Matteo Vassallo

Can high central nervous system penetrating antiretroviral regimens protect against the onset of HIV-associated neurocognitive disorders?

Objective:To assess changes over time in neuropsychological test results (NPr) and risk factors among a regularly followed HIV-infected patient population. Methods:Prospective cohort of HIV-infected patients randomly selected to undergo neuropsychological follow-up. Test score was adjusted for age, sex and education. Patients were divided into five groups: normal tests, neuropsychological deficit (one impaired cognitive domain), asymptomatic neurocognitive disorders (ANIs), mild neurocognitive disorders (MNDs) and HIV-associated dementia (HAD). Demographic and background parameters including CSF drug concentration penetration effectiveness (CPE) score 2010 were recorded. Changes in NPr and associated risk factors were analyzed. Results:Two hundred and fifty-six patients underwent neuropsychological tests and 96 accepted follow-up approximately 2 years later. The groups were comparable. Upon neuropsychological retesting, six patients improved, 31 worsened and 59 were stable. The proportion of patients with HIV-associated neurocognitive disorders (HANDs) rose from 26 to 45%, with ANIs and MNDs still mostly represented. Most patients initially diagnosed with HANDs remained stable, five of 25 showed clinical improvement and three of 25 deteriorated. Of 33 patients with normal tests, four deteriorated, whereas 24 of 38 with initial neuropsychological deficit had poorer NPr, and contributed most of the new HAND cases. Patients with clinical deterioration had a lower CPE score both at inclusion (6.9 vs. 8.1; P = 0.005) and at the end of follow-up (7.2 vs. 7.8; P = 0.08) than those with improved or stable performance. This was confirmed by multivariate analysis. Conclusion:Patients with higher CPE scores upon inclusion and at the end of follow-up were at lower risk of clinical worsening, suggesting that combination antiretroviral therapy with better CSF penetration could protect against cognitive deterioration.

Antimicrobial lock therapy in central-line associated bloodstream infections: a systematic review

PurposeAntimicrobial lock therapy (ALT) seems a promising approach for treatment of central line associated bloodstream infections (CLABSI). The recent introduction of molecules such as daptomycin and tigecycline, alone or in combination with other molecules, improved chances of efficacy of ALT, due to their activity on the bacterial biofilm. Our aim was to review the literature concerning ALT for CLABSI, including data concerning novel molecules.MethodsWe included case-control studies evaluating two or more molecules as ALT in central venous catheter infections extracted from the Medline database. Among 221 available articles in Pubmed, 54 were selected for their particular interest concerning ALT.ResultsIncidence of CLABSI is high worldwide. Mechanisms of catheter infection include contamination by skin bacteria, hand contamination and hematogenous diffusion. Catheter-infection is associated with biofilm formation, which reduces the efficacy of ALT. The most promising situation for ALT to succeed in salvaging a catheter appears to be coagulase-negative Staphylococcus infection, which is the main causative agent of CLABSI. Daptomycin, Tigecycline, Ethanol and Taurolidine appear as the best options for treating CLABSI; data are mostly available for Daptomycin, which showed, alone or associated with Rifampin, good in vitro potency on biofilm, but few in vivo data exist on efficacy.ConclusionsThe introduction of novel molecules has increased chances of catheter salvage with ALT in case of CLABSI, but further in vivo studies are needed.

Virologically suppressed patients with asymptomatic and symptomatic HIV‐associated neurocognitive disorders do not display the same pattern of immune activation

Inversion of the CD4:CD8 ratio is a marker of immune activation and age‐associated disease. We measured the CD4:CD8 ratio as a marker of cognitive impairment in HIV‐infected patients and explored differences according to clinical severity.

HMGB1/anti-HMGB1 antibodies define a molecular signature of early stages of HIV-Associated Neurocognitive Disorders (HAND)

Background HIV-associated neurocognitive disorders (HAND) persist in the post-HAART era, characterized by asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorders (MND). High mobility group box 1 (HMGB1) is a non-histone chromosomal protein widely expressed in the nucleus of all eukaryotic cells, including brain cells, which acts as a potent proinflammatory cytokine when actively secreted from immune cells. Recent reports suggested that HMGB1 acts on microglial cells to promote neuroinflammation. In this study, our aim was to determine whether HMGB1 is involved in HAND, but also to identify early new markers of neurological impairment in HIV-infected patients. Methods CSF and serum were collected from 103 HIV-1-infected patients enrolled in Neuradapt, a prospective study of the prevalence of HAND in HIV-1 infected patients at Nice University Hospital. Stored fluids were assessed for immunological, virological, and brain metabolite parameters. In addition to HIV RNA and DNA measurements, expression of T-cell surface markers of activation (CD38 and HLA-DR) was analyzed on whole blood. Concentration of 27 cytokines and chemokines was measured using multiplex bead assays on serum and CSF. Concentration of HMGB1 and anti-HMGB1 IgG autoantibodies were also measured on the same samples. Changes in cerebral metabolites N-acetyl aspartate (NAA), Choline (Cho) and creatinine (Cr) were assessed by magnetic resonance microscopy (MRS). Results Clinical, virological and immunological characteristics were comparable between HAND (n = 30) and no HAND (n = 73) patients, except the absolute numbers of CD8+ T cells, which were higher in patients with HAND. Among the 29 molecules tested, only 4 of them were significantly upregulated in the CSF from HAND patients as compared to healthy donors i.e. HMGB1, anti-HMGB1 IgG antibodies, IP-10 and MCP1. CSF HMGB1 levels were positively correlated with HIV-1 DNA in aviremic HAND patients, suggesting a positive impact of HMGB1 on HIV reservoirs. Moreover, in contrast to NAA/Cr and Cho/NAA ratios, circulating anti-HMGB1 IgG antibody levels could discriminate patients with no HAND from patients with no HAND and a single deficit (average ROC-AUC = 0.744, p = 0.03 for viremic patients), thus enabling the identification of a very early stage of neurocognitive impairment, Conclusion We report that brain injury in chronically HIV-infected patients on stable HAART is strongly associated with persistent CNS inflammation, which is correlated with increased levels of HMGB1 and anti-HMGB1 IgG in the CSF. Moreover, we identified circulating anti-HMGB1 IgG as a very early biomarker of neurological impairment in patients without HAND. These results might have important implication for the identification of patients who are at high risk of developing neurological disorders.

Prevalence of urinary tract infections mimicking respiratory infections and risk factors associated

In a recent study in Infectious Diseases, it was shown that identification of the correct site of infection is important in the management of severe infections [1]. As bacteraemic urinary tract infection (UTI) can mimic respiratory infection and, especially in elderly patients, dyspnoea may overshadow urinary symptoms, the initial diagnosis of the site of infection can be challenging [2]. This atypical presentation of upper UTI is probably a consequence of uncontrolled inflammatory response to lipopolysaccharide (LPS), the main virulence factor of Gram-negative bacteria, which triggers monocyte/macrophage activation and promotes T-cell polyclonal activation, resulting in pulmonary injury [3–6]. We retrospectively studied prevalence rate of UTI with respiratory signs (UTIrs) and risk factors associated in patients admitted to Cannes General Hospital over 14 months. Files were reviewed in order to confirm diagnosis of upper UTI, on the basis of at least one of the following items: microbiological documentation, radiological signs of pyelonephritis and acute febrile renal lithiasis. After excluding patients not meeting the inclusion criteria or with abnormal chest imaging, from July 2015 to October 2016, we identified 271 subjects with upper UTI. Mean age was 63 years, 80% were women and only 65% had urinary symptoms. Renal failure at admission (45%), heart disease (41%) and respiratory insufficiency (7%) were main comorbid conditions. Prevalence rate of UTIrs was 15% and, compared to subjects with UTI without respiratory signs, the UTIrs group had higher statistically significant length of hospital stay and death rates. Among pathogens responsible for UTI, Enterobacteriaceae were the most frequent bacteria

Evaluation of Three Brief Screening Tests for Older Patients with Mild HIVAssociated Neurocognitive Disorders in the cART Era

Introduction: Prevalence of HIV-associated neurocognitive disorders (HAND) in the era of antiretrovirals is still high, the majority of clinical phenotypes being represented by mild forms of impairment. Therefore, adequate screening strategies are needed. We compared performance of three brief screening tools for detecting mild forms of HAND in an elderly population. Methods: Randomly selected patient over 50 years performed a complete neuropsychological evaluation, considered as the gold standard and three brief screening tools: International HIV Dementia Scale (IHDS), Montreal cognitive assessment (MOCA) and a French battery named FIMF and composed by: Frontal ability battery, Isaac set test, Memory span test and Five words test. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of screening tools and possible combinations were analyzed. Results: 49 patients were tested (mean age 57, 78% men, nadir CD4 252, CD4 cell count at inclusion 616, 86% with viral load below 50 copies/ml, 18% HCV co-infected, 18% previous illicit drug use, 16% with AIDS). HAND was diagnosed in 30/49 patients (90% asymptomatic neurocognitive disorder, 10% mild neurocognitive disorder). In detecting HAND, the FIMF battery showed the best performances (sensitivity 87%, specificity 47%, PPV 72%, NPV 69%). Combination of MOCA, Isaac set test and Memory span test showed sensitivity 90%, specificity 47%, PPV 73%, NPV 75%, with a combined cut-off value of 78 for discriminating HAND. Conclusion: The combination of MOCA, Isaac set test and Memory span test showed better performances than the majority of screening tools available for detecting mild forms of HAND and should therefore be considered as a useful option for identifying patients requiring neuropsychological evaluation.

A case of uveitis due to Rickettsia conorii infection in Southeastern France.

We describe a case of skin rash and bilateral uveitis secondary to Rickettsia conorii infection. A 60-year-old female patient, living in the rural hinterland of Cannes, was referred to our hospital in mid-August 2012 for skin rash, fever, and arthromyalgia. Blood tests showed increased inflammatory markers, hepatic cytolysis and anicteric cholestasis. Ophthalmic examination revealed bilateral papillitis and focal chorio-retinitis. Fluoroscopic angiography demonstrated early hypofluorescence, with a few arteriolar occlusions, and subsequent hyperfluorescence and focal vasculitis. R. conorii antibodies were identified by immunofluorescence antibody test. Investigation of other infective agents and the immunological panel were negative. A 2-week course of doxycycline 200 mg/day was prescribed, and fever rapidly subsided, the skin rash resolved and vision improved. Ophthalmic examination a month and a half later showed almost all retinal lesions had disappeared and inflammation markers had returned to normal.