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Vaccination prevents 2-3 million deaths worldwide every year. Nevertheless, vaccine-preventable diseases (VPDs) still cause a considerable number of deaths especially in subjects belonging to "risk groups." These are represented by older adults, immunocompromised individuals and all subjects with underlying chronic medical conditions (cardiovascular, pulmonary, renal and liver chronic diseases, diabetes, immunodeficiency disorders). They have a weaker immune system and, if infected, are more likely to develop severe complications of their condition or of the preventable-infectious disease. This document summarizes the recommendations for vaccination of the main Global Institutional Organizations and analyses the risks of comorbidities associated with infectious disease and the benefits of vaccination for each specific group. The document provides a clear, practical and authoritative guide to adult vaccination.

Background Disease modifying therapies for multiple sclerosis (MS) can impair the specific immune response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Specifically, it is recognized that ocrelizumab reduces or abrogates anti-SARS-CoV-2 antibody production after natural infection or vaccination, while very little is known about T-cell responses. Methods We developed an interferon (IFN)-γ release assay (IGRA) to detect T-cell responses specific to SARS-CoV-2 after overnight stimulation of whole blood with peptide libraries covering the immunodominant sequence domains of the Spike glycoprotein (S) and the Nucleocapsid phosphoprotein (N). Results Five patients with MS receiving ocrelizumab treatment for at least 1 year and recovered from SARS-CoV-2 infection were enrolled in the study. Despite the absence or the very low concentration of anti-S antibodies, a T-cell response was detectable in all the five MS patients. These results are in accordance with the marked reduction of peripheral B-lymphocyte absolute counts induced by ocrelizumab, that, conversely, did not affect peripheral blood T-lymphocyte subset absolute and relative counts and CD4/CD8 ratio. Conclusions The detection of specific T-cell responses to SARS-CoV-2 in patients receiving B-cell depleting therapies represents a useful tool to improve the diagnostic approach in SARS-CoV-2 infection and to accurately assess the immunological response after natural infection or vaccination.

Viral hemorrhagic fevers represent a group of diseases caused by enveloped RNA viruses. The epidemiology is broadly variable, ranging from geographically localized to more diffuse infections. Viral hemorrhagic fevers are classified as category A bioweapon agents by the Centers for Disease Control and Prevention. Viral hemorrhagic fevers are severe febrile illnesses with hemorrhagic phenomena. Laboratory diagnosis takes place in highly specialized reference laboratories. Treatment is essentially supportive. In this article, we focus the attention on yellow fever and viral hemorrhagic fevers other than Ebola and Lassa virus diseases that have been described elsewhere in this issue.

The aim of the study was to investigate the changes of matrix metalloproteinase (MMP)-2 and MMP-9 plasma levels during natalizumab treatment and their correlation with JC virus (JCV) reactivation and T-lymphocyte phenotypic modifications in peripheral blood samples from 34 relapsing-remitting multiple sclerosis (RRMS) patients. MMP-9 levels were assessed by zymography in plasma samples. JCV-DNA was detected through quantitative real time PCR in plasma samples. T-lymphocyte phenotype was assessed with flow cytometry. MMP-9 plasma levels resulted increased from 12 to 24 natalizumab infusions. Stratifying plasma samples according to JCV-DNA detection, MMP-9 plasma levels were significantly increased in JCV-DNA positive than JCV-DNA negative samples. MMP-9 plasma levels resulted positively correlated with JCV viral load. CD4 immune senescence, CD8 immune activation and CD8 effector percentages were positively correlated to MMP-9 plasma levels, whereas a negative correlation between CD8 naïve percentages and MMP-9 plasma levels was found. Our data indicate an increase of MMP-9 plasma levels between 12 and 24 natalizumab infusions and a correlation with JCV-DNA detection in plasma, T-lymphocyte immune activation and senescence. These findings could contribute to understand PML pathogenesis under natalizumab treatment, suggesting a potential role of MMP-9 as a predictive marker of PML in RRMS patients.

We described short-term HIV tropism changes occurring in peripheral blood mononuclear cells and the correlations with HIV DNA value in HIV-HCV co-infected patients cured for HCV disease and with undetectable HIV viremia or residual viremia (RV). Plasma HIV RNA, cellular HIV DNA and tropism were evaluated pre-HCV treatment (baseline, BL) and at 12(T1) and 24(T2) weeks after HCV treatment start. V3 sequences were interpreted using Geno2pheno and classified as R5 only if all three sequences had an FPR ≥ 10% and as X4 when at least one replicate sequence had an FPR

BackgroundEmerging evidence argues that monocytes, circulating innate immune cells, are principal players in COVID-19 pneumonia. The study aimed to investigate the role of soluble (s)CD163 and sCD14 plasmatic levels in predicting disease severity and characterize peripheral blood monocytes and dendritic cells (DCs), in patients with COVID-19 pneumonia (COVID-19 subjects).MethodsOn admission, in COVID-19 subjects sCD163 and sCD14 plasmatic levels, and peripheral blood monocyte and DC subsets were compared to healthy donors (HDs). According to clinical outcome, COVID-19 subjects were divided into ARDS and non-ARDS groups.ResultsCompared to HDs, COVID-19 subjects showed higher sCD163 (pConclusionsThe increase in sCD163 and sCD14 plasmatic levels, observed on hospital admission in COVID-19 subjects, especially in those who developed ARDS, and the correlations of these monocyte/macrophage activation markers with typical inflammatory markers of COVID-19 pneumonia, underline their potential use to assess the risk of progression of the disease. In an early stage of the disease, the assessment of sCD163 plasmatic levels could have clinical utility in predicting the severity of COVID-19 pneumonia.

Background Despite an impressive effort in clinical research, no standard therapeutic approach for coronavirus disease 2019 (COVID-19) patients has been established, highlighting the need to identify early biomarkers for predicting disease progression and new therapeutic interventions for patient management. The present study aimed to evaluate the involvement of the human endogenous retrovirus -W envelope (HERV-W ENV) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection considering recent findings that HERVs are activated in response to infectious agents and lead to various immunopathological effects. We analysed HERV-W ENV expression in blood cells of COVID-19 patients in correlation with clinical characteristics and have discussed its potential role in the outcome of the disease. Methods We analysed HERV-W ENV expression in blood samples of COVID-19 patients and healthy donors by flow cytometry and quantitative reverse transcriptase PCR analysis, and evaluated its correlation with clinical signs, inflammatory markers, cytokine expression, and disease progression. Findings HERV-W ENV was highly expressed in the leukocytes of COVID-19 patients but not in those of healthy donors. Its expression correlated with the markers of T-cell differentiation and exhaustion and blood cytokine levels. The percentage of HERV-W ENV-positive lymphocytes correlated with inflammatory markers and pneumonia severity in COVID-19 patients. Notably, HERV-W ENV expression reflects the respiratory outcome of patients during hospitalization. Interpretation Given the known immuno- and neuro-pathogenicity of HERV-W ENV protein, it could promote certain pathogenic features of COVID-19 and therefore serve as a biomarker to predict clinical progression of disease and open to further studies for therapeutic intervention. Funding Information available at the end of the manuscript.

Low CD4+ cell count in patients with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) coinfection during combination antiretroviral therapy (cART) has been described; however, notably few studies have investigated coinfected patients positive for antibodies to the HBV c antigen (HBcAb). An observational retrospective study enrolling 190 patients was conducted by grouping patients with respect to HBV status and recording CD4+ T cell counts and percentages (CD4%), CD8+ T cell counts and percentages (CD8%), and the CD4+ to CD8+ T cell ratio (CD4/CD8) at the time of HIV diagnosis, at the start of treatment and at months 1, 2, 3, 4, 5, 6, 12, and 24 after beginning cART. One hundred and twenty patients (63.2%) were negative for previous HBV infection, while 70 (36.8%) were HBcAb-positive. A significant increase in the CD4/CD8 ratio was recorded in HIV monoinfected subjects compared to HBV coinfected patients from months 4 to 12 from the beginning of cART (p value = 0.02 at month 4, p value = 0.005 at month 5, p value = 0.006 at month 6, and p value = 0.008 at month 12). A significant increase in the absolute count of CD8+ T lymphocytes was described from months 2 to 24 from the start of cART in the subgroup of HBV coinfected patients with an AIDS event at the onset of HIV infection. The presence of HBcAb was observed to be associated with reduced CD4/CD8 ratio growth and a significantly higher proportion of subjects with CD4/CD8

Gram-positive anaerobic cocci (GPAC) are responsible for 30% of anaerobic infections. Parvimonas micra is an emergent pathogen that is part of the oral and gastrointestinal commensal flora, and its role in several infection processes has recently emerged thanks to the improvement of diagnostic techniques. P. micra bacteraemia is reported in immunocompromised patients and is often complicated by abscesses. Here, we present a case study of multiple hepatic and brain abscesses caused by P. micra bacteraemia in a patient with complicated diverticulitis.

Background: CD169 has been found overexpressed in the blood of COVID-19 patients and identified as a biomarker in the early disease. We have analysed CD169 in blood cells of COVID-19 patients to assess its role as predictive marker of the disease. Methods : The ratio of the CD169 Median median Fluorescence fluorescence Intensity intensity of CD169 between monocytes and lymphocytes (CD169 RMFI ) was analysed by flow cytometry in blood samples of COVID-19 patients (COV) and healthy donors (HD ) and correlated with immunophenotyping, inflammatory markers, cytokines mRNA expression, pulmonary involvement and disease progression. Results: CD169 RMFI increased in COV but not in HD. CD169 RMFI correlated with T-cell differentiation and exhaustion markers as well as with B cells maturation and differentiation. In vitro stimulation of PBMCs of HD with SARS-CoV-2 Spike spike protein induced CD169 RMFI together with IL-6 and IL-10 gene expression. Likewise, CD169 RMFI correlated with blood cytokine mRNA levels, inflammatory markers, and pneumonia severity in patients which that had not received any treatment at sampling. Notably, in untreated patients, CD169 RMFI reflected the respiratory outcome during hospitalization. Conclusion : Considering the immunological role of CD169 and its involvement during the infection and the progression of COVID-19, it could be considered as an early biomarker to evaluate disease progression and clinical outcome.

Background Coronavirus disease 2019 (COVID-19) is characterized by immune-mediated lung injury and complex alterations of the immune system, such as lymphopenia and cytokine storm, that have been associated with adverse outcomes underlining a fundamental role of host response in severe acute respiratory syndrome coronavirus 2 infection and the pathogenesis of the disease. Thymosin alpha 1 (Tα1) is one of the molecules used in the management of COVID-19, because it is known to restore the homeostasis of the immune system during infections and cancer. Methods In this study, we captured the interconnected biological processes regulated by Tα1 in CD8+ T cells under inflammatory conditions. Results Genes associated with cytokine signaling and production were upregulated in blood cells from patients with COVID-19, and the ex vivo treatment with Tα1-mitigated cytokine expression, and inhibited lymphocyte activation in a CD8+ T-cell subset specifically. Conclusion These data suggest the potential role of Tα1 in modulating the immune response homeostasis and the cytokine storm in vivo., Graphical Abstract Graphical Abstract, Tα1 restores dysregulated pathways under proinflammatory conditions. Tα1 inhibits cytokine-related gene expression in blood cells from COVID-19 individuals. Tα1 disrupts cytokines and T-cell activation in COVID-19. Modulation of CD38 in CD8+ T cells by Tα1 depends on the clinical score.

Background A growing body of observational evidence supports the value of ceftazidime-avibactam (CAZ-AVI) in managing infections caused by carbapenem-resistant Enterobacteriaceae. Methods We retrospectively analyzed observational data on use and outcomes of CAZ-AVI therapy for infections caused by Klebsiella pneumoniae carbapenemase–producing K. pneumoniae (KPC-Kp) strains. Multivariate regression analysis was used to identify variables independently associated with 30-day mortality. Results were adjusted for propensity score for receipt of CAZ-AVI combination regimens versus CAZ-AVI monotherapy. Results The cohort comprised 577 adults with bloodstream infections (n = 391) or nonbacteremic infections involving mainly the urinary tract, lower respiratory tract, and intra-abdominal structures. All received treatment with CAZ-AVI alone (n = 165) or with ≥1 other active antimicrobials (n = 412). The all-cause mortality rate 30 days after infection onset was 25% (146/577). There was no significant difference in mortality between patients managed with CAZ-AVI alone and those treated with combination regimens (26.1% vs 25.0%, P = .79). In multivariate analysis, mortality was positively associated with presence at infection onset of septic shock (P = .002), neutropenia (P < .001), or an INCREMENT score ≥8 (P = .01); with lower respiratory tract infection (LRTI) (P = .04); and with CAZ-AVI dose adjustment for renal function (P = .01). Mortality was negatively associated with CAZ-AVI administration by prolonged infusion (P = .006). All associations remained significant after propensity score adjustment. Conclusions CAZ-AVI is an important option for treating serious KPC-Kp infections, even when used alone. Further study is needed to explore the drug’s seemingly more limited efficacy in LRTIs and potential survival benefits of prolonging CAZ-AVI infusions to ≥3 hours.

(1) Background: Tuberculosis (TB) is one of the world’s top infectious killers, in fact every year 10 million people fall ill with TB and 1.5 million people die from TB. Vitamins have an important role in vital functions, due to their anti-oxidant, pro-oxidant, anti-inflammatory effects and to metabolic functions. The aim of this review is to discuss and summarize the evidence and still open questions regarding vitamin supplementation as a prophylactic measure in those who are at high risk of Mycobacterium tuberculosis (MTB) infection and active TB; (2) Methods: We conducted a search on PubMed, Scopus, Google Scholar, EMBASE, Cochrane Library and WHO websites starting from March 1950 to September 2021, in order to identify articles discussing the role of Vitamins A, B, C, D and E and Tuberculosis; (3) Results: Supplementation with multiple micronutrients (including zinc) rather than vitamin A alone may be more beneficial in TB. The WHO recommend Pyridoxine (vitamin B6) when high-dose isoniazid is administered. High concentrations of vitamin C sterilize drug-susceptible, MDR and extensively drug-resistant MTB cultures and prevent the emergence of drug persisters; Vitamin D suppresses the replication of mycobacterium in vitro while VE showed a promising role in TB management as a result of its connection with oxidative balance; (4) Conclusions: Our review suggests and encourages the use of vitamins in TB patients. In fact, their use may improve outcomes by helping both nutritionally and by interacting directly and/or indirectly with MTB. Several and more comprehensive trials are needed to reinforce these suggestions.

Background: Despite an impressive effort in clinical research, no standard therapeutic approach for coronavirus disease 2019 (COVID-19) patients has been established, highlighting the need to identify early biomarkers for predicting disease progression and new therapeutic intervention for patient management. The present study aimed to evaluate the involvement of the human endogenous retrovirus -W envelope (HERV-W ENV) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection considering recent findings that HERVs are activated in response to infectious agents and lead to various immunopathological effects. We analysed HERV-W ENV expression in blood cells of COVID-19 patients in correlation with clinical characteristics and have discussed its potential role in the outcome of the disease. Methods: We analysed HERV-W ENV expression in blood samples of Covid-19 patients and healthy donors by flow cytometry and quantitative reverse transcriptase PCR analysis, and evaluated its correlation with clinical signs, inflammatory markers, cytokine expression, and disease progression. Findings: HERV-W ENV was highly expressed in the leukocytes of COVID-19 patients but not in those of healthy donors. Its expression correlated with the markers of T-cell differentiation and exhaustion and blood cytokine levels. The percentage of HERV-W ENV-positive lymphocytes correlated with inflammatory markers and pneumonia severity in COVID-19 patients. Notably, HERV-W ENV expression reflects the respiratory outcome of patients during hospitalization. Interpretation: Given the known immuno- and neuro-pathogenicity of HERV-W ENV protein, it could promote certain pathogenic features of COVID-19 and therefore serve as a biomarker to predict clinical progression of disease and as a potential therapeutic target. Funding: Genero Innovation Declaration of Interests: C.M. reports grant from Gilead, outside the submitted work; L.S. reports personal fees and other from Merck, Gilead, and Abbvie, grants from Gilead, outside the submitted work; HP and BC receive compensation for their work by Geneuro-Innovation. The other authors declare no competing interests. Ethics Approval Statement: Ethical approval for the collection and use of human samples was obtained from the ethical board of the Hospital, COronaVIrus Disease: Safety and Efficacy of Experimental Treatment (COVID_SEET prot.7562/2020, 9th April 2020, experimental register 46.20).

Testing HIV-1 RNA in plasma by PCR is universally accepted as the ultimate standard to confirm diagnosis of HIV-1 infection and to monitor viral load in patients under treatment. However, in some cases, this assay could either underestimate or overestimate the replication capacity of a circulating or latent virus. In the present study, we performed the assessment of evaluating the HIV-1 reverse transcriptase (RT) activity by means of a new assay for the functional screening of the status of HIV-1 patients. To this purpose, we utilized, for the first time on blood samples, an adapted version of a real-time RT quantitative PCR assay, utilized to evaluate the HIV-1-RT inhibitory activity of compounds. The study analyzed blood samples from 28 HIV-1-infected patients, exhibiting a wide range of viremia and immunological values. Results demonstrated that plasma HIV-1 RT levels, expressed as cycle threshold values obtained with the assay under appraisal, were inversely and highly significantly correlated with the plasma HIV-1-RNA levels of the patients. Thus, an HIV-1 RT quantitative PCR assay was created which we describe in this study, and it may be considered as a promising basis for an additional tool capable of furnishing information on the functional virological status of HIV-1-infected patients.

The Republic of Congo (RoC) declared a chikungunya (CHIK) outbreak on 9 February 2019. We conducted a ONE-Human-Animal HEALTH epidemiological, virological and entomological investigation. Methods: We collected national surveillance and epidemiological data. CHIK diagnosis was based on RT-PCR and CHIKV-specific antibodies. Full CHIKV genome sequences were obtained by Sanger and MinION approaches and Bayesian tree phylogenetic analysis was performed. Mosquito larvae and 215 adult mosquitoes were collected in different villages of Kouilou and Pointe-Noire districts and estimates of Aedes (Ae.) mosquitos’ CHIKV-infectious bites obtained. We found two new CHIKV sequences of the East/Central/South African (ECSA) lineage, clustering with the recent enzootic sub-clade 2, showing the A226V mutation. The RoC 2019 CHIKV strain has two novel mutations, E2-T126M and E2-H351N. Phylogenetic suggests a common origin from 2016 Angola strain, from which it diverged around 1989 (95% HPD 1985–1994). The infectious bite pattern was similar for 2017, 2018 and early 2019. One Ae. albopictus pool was RT-PCR positive. The 2019 RoC CHIKV strain seems to be recently introduced or be endemic in sylvatic cycle. Distinct from the contemporary Indian CHIKV isolates and in contrast to the original Central-African strains (transmitted by Ae. aegypti), it carries the A226V mutation, indicating an independent adaptive mutation in response to vector replacement (Ae. albopictus vs Ae. aegypti).

Objective Coronavirus disease 2019 (COVID-19) represents a novel pneumonia leading to severe acute respiratory syndrome (SARS). Recent studies documented that SARS-Coronavirus2 (SARS-CoV2), responsible for COVID-19, can affect the nervous system. The aim of the present observational study was to prospectively assess subjective neurological symptoms (sNS) in patients with SARS-CoV2 infection. Methods We included patients hospitalized at the University Hospital of Rome “Tor Vergata”, medical center dedicated to the treatment of patients with COVID-19 diagnosis, who underwent an anamnestic interview about sNS consisting of 13 items, each related to a specific symptom, requiring a dichotomized answer. Results We included 103 patients with SARS-CoV2 infection. Ninety-four patients (91.3%) reported at least one sNS. Sleep impairment was the most frequent symptom, followed by dysgeusia, headache, hyposmia, and depression. Women more frequently complained hyposmia, dysgeusia, dizziness, numbeness/paresthesias, daytime sleepiness, and muscle ache. Moreover, muscle ache and daytime sleepiness were more frequent in the first 2 days after admission. Conversely, sleep impairment was more frequent in patients with more than 7 days of hospitalization. In these patients we also documented higher white blood cells and lower C-reactive protein levels. These laboratory findings correlated with the occurrence of hyposmia, dysgeusia, headache, daytime sleepiness, and depression. Conclusions Patients with SARS-CoV2 infection frequently present with sNS. These symptoms are present from the early phases of the disease. The possibly intrinsic neurotropic properties of SARS-CoV2 may justify the very high frequency of sNS. Further studies targeted at investigating the consequences of SARS-CoV2 infection on the CNS should be planned.

Aim: Carbapenemase-resistant Enterobacteriaceae represents a major concern in hospital setting. Materials & methods: The evolutionary history of carbapenem-resistant Klebsiella pneumonia strains was analyzed by core genome multilocus sequence typing and Bayesian phylogenesis by whole genomes sequencing. Results: A great increase carbapenem-resistant K. pneumoniae causing blood stream infection was observed in the years 2015–2016. At multilocus sequence typing (MLST), they were prevalently ST512 and ST101. ST512 were core genome (cg)MLST 53, while ST101 mainly cgMLST453. The minimum-spanning tree, based on cgMLST, showed strains clustering based on the different STs. By Bayesian phylogenetic analysis, maximum clade credibility tree showed that strains were introduced in the year 2005 with the most probable location in the ICU ward. Two outbreaks by ST101 and ST512 strains with Tower T8 as the probable location were evidenced. Conclusion: Molecular epidemiology is a powerful tool to track the way of transmission of resistant bacteria within the hospital setting.

Immune-suppression driven Hepatitis B Virus (HBV)-reactivation poses serious concerns since it occurs in several clinical settings and can result in severe forms of hepatitis. Previous studies showed that HBV strains, circulating in patients with HBV-reactivation, are characterized by an enrichment of immune-escape mutations in HBV surface antigen (HBsAg). Here, we focused on specific immune-escape mutations associated with the acquisition of N-linked glycosylation sites in HBsAg (NLGSs). In particular, we investigated profiles of NLGSs in 47 patients with immunosuppression-driven HBV-reactivation and we evaluated their impact on HBsAg-antigenicity and HBV-replication in vitro. At HBV-reactivation, despite a median serum HBV-DNA of 6.7 [5.3&ndash, 8.0] logIU/mL, 23.4% of patients remained HBsAg-negative. HBsAg-negativity at HBV-reactivation correlated with the presence of &gt, 1 additional NLGSs (p &lt, 0.001). These NLGSs are located in the major hydrophilic region of HBsAg (known to be the target of antibodies) and resulted from the single mutation T115N, T117N, T123N, N114ins, and from the triple mutant S113N+T131N+M133T. In vitro, NLGSs strongly alter HBsAg antigenic properties and recognition by antibodies used in assays for HBsAg-quantification without affecting HBsAg-secretion and other parameters of HBV-replication. In conclusion, additional NLGSs correlate with HBsAg-negativity despite HBV-reactivation, and hamper HBsAg-antigenicity in vitro, supporting the role of NGSs in immune-escape and the importance of HBV-DNA for a proper diagnosis of HBV-reactivation.

Objectives This study aims to identify the risk factors for intensive care (IC) in severe malaria patients admitted to the "Lazzaro Spallanzani" National Institute for Infectious Diseases, Rome, Italy. Methods All patients with confirmed severe malaria and hospitalized between 2007 and 2015 were included in the analysis and stratified into two groups: those requiring IC and those who did not. Five prognostic malaria scores were estimated; clinical severity at IC unit admission was assessed using the Sequential Organ Failure Assessment and the quick-Sequential Organ Failure Assessment scores. Univariate and multivariate analysis were performed to assess factors independently associated to IC. Results A total of 98 severe malaria patients were included; 10 of them required IC. There were no deaths or sequelae. Patients requiring IC had higher severity scores. At the multivariate analysis, only the number of World Health Organization criteria and the aspartate aminotransferase value were independently associated with the need of IC. Conclusions An early and accurate assessment of the severity score is essential for the management of severe malaria patients.

Ocrelizumab is an anti-CD20 monoclonal antibody for the treatment of multiple sclerosis (MS) that is closely related to rituximab. We describe a case of hepatitis B virus (HBV) reactivation in an MS patient with resolved HBV infection receiving ocrelizumab. HBV reactivation was monitored with HBV-DNA and HBV surface antigen periodic assessment. Anti-HBV treatment with entecavir was started after HBV-DNA detection. Ocrelizumab can reactivate viral replication in patients with resolved HBV infection. HBV reactivation monitoring seems an effective and safe option for the management of these patients. More studies are needed to assess the optimal management of HBV reactivation in MS patients on ocrelizumab treatment.

HCV is an important cause of hepatocellular carcinoma (HCC). HCV NS5A domain-1 interacts with cellular proteins inducing pro-oncogenic pathways. Thus, we explore genetic variations in NS5A domain-1 and their association with HCC, by analyzing 188 NS5A sequences from HCV genotype-1b infected DAA-naïve cirrhotic patients: 34 with HCC and 154 without HCC. Specific NS5A mutations significantly correlate with HCC: S3T (8.8% vs. 1.3%, p = 0.01), T122M (8.8% vs. 0.0%, p &lt, 0.001), M133I (20.6% vs. 3.9%, p &lt, 0.001), and Q181E (11.8% vs. 0.6%, p &lt, 0.001). By multivariable analysis, the presence of &gt, 1 of them independently correlates with HCC (OR (95%CI): 21.8 (5.7–82.3), p &lt, 0.001). Focusing on HCC-group, the presence of these mutations correlates with higher viremia (median (IQR): 5.7 (5.4–6.2) log IU/mL vs. 5.3 (4.4–5.6) log IU/mL, p = 0.02) and lower ALT (35 (30–71) vs. 83 (48–108) U/L, p = 0.004), suggesting a role in enhancing viral fitness without affecting necroinflammation. Notably, these mutations reside in NS5A regions known to interact with cellular proteins crucial for cell-cycle regulation (p53, p85-PIK3, and β-catenin), and introduce additional phosphorylation sites, a phenomenon known to ameliorate NS5A interaction with cellular proteins. Overall, these results provide a focus for further investigations on molecular bases of HCV-mediated oncogenesis. The role of theseNS5A domain-1 mutations in triggering pro-oncogenic stimuli that can persist also despite achievement of sustained virological response deserves further investigation.

Highlights • Ocrelizumab is not associated to increased severity in MS patients with COVID-19. • B-cell depleting treatment could impact on virus-specific antibody production. • B-cell depleting therapies can reduce IL-6 production, thus modulating inflammation., Background Recently SARS-CoV-2 has spread worldwide causing a pandemic. Little is known about disease severity in immunocompromised hosts and people receiving disease modifying therapies (DMTs). In the last decades DMTs have been widely employed, and ocrelizumab represents one of the newest therapies for the relapsing remitting and progressive forms of multiple sclerosis (MS). Objectives to describe SARS-CoV-2 related pneumonia in two MS patients under ocrelizumab treatment. Methods Case series. Results Patients showed a mild clinical course of SARS-CoV-2 related pneumonia without complications or sequelae. Conclusion Ocrelizumab treatment is not necessarily associated to increased severity in MS patients with SARS-CoV-2 infection.

Background Occult hepatitis B infection (OBI) is recognized as a risk factor for cirrhosis and hepato-cellular carcinoma. However, OBI brings together a large spectrum of patients who might harbor different characteristics and prognosis. Methods We analyzed the databases of a university hospital in Paris to identify OBI among patients (n = 3966) concomitantly tested for hepatitis B virus (HBV) DNA and serology during a 7-year period. OBI patients were gathered into clinical entities according to their clinical records. Results Forty-seven OBIs were identified (1.2%). All patients had detectable anti-HBc, isolated (n = 26) or associated with anti-HBs (n = 21). The proportion of OBIs was 3.4% for patients with isolated anti-HBc and 4.2% for patients with both anti-HBc and anti-HBs. Four clinical categories of OBI patients were identified: patients with a passed HBV infection with HBs Ag clearance (group A, 23.4%); HBV-exposed patients receiving immunosuppressive therapy (group B, 29.8%); HIV/HBV-coinfected patients with therapy discontinuation (group C, 17%); HBV-exposed patients with severe liver conditions (group D, 29.8%). Significant follow-up was available for 32 patients, showing a more deleterious prognosis in group D patients, associated more with their underlying condition than the OBI status. Conclusions OBI is a heterogeneous condition with various clinical implications.

This study reports the presence of dengue virus RNA in longitudinally collected semen samples of a previously healthy Caucasian man, returning to Italy from Thailand with primary dengue fever, up to 37 days post-symptom onset, when viraemia and viruria were undetectable. This finding, coupled with the evidence of dengue virus negative-strand RNA, an indirect marker of ongoing viral replication, in the cellular fraction of semen, indicates a need to further investigate possible sexual transmission.

HIV infection is characterized by a state of chronic activation of the immune system, which is not completely reversed by antiretroviral treatment (ART). The aim of this study was to assess myeloid and lymphoid activation markers during HIV infection, before and one year after ART initiation, in AIDS and non-AIDS presenters. Treatment naïve HIV positive patients were enrolled in this study. Myeloid dendritic cell (mDC), plasmacytoid dendritic cell (pDC), slanDC, monocyte and T-lymphocyte cell counts and activation status, were assessed by flow cytometry in peripheral blood samples. Soluble (s)CD14 and sCD163 were assessed in plasma samples using ELISA assays. Statistical analyses were performed using GraphPad Prism and Minitab Express. Thirty-four ART naïve HIV-1 infected subjects were enrolled in this study (22 non-AIDS and 12 AIDS presenters). Seventeen healthy donors (HD) were included as control group. Although circulating mDC levels resulted unchanged, HLA-DR expression was decreased on mDCs of HIV positive subjects compared to HD (p 0,0001). AIDS presenters showed the lowest level of expression of HLA-DR on mDCs. Circulating levels of pDCs were decreased in HIV patients compared to HD (p 0,001), without any changes in HLA-DR expression. SlanDC cell counts were extremely reduced in AIDS presenters, compared to non-AIDS presenters and HD (p 0,01 and p 0,0001, respectively) and showed higher HLA-DR expression in HIV patients compared to HD (p 0,01). Intermediate monocyte (IM) cell counts were increased in AIDS and non-AIDS presenters compared to HD (p 0,001 and p 0,001 respectively). Furthermore, IM expansion was directly correlated to HIV viral load (p = 0,036) and independent from CD4 cell counts and activation levels. Plasma concentrations of sCD14 and sCD163 resulted increased in HIV infected subjects compared to HD (p 0,0001 and p 0,001), with the highest levels observed in AIDS presenters. After 1 year, ART was able to increase pDC and decrease IM absolute cell counts and modify HLA-DR expression on mDCs and slanDCs, approaching the levels observed in HD. ART reduced also CD4 and CD8 activation levels. In conclusion, in untreated HIV infected subjects circulating dendritic cells resulted altered either in numbers or in HLA-DR expression, especially in AIDS presenters. IM absolute counts were equally increased in AIDS and non-AIDS presenters. ART was able to reduce myeloid and lymphoid inflammation in both advanced and non-advanced HIV patients, confirming the role of ART in hampering disease progression and immune activation associated non-AIDS events.

Congenital malaria (CM) is uncommon in both malaria-endemic and non-endemic countries. It may be caused by any Plasmodium spp., although Plasmodium falciparum and Plasmodium vivax are the more frequent etiologic agents. We report a case of delayed diagnosis of CM by P. vivax in a newborn of an Eritrean primigravida. The mother developed pregnancy-related immunodepression and varicella-zoster viral infection 9 days before natural delivery; therefore, the child was admitted in the neonatal intensive care unit (NICU) to administer specific varicella-zoster immunoglobulin prophylaxis and for clinical monitoring. During the NICU stay, the newborn presented a febrile syndrome with vomiting, anemia, and thrombocytopenia. A P. vivax severe malaria diagnosis was made by detecting trophozoites in the thick and thin blood smears. The infant was successfully treated with intravenous artesunate and clindamycin. Our experience suggests that malaria diagnostic tests need to be included in routine blood analyses in newborns with febrile syndrome from mothers with an epidemiologic link to malaria-endemic areas.

Background and aims Measles is an infectious disease that represents a serious public health problem worldwide, being associated with increased susceptibility to secondary infections, especially in the respiratory and gastrointestinal tracts. The aim of this study was to evaluate sCD163 and sCD14 levels in measles virus (MV) infected patients, as markers of immune activation, in order to better understand their role in the pathogenesis of the disease. TNF-α plasma levels were also evaluated. Methods sCD163, sCD14 and TNF-α were measured by ELISA in plasma samples of 27 MV infected patients and 27 healthy donors (HD) included as controls. Results At the time of hospital admission, sCD163 and sCD14 levels were significantly higher in MV infected patients than in HD, while a decrease in TNF-α levels were found even if without statistical significance. sCD163 and sCD14 levels were significantly decreased after two months from acute infection compared to hospital admission although they remained significantly higher compared to HD. TNF-α levels increased significantly during the follow-up period. Considering clinical parameters, sCD163 levels positively correlated with aspartate aminotransferase, white blood cell count and neutrophils rate, while negatively correlated with the lymphocyte percentage. sCD14 levels positively correlated with the neutrophil and lymphocyte percentages. Conclusions These results indicate that, despite the resolution of symptoms, an important macrophage/monocyte activation persists in measles patients, even after two months from infection.

Background Although Plasmodium ovale is considered the cause of only mild malaria, a case of severe malaria due to P. ovale with acute respiratory distress syndrome is reported. Case presentation A 37-year old Caucasian man returning home from Angola was admitted for ovale malaria to the National Institute for Infectious Diseases Lazzaro Spallanzani in Rome, Italy. Two days after initiation of oral chloroquine treatment, an acute respiratory distress syndrome was diagnosed through chest X-ray and chest CT scan with intravenous contrast. Intravenous artesunate and oral doxycycline were started and he made a full recovery. Conclusion Ovale malaria is usually considered a tropical infectious disease associated with low morbidity and mortality. However, severe disease and death have occasionally been reported. In this case clinical failure of oral chloroquine treatment with clinical progression towards acute respiratory distress syndrome is described.

Although natalizumab (anti-α4 integrin) represents an effective therapy for relapsing remitting multiple sclerosis (RRMS), it is associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML), caused by the polyomavirus JC (JCV). The aim of this study was to explore natalizumab-induced phenotypic changes in peripheral blood T-lymphocytes and their relationship with JCV reactivation. Forty-four patients affected by RRMS were enrolled. Blood and urine samples were classified according to natalizumab infusion number: 0 (N0), 1–12 (N12), 13–24 (N24), 25–36 (N36), and over 36 (N>36) infusions. JCV-DNA was detected in plasma and urine. T-lymphocyte phenotype was evaluated with flow cytometry. JCV serostatus was assessed. Ten healthy donors (HD), whose ages and sexes matched with the RRMS patients of theN0 group, were enrolled. CD8 effector (CD8 E) percentages were increased in natalizumab treated patients with detectable JCV-DNA in plasma or urine compared to JCV-DNA negative patients (JCV−) (p<0.01andp<0.001, resp.). Patients with CD8 E percentages above 10.4% tended to show detectable JCV-DNA in plasma and/or urine (ROC curvep=0.001). The CD8 E was increased when JCV-DNA was detectable in plasma or urine, independently from JCV serology, forN12 andN24 groups (p<0.01). As long as PML can affect RRMS patients under natalizumab treatment with a negative JCV serology, the assessment of CD8 E could help in the evaluation of JCV reactivation.

Patients co-infected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are at high risk of liver disease progression. We report a favorable safety profile and SVR12 rates of 96.7% among HIV/HCV co-infected patients participating in an Italian compassionate-use program of ombitasvir/paritaprevir/ritonavir + dasabuvir (OBV/PTV/r + DSV) ± ribavirin (RBV).

Background and aims Increased levels of chemokine interferon-gamma (IFN-γ)-inducible protein-10 (CXCL10), soluble CD163 (sCD163) and soluble CD14 (sCD14) have been reported in HCV infection. The aim of this study was to compare, sCD163 and sCD14 levels in HCV-infected patients undergoing direct acting antiviral (DAA)-containing regimens with or without interferon (IFN). Methods sCD163, sCD14 and CXCL10 were longitudinally measured by ELISA in 159 plasma samples from 25 HCV-infected patients undergoing IFN-based treatment plus telaprevir or boceprevir and 28 HCV infected subjects treated with DAA IFN-free regimens. Twenty-five healthy donors (HD) were included as controls. Results At baseline CXCL10, sCD163 and sCD14 levels were higher in HCV-infected patients than in HD. CXCL10 and sCD163 levels were significantly decreased in responder (R) patients who achieved sustained virological response (SVR), with both IFN-based and IFN-free regimens, while they were persistently elevated in non-responders (NR) patients who stopped IFN-based treatments because of failure or adverse events. Conversely, sCD14 levels were apparently unchanged during therapy, but at the end of treatment the levels reached normal ranges. Comparing the two regimens, the extent of CXCL10 reduction was more pronounced in patients undergoing DAA IFN-free therapies, whereas sCD163 and sCD14 reduction was similar in the two groups. Interestingly, only in IFN-based regimens baseline sCD163 levels were significantly higher in NR than in R patients, while in the IFN-free treatment group also patients with high sCD163 plasma levels obtained SVR. At the end of therapy, even if the biomarkers were largely decreased, their levels remained significantly higher compared to HD. Only in the early fibrosis stages, sCD163 values tended to normalize. Conclusions These results indicate that IFN-free regimens including newer DAA induce an early and marked decrease in circulating inflammatory biomarkers. However, the full normalization of biomarkers was not obtained, especially in patients with advanced fibrosis, thus underlying the need for a treatment in the early stages of HCV infection.

We describe the dynamics of dengue virus (DENV) infection in a woman in her mid-30s who developed fever after returning from Sri Lanka to Italy in April 2017. Laboratory testing demonstrated detectable DENV-RNA in plasma, urine, saliva, vaginal secretion. Persistent shedding of DENV-RNA was demonstrated in vaginal secretion, and DENV-RNA was detectable in the pelleted fraction up to 18 days from symptom onset. These findings give new insights into DENV vaginal shedding and vertical transmission.

The nuclear magnetic resonance (NMR)-based metabolomic approach was used as analytical methodology to study the urine samples of chronic inflammatory rheumatic disease (CIRD) patients. The urine samples of CIRD patients were compared to the ones of both healthy subjects and patients with multiple sclerosis (MS), another immuno-mediated disease. Urine samples collected from 39 CIRD patients, 25 healthy subjects, and 26 MS patients were analyzed using 1H NMR spectroscopy, and the NMR spectra were examined using partial least squares-discriminant analysis (PLS-DA). PLS-DA models were validated by a double cross-validation procedure and randomization tests. Clear discriminations between CIRD patients and healthy controls (average diagnostic accuracy 83.5 ± 1.9%) as well as between CIRD patients and MS patients (diagnostic accuracy 81.1 ± 1.9%) were obtained. Leucine, alanine, 3-hydroxyisobutyric acid, hippuric acid, citric acid, 3-hydroxyisovaleric acid, and creatinine contributed to the discrimination; all of them being in a lower concentration in CIRD patients as compared to controls or to MS patients. The application of NMR metabolomics to study these still poorly understood diseases can be useful to better clarify the pathologic mechanisms; moreover, as a holistic approach, it allowed the detection of, by means of anomalous metabolic traits, the presence of other pathologies or pharmaceutical treatments not directly connected to CIRDs, giving comprehensive information on the general health state of individuals.

Summary Background and objective Interferon-gamma (IFN-γ)-inducible protein-10 (IP-10), soluble (s) CD163 and sCD14 play an important role in the pathogenesis of HCV and HIV infection and are involved in inflammation and liver fibrosis. The aim of the present study was to evaluate at a single time point, plasma soluble biomarkers and inflammatory monocytes subsets in different groups of subjects: (i) HIV monoinfected patients on suppressive ART; (ii) HIV/HCV coinfected patients on ART, with undetectable HIV viremia (including either subjects who had active HCV replication or those who cleared HCV); (iii) HCV monoinfected individual with active viral replication. Methods Hundred and twenty-nine plasma samples were analyzed including HCV and HIV monoinfected patients, HIV/HCV coinfected patients, with active HCV infection (AHI) or with HCV viral clearance (VHC) and healthy donors (HD). Levels of IP-10, sCD163 and sCD14 were measured by ELISA. Absolute cell counts of monocyte subpopulations were enumerated in whole blood by using flow cytometric analyses. Results IP-10 and sCD163 plasma levels were higher in HCV monoinfected and in AHI coinfected pts compared to HIV monoinfected and HD, whereas sCD14 levels were higher only in HIV monoinfected patients. Considering the degree of fibrosis, sCD163 and sCD14 levels positively correlated with kPa values (as assessed by fibroscan) and FIB-4 in HCV monoinfected group. On the other hand, IP-10 did not correlate with the fibrosis stage and it was found increased also in patients with low fibrosis. Moreover, we found an increase of the inflammatory NCM subset, in non-cirrhotic HCV subjects, while no alterations were observed in HIV, AHI and VHC. Conclusions Our study suggests a scenario in which active HCV infection is associated with a strong pro-inflammatory state, even in the initial stage of liver fibrosis, regardless the presence of HIV coinfection, thus underlying the need of an early anti-HCV treatment.

Transplant recipients are at high risk of infections caused by multidrug resistant microorganisms. Due to the limited therapeutic options, innovative antimicrobial combinations against carbapenem-resistant Enterobacteriaceae causing severe infections are necessary. A 61-year-old woman with a history of congenital solitary kidney underwent renal transplantation. The postoperative course was complicated by nosocomial pneumonia due to Stenotrophomonas maltophilia and pan-sensitive Escherichia coli, successfully treated with antimicrobial therapy. On postoperative day 22, diagnosis of surgical site infection and nosocomial pneumonia with concomitant bacteremia due to a Klebisella pneumoniae carbapenemase-producer E coli was made. The patient was treated with the double-carbapenem regimen (high dose of meropenem plus ertapenem) and a potent synergistic and bactericidal activity of this un-conventional therapeutic strategy was observed in vitro. Despite a microbiological response with prompt negativity of blood cultures, the patient faced a worse outcome because of severe hemorrhagic shock. The double-carbapenem regimen might be considered as a rescue therapy in those subjects, including transplant recipients, in whom previous antimicrobial combinations failed or when colistin use might be discouraged. Performing in vitro synergy testing should be strongly encouraged in cases of infections caused by pan-drug resistant strains, especially in high-risk patients.

Background: Polyomaviruses (PyVs) are potential transforming viruses. Despite their involvement in human tumours still being debated, there is evidence to suggest a role for PyVs in bladder carcinoma (BC). Therefore, a possible association between PyVs and BC was investigated. Materials and Methods: Urine, blood and fresh bladder tissue specimens were collected from 29 patients with BC. PyV prevalence, non-coding control region (NCCR) organization and genotypic analysis were assessed. Results: Data showed a significant prevalence of John Cunningham (JC) PyV in BC tissues and in urine with respect to BKPyV, while simian virus 40 was not revealed. A BKPyV rearranged NCCR sequence was isolated, whereas a JCPyV archetypal structure was consistently retained. A prevalence of European genotypes was observed. Conclusion: Our data would suggest a JCPyV involvement in cancer progression and a BKPyV association with BC pathogenesis in immunocompetent patients. However, further work is necessary to better understand the exact role of PyVs in urothelial carcinogenesis.

HIV-infected patients appear to have a significantly greater risk of non-AIDS comorbidities such as osteoporosis and atherosclerosis. Subjects with osteoporosis are at a higher risk of developing cardiovascular disease than those with normal bone mass, therefore a possible relation between these two conditions can be hypothesized. In the setting of HIV infection, several factors might contribute to bone disease and endothelial dysfunction. The aim of our study was to evaluate the relationship between bone and cardiovascular disease and to investigate the role of traditional factors, T-cell phenotype and osteoprotegerin in HIV positive subjects on effective antiretroviral therapy. We included 94 HIV positive subjects on antiretroviral therapy with virological suppression and 41 healthy subjects matched for age and gender as a control group. Carotid-Intima Media Thickness (c-IMT) and bone mineral density (BMD) were performed by ultrasound and DEXA, respectively. CD4+/CD8+ T-cell activation, senescence and osteoprotegerin plasma levels were measured by flow-cytometry and ELISA, respectively. Among HIV positive patients, 56.4% had osteopenia/osteoporosis and 45.7% had pathological c-IMT (>0.9 mm). Subjects with pathological c-IMT and BMD exhibited higher CD4+ and CD8+ activated, CD8+ senescent and osteoprotegerin than subjects with normal c-IMT and BMD. HIV positive subjects with osteopenia/osteoporosis had higher c-IMT than subjects with normal BMD, and linear regression analysis showed a negative correlation between BMD and c-IMT. Several factors are implicated in the pathogenesis of non-AIDS comorbidities in HIV positive patients. Osteoprotegerin together with inflammation and immunosenescence in HIV positive patients could affect bone and vascular system and could be considered as a possible common link between these two diseases.

HIV-infected patients have a significantly greater risk of cardiovascular disease. Several markers including osteoprotegerin have been shown to be involved in the development and progression of atherosclerosis. We investigated the relationship between T-cell phenotype, osteoprotegerin, and atherosclerosis evaluated by carotid intima-media thickness (c-IMT) in 94 HIV+ patients on suppressive antiretroviral therapy with Framingham score

Background The aim of our work was to evaluate the potential impact of the European policy of testing for HIV all individuals presenting with an indicator disease, to prevent late diagnosis of HIV. We report on a retrospective analysis among individuals diagnosed with HIV to assess whether a history of certain diseases prior to HIV diagnosis was associated with the chance of presenting late for care, and to estimate the proportion of individuals presenting late who could have been diagnosed earlier if tested when the indicator disease was diagnosed. Methods We studied a large cohort of individuals newly diagnosed with HIV infection in 13 counselling and testing sites in the Lazio Region, Italy (01/01/2004-30/04/2009). Considered indicator diseases were: viral hepatitis infection (HBV/HCV), sexually transmitted infections, seborrhoeic dermatitis and tuberculosis. Logistic regression analysis was performed to estimate association of occurrence of at least one indicator disease with late HIV diagnosis. Results In our analysis, the prevalence of late HIV diagnosis was 51.3% (890/1735). Individuals reporting at least one indicator disease before HIV diagnosis (29% of the study population) had a lower risk of late diagnosis (OR = 0.7; 95%CI: 0.5-0.8) compared to those who did not report a previous indicator disease. 52/890 (5.8%) late presenters were probably already infected at the time the indicator disease was diagnosed, a median of 22.6 months before HIV diagnosis. Conclusions Our data suggest that testing for HIV following diagnosis of an indicator disease significantly decreases the probability of late HIV diagnosis. Moreover, for 5.5% of late HIV presenters, diagnosis could have been anticipated if they had been tested when an HIV indicator disease was diagnosed. However, this strategy for enhancing early HIV diagnosis needs to be complemented by client-centred interventions that aim to increase awareness in people who do not perceive themselves as being at risk for HIV.

Cardiovascular disease is increased in HIV-infected patients. Cytokines such as osteoprotegerin are implicated in atherosclerosis. The aim of our study was to evaluate the role of osteoprotegerin in the development and progression of atherosclerosis in HIV infected subjects on suppressive antiretroviral treatment. We enrolled 76 patients; 35 HIV infected men on suppressive Highly Active Antiretroviral Therapy with Framingham score 10% as control groups. HIV positive subjects underwent echocardiography, electrocardiography, and heart multidetector computed tomography, whereas in HIV negative subjects, tomography was only performed in case of any abnormalities either in echocardiography or electrocardiography. In HIV positive patients, computed tomography showed stenosis in 51.4% of the subjects. Osteoprotegerin plasma levels were higher in HIV-infected patients than those in healthy controls but lower than in HIV negative subjects with Framingham score >10%. Higher osteoprotegerin plasma levels were found in HIV positive patients with grade I stenosis than in patients with grade II/III stenosis. In conclusion, in HIV infected subjects with Framingham score

The anti-CD49d monoclonal antibody natalizumab is currently an effective therapy against the relapsing-remitting form of multiple sclerosis (RRMS). Natalizumab therapeutic efficacy is limited by the reactivation of the John Cunningham polyomavirus (JCV) and development of progressive multifocal leukoencephalopathy (PML). To correlate natalizumab-induced phenotypic modifications of peripheral blood T-lymphocytes with JCV reactivation, JCV-specific antibodies (serum), JCV-DNA (blood and urine), CD49d expression and relative abundance of peripheral blood T-lymphocyte subsets were longitudinally assessed in 26 natalizumab-treated RRMS patients. Statistical analyses were performed using GraphPad Prism and R. Natalizumab treatment reduced CD49d expression on memory and effector subsets of peripheral blood T-lymphocytes. Moreover, accumulation of peripheral blood CD8+ memory and effector cells was observed after 12 and 24 months of treatment. CD4+ and CD8+ T-lymphocyte immune-activation was increased after 24 months of treatment. Higher percentages of CD8+ effectors were observed in subjects with detectable JCV-DNA. Natalizumab reduces CD49d expression on CD8+ T-lymphocyte memory and effector subsets, limiting their migration to the central nervous system and determining their accumulation in peripheral blood. Impairment of central nervous system immune surveillance and reactivation of latent JCV, can explain the increased risk of PML development in natalizumab-treated RRMS subjects.

Corynebacterium striatum is a commensal of human skin and has been recently recognized as an emerging pathogen. A case of nosocomial pacemaker lead endocarditis due to a multidrug-resistant C. striatum strain is described, highlighting the role of sonication as a diagnostic tool in cardiac device infections.

In a longitudinal study on 181 naïve patients who responded to therapy (mean follow-up 4 years), high baseline human immunodeficiency virus (HIV)-RNA values correlated with high levels of cellular HIV-DNA at all time points (p

Background In recent years, the impact of antituberculous treatment on interferon (IFN)-gamma response to Mycobacterium tuberculosis antigens has been widely investigated, but the results have been controversial. The objective of the present study was: i) to evaluate longitudinal changes of IFN-gamma response to M. tuberculosis-specific antigens in TB patients during antituberculous treatment by using the QuantiFERON-TB Gold (QFT-G) assay; ii) to compare the differences in T-cell response after a short or prolonged period of stimulation with mycobacterial antigens; iii) to assess the CD4+ and CD8+ T cells with effector/memory and central/memory phenotype; iv) to investigate the direct in vitro effects of antituberculous drugs on the secretion of IFN-gamma. Principal findings 38 TB patients was evaluated at baseline and at month 2 and 4 of treatment and at month 6 (treatment completion). 27 (71%) patients had a QFT-G reversion (positive to negative) at the end of therapy, while 11 (29%) TB patients remained QFT-G positive at the end of therapy. Among the 11 patients with persistent positive QFT-G results, six had a complete response to the treatment, while the remaining 5 patients did not have a resolution of the disease. All 27 patients who became QFT-G negative had a complete clinical and microbiological recovery of the TB disease. In these patients the release of IFN-gamma is absent even after a prolonged 6-day incubation with both ESAT-6 and CFP-10 antigens and the percentage of effector/memory T-cells phenotype was markedly lower than subjects with persistent positive QFT-G results. The in vitro study showed that antituberculous drugs did not exert any inhibitory effect on IFN-gamma production within the range of therapeutically achievable concentrations. Conclusions The present study suggests that the decrease in the M. tuberculosis-specific T cells responses following successful anti-TB therapy may have a clinical value as a supplemental tool for the monitoring of the efficacy of pharmacologic intervention for active TB. In addition, the antituberculous drugs do not have any direct down-regulatory effect on the specific IFN-gamma response.

In the last years, the treatment of multiple sclerosis (MS) patients with natalizumab has been associated with the occurrence of progressive multifocal leukoencephalopathy (PML) caused by human polyomavirus JC (JCV). Here, we have shown a significant correlation between patients with JC viruria and positive JC-specific antibody response and patients without JCV-specific antibodies after 1 year of natalizumab (p = 0.0006). Furthermore, JCV-specific quantitative PCR on urine and plasma samples, collected at the enrollment (t0) and every 4 months (t1, t2, t3) in the first year and at two time points (t4 and t5) in the second year of natalizumab treatment, indicated the prevalence of JC viremia rather than JC viruria only in the second year of treatment (p = 0.04). Moreover, the analysis of JCV non-coding control region (NCCR) sequences in peripheral blood mononuclear cells of patients with JC-specific antibodies after 12 natalizumab infusions (t3) revealed the presence of rearranged sequences, whereas the prevalence of genotypes 1A, 1B, and 4 was detected in these patients by VP1 sequence analysis. In summary, JC viruria evaluation seems to be useful to identify early those patients who do not already develop a humoral immune response against JCV. It may also be interesting to study the JCV NCCR rearrangements since they could give us new insights on the onset of neuro-invasive viral variants.

John Cunningham virus (JCV), the etiological agent of progressive multifocal leukoencephalopathy (PML), contains a hyper-variable non-coding control region usually detected in urine of healthy individuals as archetype form and in the brain and cerebrospinal fluid (CSF) of PML patients as rearranged form. We report a case of HIV-related PML with clinical, immunological and virological data longitudinally collected. On admission (t0), after 8-week treatment with a rescue highly active antiretroviral therapy (HAART), the patient showed a CSF-JCV load of 16,732 gEq/ml, undetectable HIV-RNA and an increase of CD4+ cell count. Brain magnetic resonance imaging (MRI) showed PML-compatible lesions without contrast enhancement. We considered PML-immune reconstitution inflammatory syndrome as plausible because of the sudden onset of neurological symptoms after the effective HAART. An experimental JCV treatment with mefloquine and mirtazapine was added to steroid boli. Two weeks later (t1), motor function worsened and MRI showed expanded lesions with cytotoxic oedema. CSF JCV-DNA increased (26,263 gEq/ml) and JCV viremia was detected. After 4 weeks (t2), JCV was detected only in CSF (37,719 gEq/ml), and 8 weeks after admission (t3), JC viral load decreased in CSF and JCV viremia reappeared. The patient showed high level of immune activation both in peripheral blood and CSF. He died 4 weeks later. Considering disease progression, combined therapy failure and immune hyper-activation, we finally classified the case as classical PML. The archetype variant found in CSF at t0/t3 and a rearranged sequence detected at t1/t2 suggest that PML can develop from an archetype virus and that the appearance of rearranged genotypes contribute to faster disease progression.