Search

Aim of this review is to summarize the alterations occurring in gut microbiome composition after HIV infection, and to underline how intestinal dysbiosis can affect immune homeostasis, immune recovery, and persisting immune activation under antiretroviral therapy (ART). Many interventions have been suggested, mostly with inconclusive results.Recent evidence showed that gut microbiota from HIV-infected patients harbor reproducible differences compared to uninfected individuals. In this line, there is growing evidence that alterations in gut ecology during HIV infection correlate with persistence of immune defects and chronic inflammation. A reduced microbial diversity in feces of HIV-infected patients is highly associated with microbial translocation and monocyte activation markers; moreover, changes in mucosa-associated bacteria correlate with inflammation and T-cell activation.Studying the human host-microbiota interaction suggests that the consequences of HIV infection on microbial composition can influence immune status in HIV patients. ART induces microbiome changes that are independent of HIV infection, and some imply that ART may enhance dysbiosis. Studies and trials evaluated the effects of administering probiotics and prebiotics, finding a potential benefit on inflammation markers and immune cell activation. Emerging data on fecal microbial transplantation need to be assessed with further studies.

Early etiological diagnosis and characterization of host response to infection are becoming central in sepsis recognition and management. Still, limitations in conventional diagnosis and patient stratification contribute to the high mortality rates of septic patients despite new antimicrobials and resuscitation agents. Novel microbiological techniques and omics analyses have recently led to the development of several tests that are now commercially available or in the pipeline as rapid diagnostic tools. In this review, we first summarize emerging assays for the etiological diagnosis starting directly from whole blood, based on target-specific PCRs or metagenomics. We then investigate results of different omics approaches for both bedside diagnosis of immune dysfunction and detection of patients’ signatures associated with different clinical outcomes or potential response to individualized therapies. Finally, we discuss about the translation of these novel laboratory tools into clinical practice, showing how their best performance is achieved when integrated within antimicrobial stewardship programs.

International audience; Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only medical intervention that has led to an HIV cure. Whereas the HIV reservoir sharply decreases after allo-HSCT, the dynamics of the T cell reconstitution has not been comprehensively described. We analyzed the activation and differentiation of CD4+ and CD8+ T cells, and the breadth and quality of HIV- and CMV-specific CD8+ T cell responses in 16 patients with HIV who underwent allo-HSCT (including five individuals who received cells from CCR5Δ32/Δ32 donors) to treat their underlying hematological malignancy and who remained on antiretroviral therapy (ART). We found that reconstitution of the T cell compartment after allo-HSCT was slow and heterogeneous with an initial expansion of activated CD4+ T cells that preceded the expansion of CD8+ T cells. Although HIV-specific CD8+ T cells disappeared immediately after allo-HSCT, weak HIV-specific CD8+ T cell responses were detectable several weeks after transplant and could still be detected at the time of full T cell chimerism, indicating that de novo priming, and hence antigen exposure, occurred during the time of T cell expansion. These HIV-specific T cells had limited functionality compared with CMV-specific CD8+ T cells and persisted years after allo-HSCT. In conclusion, immune reconstitution was slow, heterogeneous, and incomplete and coincided with de novo detection of weak HIV-specific T cell responses. The initial short phase of high T cell activation, in which HIV antigens were present, may constitute a window of vulnerability for the reseeding of viral reservoirs, emphasizing the importance of maintaining ART directly after allo-HSCT.

Background: During the last decade, the spread of Klebsiella pneumoniae-carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) has increased dramatically worldwide. In this scenario, growing interest has been addressed to genotyping of KPC-Kp strains, which emerged as an important tool for a better understanding of the epidemiological and clinical characteristics of the outbreaks. Methods: We performed a retrospective cohort study on patients infected with KPC-Kp during a 28-month outbreak period (January 2010–April 2012) at San Gerardo Hospital (Monza, Italy), investigating KPC-Kp genotypes by means of repetitive element sequence-based polymerase chain reaction (Rep-PCR). Results: We enrolled 97 patients infected with KPC-Kp. Rep-PCR analysis identified 5 distinct clone types, with different distribution over time. During the first 12 months of the outbreak period, only 1 clone was detected (clone A, in 47 patients), while the 4 other clones were identified over the remaining 16 months (clones C, E, and F/L in 23, 24, and 3 patients respectively). Mechanical ventilation was less frequent in patients infected with clones C/E/F/L (OR = 0.14; 95% CI: 0.05-0.37) compared to clone A, and the Charlson comorbidity index (CI) was more likely to have a score >5 in patients infected with clones C/E/F/L (OR = 7.21; 95% CI: 2.24-23.14) compared to clone A. Overall mortality was higher in patients infected with clones C/E/F/L (13/20 patients, 65%) compared to those infected with clone A (7/20, 35%). Mortality in patients infected with clones C/E/F/L remained significantly higher even after adjusting for the potential confounding effect of comorbidities (ie, CI), with a hazard ratio (HR) of 4.65 (95% CI: 1.83-11.89). Conclusions: Our results suggested a close relationship between strain genotype and clinical outcome.

The contribution of HCV-related variables to cognitive impairment in HIV-HCV-coinfected patients has been poorly investigated. We selected HIV-HCV-coinfected patients undergoing cognitive examination (exploring memory, language, speed of mental processing and fine motor function) at three clinical centres. Cognitive performance was evaluated using Z-transformed scores. Logistic regression analysis was used to investigate variables associated to cognitive impairment (defined as a composite Z-score ≤ − 1). Overall, 146 HIV-HCV-coinfected patients were enrolled. Median HCV-RNA was 6.2logU/mL. HCV genotype 1a/b was the most represented (53.4%). Liver fibrosis was mild (Fib4 ≤ 1.45) in the majority of patients (44.5%). Global cognitive impairment was diagnosed in 35 (24%) subjects. Exploring each domain, a higher proportion of impairment was observed for memory (37%) followed by speed of mental processing (32.2%), fine motor functioning (24%) and language (18.5%). Among HCV-related variables, the duration of HCV infection was independently associated with global cognitive impairment (aOR 1.13 per +1 year, p = 0.016) and abnormal speed of mental processing (aOR 1.16 per +1 year, p = 0.001), while higher HCV-RNA was independently associated to fine motor functioning impairment (aOR 1.98 per +1log, p = 0.037). HCV genotype, fibrosis stage, transaminases or bilirubin levels were not related to cognitive performance. Of note, integrase inhibitor (InSTI) use was independently associated to a pathological performance in fine motor functioning (aOR 3.34, p = 0.035) and memory (aOR 3.70, p = 0.014). In conclusion, the duration of HCV infection and HCV-RNA load showed an association with cognitive impairment, suggesting a role of hepatitis-related factors in the development of cognitive disorders in HIV-HCV-coinfected patients. The association between InSTI use and altered cognitive performance should prompt investigations about potential neurotoxicity of these drugs.

Combination antiretroviral therapy (ART) has significantly reduced the morbidity and mortality resulting from HIV infection. ART is, however, unable to eradicate HIV, which persists latently in several cell types and tissues. Phylogenetic analyses suggested that the proliferation of cells infected before ART initiation is mainly responsible for residual viremia, although controversy still exists. Conversely, it is widely accepted that drug resistance mutations (DRMs) do not appear during ART in patients with suppressed viral loads. Studies based on sequence clustering have in fact indicated that, at least in developed countries, HIV-infected ART-naive patients are the major source of drug-resistant viruses. Analysis of longitudinally sampled sequences have also shown that DRMs have variable fitness costs, which are strongly influenced by the viral genetic background.

Genetic variation at a multigene cluster at chromosome 3p21.31 and the ABO blood group have been associated with the risk of developing severe COVID-19, but the mechanism remains unclear. Complement activation has been associated with COVID-19 severity.The aim of this study was to examine whether chromosome 3p21.31 and the ABO variants are linked to the activation of the complement cascade in COVID-19 patients.We considered 72 unrelated European hospitalized patients with genetic data and evaluation of circulating C5a and soluble terminal complement complex C5b-9 (SC5b-9). Twenty-six (36.1%) patients carried the rs11385942 GGA variant and 44 (66.1%) non-O blood group associated with increased risk of severe COVID-19.C5a and SC5-b9 plasma levels were higher in rs11385949 GA carriers than in non-carriers (P = 0.041 and P = 0.012, respectively), while C5a levels were higher in non-O group than in O group patients (P = 0.019). The association between rs11385949 and SC5b-9 remained significant after adjustment for ABO and disease severity (P = 0.004) and further correction for C5a (P = 0.018). There was a direct relationship between upper airways viral load and SC5b-9 in carriers of the rs11385949 risk allele (P = 0.032), which was not observed in non-carriers.The rs11385949 GGA variant, tagging the chromosome 3 gene cluster variation and predisposing to severe COVID-19, is associated with enhanced complement activation, both with C5a and terminal complement complex, while non-O blood group with C5a levels. These findings provide a link between genetic susceptibility to more severe COVID-19 and complement activation.

The disease burden due to nontuberculous mycobacteria is growing worldwide, consequently to improved diagnostic abilities and an increase in the individuals at risk. Uncertainties exist about the right moment on which start treatment. We investigated the clinical features associated with starting an antimicrobial treatment in patients with nontuberculous mycobacterial lung disease among Italian physicians involved in the field. We found that in real life predictors of starting antimicrobial treatment are quite adherent to international guidelines, with some uncertainties regarding the implication of immunosuppressive drugs.

ObjectivesTo assess the seroprevalence of anti-SARS-CoV-2 IgG among health careworkers (HCWs) in our university hospital and verify the risk of acquiring the infection according to work area.DesignCross-sectional study.SettingMonocentric, Italian, third-level university hospital.ParticipantsAll the employees of the hospital on a voluntary base, for a total of 4055 participants among 4572 HCWs (88.7%).Primary and secondary outcome measuresNumber of anti-SARS-CoV-2 positive serology according to working area. Association of anti-SARS-CoV-2 positive serology to selected variables (age, gender, country of origin, body mass index, smoking, symptoms and contact with confirmed cases).ResultsFrom 27 April 2020 to 12 June 2020, 4055 HCWs were tested and 309 (7.6%) had a serological positive test. No relevant difference was found between men and women (8.3% vs 7.3%, p=0.3), whereas a higher prevalence was observed among foreign-born workers (27/186, 14.5%, pConclusionsSARS-CoV-2 infection occurred undetected in a large fraction of HCWs and it was not associated with working in COVID-19 frontline areas. Beyond the hospital setting, exposure within the community represents an additional source of infection for HCWs.

This study aimed to assess the predictors of acute kidney injury (AKI) during colistin therapy in a cohort of patients with bloodstream infections (BSI) due to colistin-susceptible Gram-negative bacteria, focusing on the role of serum albumin levels. The study consisted of two parts: (1) a multicentre retrospective clinical study to assess the predictors of AKI during colistin therapy, defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria; and (2) bioinformatic and biochemical characterization of the possible interaction between human serum albumin and colistin. Among the 170 patients included in the study, 71 (42%), 35 (21%), and 11 (6%) developed KDIGO stage 1 (K1-AKI), KDIGO stage 2 (K2-AKI), and KDIGO stage 3 (K3-AKI), respectively. In multivariable analyses, serum albumin

Background Recently, some systemic inflammation-based biomarkers have been demonstrated useful for predicting risk of death in patients with solid cancer independently of tumor characteristics. This study aimed to investigate the prognostic role of systemic inflammation-based biomarkers in HIV-infected patients with solid tumors and to propose a risk score for mortality in these subjects. Methods Clinical and pathological data on solid AIDS-defining cancer (ADC) and non-AIDS-defining cancer (NADC), diagnosed between 1998 and 2012 in an Italian cohort, were analyzed. To evaluate the prognostic role of systemic inflammation- and nutrition-based markers, univariate and multivariable Cox regression models were applied. To compute the risk score equation, the patients were randomly assigned to a derivation and a validation sample. Results A total of 573 patients (76.3% males) with a mean age of 46.2 years (SD = 10.3) were enrolled. 178 patients died during a median of 3.2 years of follow-up. For solid NADCs, elevated Glasgow Prognostic Score, modified Glasgow Prognostic Score, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and Prognostic Nutritional Index were independently associated with risk of death; for solid ADCs, none of these markers was associated with risk of death. For solid NADCs, we computed a mortality risk score on the basis of age at cancer diagnosis, intravenous drug use, and Prognostic Nutritional Index. The areas under the receiver operating characteristic curve were 0.67 (95% confidence interval: 0.58 to 0.75) in the derivation sample and 0.66 (95% confidence interval: 0.54 to 0.79) in the validation sample. Conclusions Inflammatory biomarkers were associated with risk of death in HIV-infected patients with solid NADCs but not with ADCs.

Background Inflammasome-mediated activation of caspase-1 regulates inflammatory responses and pyroptosis. We analyzed possible associations between inflammasome-related genes and immune reconstitution in HIV-infected antiretroviral therapy (ART)-treated patients. Methods Cross-sectional, case–control study. HIV-infected patients on ART for ≥24 months with HIV-RNA

A 50-year-old man was admitted to intensive care unit because of acute respiratory failure due interstitial pneumonia; after admission, a diagnosis of acute human immunodeficiency virus (HIV)-1 infection was made. Clinical and radiological improvement was observed only after introduction of antiretroviral treatment. We discuss the hypothesis of interstitial pneumonia induced by the acute HIV-1 infection.

Early consolidation with high-dose therapy and autologous stem cell transplantation is a feasible and effective treatment option in HIV-associated non-Hodgkin lymphoma at high risk

The high potency and tolerability of the currently available antiretroviral drugs has modified HIV-1 infection from a life-threatening disease to a chronic illness. Nevertheless, some issues still remain open to optimize the management of HIV-1 infected patients in term of maintenance of virological suppression over time, identifying patients that could benefit from simplification therapy, and reducing co-mordibities driven by chronic inflammation. The availability of robust and affordable virological and immunological markers can help in solving these issues by providing information on the burden of HIV-1 reservoir in all the anatomical compartments in which the virus replicates as well as on persistent inflammation, immune activation and senescence despite successful virological suppression. In this light, this review is aimed at providing new insights (arising from a two-day Italian expert meeting hold in Rome in March 2016) in evaluation and monitoring of HIV-1 infection from a virological, immunological and clinical perspective. Particular attention has been focused on role of novel parameters (such as total HIV-1 DNA, residual viremia, and immunological markers) in optimizing treatment strategies, enhancing medical adherence, and individualizing monitoring.

Background Two biomarkers, the neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR), have been shown to be indicative of systemic inflammation and predictive of mortality in general population. We aimed to assess the association of NLR and PLR, with risk of death in HIV-infected subjects when also taking account of HIV-related factors. Methods We conducted a multicenter Italian cohort study from 2000 to 2012 including HIV-infected subjects naïve at antiretroviral treatment. The associations of NLR and PLR with all-cause mortality were tested by univariate and multivariate analyses using both time independent and dependent Cox proportional hazard models. We also fitted models with a cubic-spline for PLR and NLR to evaluate the possible non-linear relationship between biomarkers values and risk of death. Results Eight-thousand and two hundred thirty patients (73.1% males) with a mean age of 38.4 years (SD 10.1) were enrolled. During a median follow-up of 3.9 years, 539 patients died. PLR

Background: The contribution of monocyte activation in the development of HIV-associated neurocognitive disorders is not completely understood. This study aimed to explore the predictive value of peripheral monocyte/macrophage (M/M) phenotypes on the evolution of cognitive performance in a population of virologically suppressed HIV-infected patients. Setting: Prospective, observational, longitudinal study. Methods: HIV-1-infected patients with HIV-RNA 12 months underwent neuropsychological examination at baseline and after 1 year. Cognitive performance was evaluated using Z-transformed scores, and neurocognitive impairment (NCI) was defined according to Frascati criteria. Peripheral M/M phenotypes (classic CD14 ++ CD16 -, intermediate CD14 ++ CD16 +, and nonclassic CD14 + CD16 ++) and specific surface activation markers (eg, CD163, CD11b, and CD38) were evaluated using flow cytometry at baseline. Predictive value of peripheral M/M phenotypes on the evolution of cognitive performance over 1-year follow-up was also evaluated. Results: Overall, 54 patients [85.2% men, median age 50 years (range 27-60 years), 27.8% hepatitis C virus coinfected, 48.1% with past AIDS-defining events, median nadir CD4 83 cells/L (range 1-334), median baseline CD4 547 cells/L (range 136-1652)] were enrolled. Proportion of patients with NCI was low, accounting for 13% at baseline and 16.5% after 1 year (P = 0.687). Memory was the only single domain in which decreased performance after 1 year was observed (-0.25 Z-score, P = 0.025). In patients with significant decrease (≥0.5 SD) in memory performance (n = 20), significantly lower CD14 ++ CD16 + CD163 + (% CD14 ++ CD16 +) (P = 0.038) and higher CD14 + CD38 + (% CD14 +) (P = 0.030) levels were observed. Conclusions: In virologically suppressed HIV-infected patients, the evolution of memory performance could be linked to the expression of certain peripheral activated M/M phenotypes. Such associations should be verified in larger populations over the long term.

Background Few data are available about efficacy and durability of simplification from multi-tablet antiretroviral regimens to co-formulated efavirenz (EFV)/emtricitabine (FTC)/tenofovir (TDF) versus rilpivirine (RPV)/FTC/TDF in virologically suppressed HIV-1-infected patients. Methods We retrospectively analysed HIV-infected patients with HIV RNA 50 copies/ml or a single determination >1,000 copies/ml) and their predictors were investigated. Results 1,560 patients were reviewed of which 1,097 (70%) switched to EFV/FTC/TDF and 463 (30%) to RPV/FTC/TDF. During follow-up, VF and TD occurred in 44 (4%) and 242 (22%) patients in EFV/FTC/TDF and in 29 (6%) and 50 (11%) patients in RPV/FTC/TDF, respectively. The 3-year estimated probability of remaining free from VF was 96.2% with EFV/FTC/TDF versus 92.7% with RPV/FTC/TDF ( P=0.003). At multivariate analysis, regimen type (EFV/FTC/TDF versus RPV/FTC/TDF aHR 0.24; P=0.004) and time of virological suppression (aHR 0.85; P=0.048) were the only independent predictors of VF. The estimated 3-year probability of remaining free from TD was 77.4% with EFV/FTC/TDF versus 88.4% with RPV/FTC/TDF ( P=0.001). Predictors of TD were female sex, switching from PI-based regimens, older age, shorter time of virological suppression and regimen type (EFV/FTC/TDF versus RPV/FTC/TDF aHR 2.48; PConclusions Both regimens showed good safety and efficacy in this real-life setting, although switch to RPV/ FTC/TDF seemed better tolerated while EFV/FTC/TDF was associated with a lower probability of VF.

Background: Invasive mold infections in children with hematological malignancies are associated with high mortality rates. The use of combination antifungal therapy in cases with a severe clinical course is increasing, although information on the efficacy and safety of this approach is limited. Methods: We present a case series of 13 children affected by hemato-oncological disorders who received combination antifungal therapy for invasive mold infections at our center (Pediatric Hematology, San Gerardo Hospital, Monza, Italy) from 2011 to 2016, with the aim of describing their clinical characteristics, types of infections, treatment regimens, clinical outcomes, and treatment safety. Medical records were retrospectively reviewed in order to describe patients’ characteristics. Results: Combination antifungal therapy included liposomal amphotericin associated with caspofungin (5/13, 38.4%), voriconazole (5/13, 38.4%), or posaconazole (3/13, 23.1%). The 12-week treatment response rate was 69.2% (6/13 patients showed complete response, 3/13 partial response). The crude mortality was 30.7% (4/13): half was related to invasive mold infections (2/13, 15.38%) and half to disease progression (2/13, 15.38%). Overall, treatment was well tolerated, and we did not observe any permanent discontinuation of antifungals due to related side effects. Conclusions: In our experience, combination antifungal therapy seems to be a safe option in immunocompromised children with invasive mold infections. Well-designed studies are needed to confirm the safety of this approach and to better understand its efficacy in the pediatric setting. Keywords: antifungal therapy; mold; hematological malignancies

Antiretroviral treatment of HIV infection reduces, but does not eliminate, viral replication and down modulates immune activation. The persistence of low level HIV replication in the host, nevertheless, drives a smouldering degree of immune activation that is observed throughout the natural history of disease and is the main driving force sustaining morbidity and mortality. Areas covered: Early start of antiretroviral therapy (ART) and intensive management of behavioural risk factors are possible but, at best, marginally successful ways to manage immune activation. We review alternative, possible strategies to reduce immune activation in HIV infection including timing of ART initiation and ART intensification to reduce HIV residual viremia; switch of ART to newer molecules with reduced toxicity; use of anti inflammatory/immunomodulatory agents and, finally, interventions aimed at modifying the composition of the microbiota. Expert commentary: Current therapeutic strategies to limit immune activation are only marginally successful. Because HIV eradication is currently impossible, intensive studies are needed to determine if and how immune activation can be silenced in HIV infection.

Investigation of the relationship between high-density lipoprotein-cholesterol (HDL-c) and the risk of developing cancer in a prospective cohort of human immunodeficiency virus (HIV)-infected patients. The Italian Cohort of Antiretroviral-naive Patients Foundation Cohort is an Italian multicenter observational study recruiting HIV-positive patients while still antiretroviral treatment-naive, regardless of the reason since 1997. Patients with at least 1 HDL-c value per year since enrollment and one such value before antiretroviral treatment initiation were included. HDL-c values were categorized as either low (

Despite suppressive combination antiretroviral therapy, a considerable proportion of HIV-infected patients do not achieve adequate immune recovery in terms of the CD4+ T-cell count, although they have controlled viremia values. Many questions remain for clinicians in the management of these patients, defined as immunological nonresponders, including questions about the mechanisms underlying the lack of immune restoration and possible therapeutic approaches to this particular group of patients.

Objective.To investigate intrathecal immune activation parameters and HIV-RNA in HIV-associated neurocognitive disorders (HAND) of advanced naïve HIV-infected patients and to evaluate their dynamics before and after initiation of antiretroviral therapy (ART).Methods.Cross-sectional and longitudinal analysis of HIV RNA, proinflammatory cytokines (IL-6, IL-10, INF-γ, TNF-α, TGF-β1, and TGF-β2) and chemokines (MIP-1α, MIP-1β, and MCP-1) in plasma and cerebrospinal fluid (CSF) of HIV-infected patients with CD4 μL.Results.HAND was diagnosed at baseline in 6/12 patients. Baseline CSF HIV-RNA was comparable in patients with or without HAND, whereas CSF concentration of IL-6 and MIP-1β, proinflammatory cytokines, was increased in HAND patients. CSF evaluation at 12 weeks was available in 10/12 cases. ART greatly reduced HIV-RNA in all patients. Nevertheless, IL-6 and MIP-1βremained elevated after 12 weeks of therapy in HAND patients, in whom CSF HIV RNA decay was slower than the plasmatic one as well.Conclusion.Immune activation, as indicated by inflammatory cytokines, but not higher levels of HIV-RNA is observed in advanced naïve HIV-infected patients with HAND. In HAND patients, ART introduction resulted in a less rapid clearance of CSF viremia compared to plasma and no modifications of intratechal immune activation.

Background: The multifactorial mechanisms associated with radical reductions in HIV-1 reservoirs after allogeneic hematopoietic stem cell transplant (allo-HSCT), including a case of HIV cure, are not fully understood. Objective: To investigate the mechanism of HIV-1 eradication associated with allo-HSCT. Design: Nested case series within the IciStem observational cohort. Setting: Multicenter European study. Participants: 6 HIV-infected, antiretroviral-treated participants who survived more than 2 years after allo-HSCT with CCR5 wildtype donor cells. Measurements: HIV DNA analysis, HIV RNA analysis, and quantitative viral outgrowth assay were performed in blood, and HIV DNA was also measured in lymph nodes, ilea, bone marrow, and cerebrospinal fluid. A humanized mouse model was used for in vivo detection of the replication-competent blood cell reservoir. HIV-specific antibodies were measured in plasma. Results: Analysis of the viral reservoir showed that 5 of 6 participants had full donor chimera in T cells within the first year after transplant, undetectable proviral HIV DNA in blood and tissue, and undetectable replication-competent virus (

Persistently reduced CD4(+) T-lymphocyte counts in the face of undetectable HIV viremia are seen in a sizable percentage of HIV-infected patients undergoing antiretroviral therapy (ART). We analyzed the immune correlates of this phenomenon.Sixty-seven HIV-infected patients with undetectable viremia (50 copies/microl) after more than 7 years of ART were enrolled in the study and divided into two groups (CD4 cell counts500 cells/microl or500 cells/microl). Duration of HIV infection (16 years) was comparable. Peripheral blood mononuclear cell were stimulated with gag+env or with cytomegalovirus peptides. Activated T cells (Ki67(+)), Treg lymphocytes (CD4(+)/CD25high/Foxp3+), divided into naive and activated cells based on PD1 expression, interleukin (IL)-10 and transforming growth factor (TGF)-beta production, annexin V, activation of caspases 8 and 9, Toll-like receptor (TLR)2 and TLR4 expression on immune cells, and plasma lipopolysaccharide (LPS) concentration were analyzed.CD4(+)/Ki67(+) T cells; plasma LPS; total, naive, and activated Treg; TLR2-expressing and TLR4-expressing Treg; IL-10 production; and early and late apoptotic CD4 T cells, were significantly increased in patients with undetectable viremia and CD4 cell counts less than 500 cells/microl after more than 7 years of ART. As previously shown, CD4 nadir were also lower in these individuals. Immune activation, LPS concentration, Treg, and degree of apoptosis were negatively correlated with CD4 cell counts.Lack of CD4 recovery in individuals in whom ART suppresses HIV replication is associated with complex immune alterations. Immune activation, likely driven by altered gut permeability and resulting in augmented Treg activity could play a pivotal role in this process.

We used DNA fingerprinting to analyse tuberculosis (TB) epidemiology in immigrant patients living in two major northern Italian urban areas. The study population included 1999 TB patients (1500 Italian-born and 499 immigrants). Univariate and multivariate logistic regression models were used to identify risk factors related to clustering similar proportions of immigrant and Italian-born patients (46%) had infection with TB strains that belonged to genetic clusters. This supports the hypothesis that the disease in foreign patients is more likely to have arisen from reactivation of latent infection acquired in the country of origin than from recent transmission. Gender, age, human immunodeficiency virus infection and drug resistance were not significantly linked to TB clustering. Risk factors associated with strain clustering were country of origin (Somalia, adjusted OR (AOR) 3.19, p 0.017; Peru, AOR 2.86, p 0.014; and Senegal, AOR 2.60, p 0.045) and city of residence. Immigrant status in the larger urban area was an independent risk factor for infection with clustered TB, as reinforced by a subanalysis of the Senegalese group. In conclusion, variations in TB transmission were observed among immigrants from different countries and even within national groups, where living conditions have been found to exert a profound impact. These results emphasize the importance of improving social integration of immigrant subjects in order to limit risks of TB transmission in developed countries.

An immune response mediated by type 2 cytokines is thought to contribute to the development and unfavorable outcome of aspergillosis. Adjuvant therapy with interferon-gamma (IFN-gamma) and granulocyte-macrophage colony stimulating factor (GM-CSF) was added to antifungal treatment in three nonneutropenic patients (one HIV-positive and two HIV-negative patients) with culture proven aspergillosis refractory to classical antifungal therapy. Clinical improvement was observed concomitantly with an increase in peripheral blood leukocyte proliferation and type 1 cytokines production. Our findings suggest an association between the improvement in type 1 cytokine production observed during IFN-gamma and GM-CSF administration and a better control of Aspergillus infection in patients with progressive disease despite adequate antifungal therapy.

Purpose: Recurrence of tuberculosis (TB) can be the consequence of relapse or exogenous reinfection. The study aimed to assess the factors associated with exogenous TB reinfection. Methods: Prospective cohort study based on the TB database, maintained at the Division of Infectious Diseases, Luigi Sacco Hospital (Milan, Italy). Time period: 1995–2010. Inclusion criteria: (1) ≥2 episodes of culture-confirmed TB; (2) cure of the first episode of TB; (3) availability of one Mycobacterium tuberculosis isolate for each episode. Genotyping of the M. tuberculosis strains to differentiate relapse and exogenous reinfection. Logistic regression analysis was used to assess the influence of risk factors on exogenous reinfections. Result: Of the 4682 patients with TB, 83 were included. Of these, exogenous reinfection was diagnosed in 19 (23 %). It was independently associated with absence of multidrug resistance at the first episode [0, 10 (0.01–0.95), p = 0.045] and with prolonged interval between the first TB episode and its recurrence [7.38 (1.92–28.32) p = 0.004]. However, TB relapses occurred until 4 years after the first episode. The risk associated with being foreign born, extrapulmonary site of TB, and HIV infection was not statistically significant. In the relapse and re-infection cohort, one-third of the patients showed a worsened drug resistance profile during the recurrent TB episode. Conclusions: Exogenous TB reinfections have been documented in low endemic areas, such as Italy. A causal association with HIV infection could not be confirmed. Relapses and exogenous reinfections shared an augmented risk of multidrug resistance development, frequently requiring the use of second-line anti-TB regimens.

Background The systemic inflammatory response has been postulated as having prognostic significance in a wide range of different cancer types. We aimed to assess the prognostic role of inflammatory markers on survival in HIV-infected patients with Non-Hodgkin Lymphoma (NHL), and to compute a prognostic score based on inflammatory biomarkers. Methods We evaluated data on HIV patients with NLH diagnosis between 1998 and 2012 in a HIV Italian Cohort. Using Cox proportional regression model, we assessed the prognostic role of Neutrophil-Lymphocyte Ratio (NLR), Platelet-Lymphocyte Ratio (PLR), Glasgow Prognostic Score (GPS), modified Glasgow Prognostic Score (mGPS), Prognostic Index (PI), and Prognostic Nutritional Index (PNI). We also computed a risk score equation, assigning patients to a derivation and a validation sample. The area under the curve (AUC) was use to evaluate the predictive ability of this score. Results 215 non-Hodgkin lymphoma cases (80.0% males) with a mean age of 43.2 years were included. Deaths were observed in 98 (45.6%) patients during a median follow up of 5 years. GPS, mGPS, PI and PNI were independently associated with risk of death. We also computed a mortality risk score which included PNI and occurrence of an AIDS event within six months from NHL diagnosis. The AUCs were 0.69 (95% CI 0.58 to 0.81) and 0.69 (95% CI 0.57 to 0.81) at 3 and 5 years of the follow-up, respectively. Conclusions GPS, mGPS, PI and PNI are independent prognostic factors for survival of HIV patients with NHL.

HIV infected subjects present an unfavorable cardiovascular (CV) risk profile that is determined by the infection itself, highly active anti-retroviral therapy (HAART) and other factors, such as chronic kidney disease (CKD). Information is scant and contradictory on whether these factors are associated with arterial stiffness and blood pressure (BP) alteration. Our study aimed to evaluate those parameters in HIV-positive subjects both with and without HAART and with and without CKD, which was defined as the presence of microalbuminuria with a normal glomerular filtration rate. We enrolled 94 HIV-infected subjects without known CV risk factors and compared them with 37 control subjects. We recorded brachial and central BP (pulse wave analysis) and pulse wave velocity ( SphygmoCor). HIV-positive subjects of similar ages and with similar BP values showed central pulse pressure values that were significantly greater than those of controls; this was also the case for the Aix value. Central systolic and pulse pressure values and Aix were significantly greater in HIV-positive subjects with HAART and CKD than in the other HIV-positive subgroups and control subjects. PWV was also superimposable between groups when the data were analyzed relative to the presence of HAART and CKD. Our study shows that the unfavorable CV risk profile associated with HIV infection includes an increase in both central BP and Aix. The central BP increase seems to be favored by renal damage, which apparently has a role in the early stages of the disease.

Tucaresol, a Schiff base-forming compound that is shown to enhance cytotoxic T cell responses and the production of type 1 cytokines, represents a potentially useful adjuvant factor for treating HIV-1 infection. We studied the effect of tucaresol on V3 sequences within the HIV-1 env region derived from patients with different virologic and immunologic features who were enrolled in a phase I/II randomized clinical trial. The sequence analysis of the env V3 region of the viruses at baseline has confirmed a genotypic pattern similar to a macrophagotropic virus model; we analyzed the follow-up sequences at week 16 of the protocol and did not observe any difference in the tropism determinants within the third variable fragment of the env region. The administration of tucaresol did not accelerate env V3 evolution thus preventing modifications of HIV-1 tropism over time.