) nmol/L, p < 0.001) and T1 (1.67 (1.08–1.96) nmol/L vs. 0.66 (0.53–0.95) nmol/L, p < 0.001). In vitro IFNγ production at T0 and T1 did not vary between groups. When only the subset of non-vaccinated patients was considered, both biomarkers at T1 resulted significantly associated with in-hospital mortality. AUROC for MR-proADM at T0 to predict in-hospital mortality was 0.87 (95%CI 0.79–0.94), with the best cut-off point at 1.04 nmol/L (92% sensitivity, 75% specificity and 98% negative predictive value). In patients with COVID-19 pneumonia and different degrees of respiratory failure, MR-proADM at admission and during hospitalization resulted strongly associated with in-hospital mortality. Low in vitro IFNγ production after the first week of hospitalization was associated with mortality in non-vaccinated patients possibly identifying the subgroup characterized by a higher degree of immune suppression.

Background Nevirapine has been used as antiretroviral agent since early ‘90. Although nevirapine is not currently recommended in initial anti-HIV regimens, its use remains consistent in a certain number of HIV-1-positive subjects. Thus, our aim was to determine clinical and genetic factors involved in the development of severe nevirapine induced liver toxicity. Methods We retrospectively analyzed all HIV positive patients who were followed at the Infectious Diseases Unit, DIBIC Luigi Sacco, University of Milan from May 2011 to December 2015. All patients treated with nevirapine who underwent a genotyping for the functional variants mapping into ABCB1, CYP2B6, CYP3A4 and CYP3A5 genes were included in the analysis. Severe hepatotoxicity was defined as ACTG grade 3–4 AST/ALT increase during the first three months of nevirapine treatment. The causality assessment between NVP exposure and drug-induced liver injury was performed by using the updated Roussel Uclaf Causality Assessment Methods. Hardy Weinberg equilibrium was tested by χ 2 test. A multivariable logistic regression model was constructed using a backward elimination method. Results Three hundred and sixty-two patients were included in the analysis, of which 8 (2.2%) experienced a severe liver toxicity. We observed no differences between patients with and without liver toxicity as regards gender, ethnicity, age and immune-virological status. A higher prevalence of HCV coinfection (75.0% vs 30.2%; p = .0013 ) and higher baseline AST (58 IU/L vs 26 IU/L; p = 0.041 ) and ALT (82 IU/L vs 27 IU/L; p = 0.047 ) median levels were observed in patients with liver toxicity vs those without toxicity. The genotypes CT/TT at ABCB1 rs1045642 single nucleotide polymorphism (SNP), showed a protective effect for liver toxicity when compared with genotype CC (OR = 0.18, 95%CI 0.04–0.76; p = 0.020 ) in univariate analysis. In the multivariate model, HCV coinfection was independently associated with higher risk of developing liver toxicity (aOR = 8.00, 95%CI 1.27–50.29; p = 0.027 ), whereas ABCB1 rs1045642 CT/TT genotypes (aOR = 0.10, 95%CI 0.02–0.47; p = 0.004 ) was associated with a lower risk. Conclusions According to our findings HCV coinfection and ABCB1 rs1045642 SNP represent independent determinants of severe liver toxicity related to nevirapine. This genetic evaluation could be included as toxicity assessment in HIV-1-positive subjects treated with nevirapine.

Specific immune suppression types have been associated with a greater risk of severe COVID-19 disease and death. We analyzed data from patients >17 years that were hospitalized for COVID-19 at the “Fondazione IRCCS Ca′ Granda Ospedale Maggiore Policlinico” in Milan (Lombardy, Northern Italy). The study included 1727 SARS-CoV-2-positive patients (1,131 males, median age of 65 years) hospitalized between February 2020 and November 2022. Of these, 321 (18.6%, CI: 16.8–20.4%) had at least one condition defining immune suppression. Immune suppressed subjects were more likely to have other co-morbidities (80.4% vs. 69.8%, p  < 0.001) and be vaccinated (37% vs. 12.7%, p  < 0.001). We evaluated the contribution of immune suppression to hospitalization during the various stages of the epidemic and investigated whether immune suppression contributed to severe outcomes and death, also considering the vaccination status of the patients. The proportion of immune suppressed patients among all hospitalizations (initially stable at <20%) started to increase around December 2021, and remained high (30–50%). This change coincided with an increase in the proportions of older patients and patients with co-morbidities and with a decrease in the proportion of patients with severe outcomes. Vaccinated patients showed a lower proportion of severe outcomes; among non-vaccinated patients, severe outcomes were more common in immune suppressed individuals. Immune suppression was a significant predictor of severe outcomes, after adjusting for age, sex, co-morbidities, period of hospitalization, and vaccination status (OR: 1.64; 95% CI: 1.23–2.19), while vaccination was a protective factor (OR: 0.31; 95% IC: 0.20–0.47). However, after November 2021, differences in disease outcomes between vaccinated and non-vaccinated groups (for both immune suppressed and immune competent subjects) disappeared. Since December 2021, the spread of the less virulent Omicron variant and an overall higher level of induced and/or natural immunity likely contributed to the observed shift in hospitalized patient characteristics. Nonetheless, vaccination against SARS-CoV-2, likely in combination with naturally acquired immunity, effectively reduced severe outcomes in both immune competent (73.9% vs. 48.2%, p  < 0.001) and immune suppressed (66.4% vs. 35.2%, p  < 0.001) patients, confirming previous observations about the value of the vaccine in preventing serious disease.