Giancarlo Ceccarelli

HIV-associated immune activation: From bench to bedside

HIV infection is associated with a state of chronic, generalized immune activation that has been shown in many studies to be a key predictor of progression to AIDS. Consistent with this model, nonpathogenic SIV infections of natural hosts, such as the sooty mangabeys, are characterized by low levels of immune activation during the chronic phase of infection. The molecular, cellular, and pathophysiological mechanisms underlying the HIV-associated immune activation are complex and still poorly understood. There is, however, growing consensus that both viral and host factors contribute to this phenotype, with emphasis on the role played by the mucosal immune dysfunction (and consequent microbial translocation) as well as the pattern of in vivo-infected CD4(+) T cells. The observation that antiretroviral therapy (ART)-induced suppression of HIV replication does not fully resolve immune activation provided the rationale for a number of exploratory studies of potential immune modulatory treatments to be used in HIV-infected individuals in addition to standard ART. This review provides an update on the causes and consequences of the HIV-associated immune activation, and a summary of the immune modulatory approaches that are currently under clinical investigation.

Successful Ertapenem-Doripenem Combination Treatment of Bacteremic Ventilator-Associated Pneumonia Due to Colistin-Resistant KPC-Producing Klebsiella pneumoniae

Severe infections caused by carbapenemase-producing Klebsiella pneumoniae are becoming a significant problem worldwide and are associated with high morbidity and mortality rates ([1][1][–][2][3][3]). Recently, treatments based on therapies with combinations of colistin, tigecycline, meropenem,

Probiotics Reduce Inflammation in Antiretroviral Treated, HIV-Infected Individuals: Results of the “Probio-HIV” Clinical Trial

Background HIV infection results in damage to the gastrointestinal (GI) tract, microbial translocation and immune activation. These are not completely normalized with combined antiretroviral therapy (cART). Moreover, increate morbidity and mortality of cART-treated HIV-infected individuals is associated with inflammation. Methods In order to enhance GI tract immunity, we recruited and treated 20 HIV-infected humans with cART supplemented with probiotics and followed inflammation and immunological parameters (clinical trial number NCT02164344). 11 HIV seronegative subjects were included as control group. The enumeration of CD4+, CD8+, CD38+ and HLA-DR+ lymphocytes were evaluated on peripheral blood; HIV-RNA levels, sCD14, d-dimer, C-reactive protein (CRP) high sensitivity C-reactive protein (hsCRP), IL-6 and Lipopolysaccharide Binding Protein (LBP) were assayed on plasma. Results We observe that cART does not normalize the levels of immune activation in HIV positive patients anyway inflammation and markers of microbial translocation were significantly reduced with probiotic supplementation. Patients show a clear and statistically significant reduction in the levels of immune activation on CD4 T-lymphocytes, for both markers CD38 and HLA-DR and their simultaneous expression, LBP and hsCRP plasma levels after probiotic diet supplementation settling to values comparable to controls. Conclusions Supplementing cART with probiotics in HIV-infected individuals may improve GI tract immunity and there by mitigate inflammatory sequelae, ultimately improving prognosis. Trial Registration ClinicalTrials.gov NCT02164344

HIV Persistence in the Gut Mucosa of HIV-Infected Subjects Undergoing Antiretroviral Therapy Correlates with Immune Activation and Increased Levels of LPS

We investigated the relationship between viral persistence in the gut, microbial translocation, and T cell activation during chronic HIV infection. Plasma levels of LPS, fraction of circulating CD8+CD38+ T cells, and levels of HIV-DNA in rectosigmoid biopsies and peripheral blood mononuclear cells were determined in 22 HIV-infected individuals and 10 healthy controls. We found that in untreated HIV-infected individuals, HIV-DNA load was higher in the gut mucosa than in the blood. Also, ART-treated patients exhibited lower levels of LPS and CD8+CD38+ T cells than untreated patients, but higher levels than controls. In ART-treated individuals, the level of HIV-DNA in the gut correlated with levels of LPS and fraction of CD8+CD38+ T cells. We concluded that in ART-treated individuals, higher levels of gut-associated HIV-DNA are associated with persistent immune activation and microbial translocation.

The chronic use of beta-blockers and proton pump inhibitors may affect the rate of bacterial infections in cirrhosis

Bacterial infections are among the most common and life‐threatening complications in cirrhosis. Qualitative and quantitative modifications of the gut microbiota, dysfunction of the intestinal barrier and multiple immune defects are factors that contribute to a pathological ‘bacterial translocation’ (BT), leading to a higher susceptibility to infections in cirrhotic patients. Long‐term therapies, commonly adopted in cirrhotic patients, may influence BT and modify the risk of infection in these patients. To investigate the influence of chronic therapies on the prevalence and microbiological characteristics of infections in cirrhosis.

Unusual microorganisms and antimicrobial resistances in a group of Syrian migrants: Sentinel surveillance data from an asylum seekers centre in Italy.

BACKGROUND Three years of civil war in Syria have caused death and increase of communicable diseases. The suffering population has been forced to migrate creating a fertile condition for epidemic spread of infection within the refugee camps. METHODS Forty-eight Syrian migrants, upon their arrival in Italy, were accommodated at the asylum seekers centre of Castelnuovo di Porto. They received a physical examination and were subjected to microbiological surveillance by blood, rectal, pharyngeal and nasal swabs collection and delivering to the Clinical Pathology and Microbiology Laboratory of the University Campus Bio-Medico of Rome. RESULTS All refugees resulted negative for HBV, HCV and HIV infections. In swabs a large number of unusual gram-negative bacteria species were isolated, such as Pseudomonas putida, Pseudomonas monteilii, Pseudomonas fulva, Pseudomonas moselii, Aeromonas veronii, Aeromonas caviae, Aeromonas hydrophila, Acinteobacter guilloviae, Acinteobacter lowffii; Acinetobacter johnsonii; Acinteobacter tjernbergae; Pantoea agglomerans; Pantoea calida. Among isolates, strains resistant to carbapenems, ESBL producers and methicillin resistant were found. CONCLUSIONS The microbiological surveillance performed represents a useful action to understand refugees health status and to trace unusual microorganisms movement even carriers of antimicrobial resistance during migrants traveling.

The spread of multi drug resistant infections is leading to an increase in the empirical antibiotic treatment failure in cirrhosis: a prospective survey.

Background The spread of multi-resistant infections represents a continuously growing problem in cirrhosis, particularly in patients in contact with the healthcare environment. Aim Our prospective study aimed to analyze epidemiology, prevalence and risk factors of multi-resistant infections, as well as the rate of failure of empirical antibiotic therapy in cirrhotic patients. Methods All consecutive cirrhotic patients hospitalized between 2008 and 2013 with a microbiologically-documented infection (MDI) were enrolled. Infections were classified as Community-Acquired (CA), Hospital-Acquired (HA) and Healthcare-Associated (HCA). Bacteria were classified as Multidrug-Resistant (MDR) if resistant to at least three antimicrobial classes, Extensively-Drug-Resistant (XDR) if only sensitive to one/two classes and Pandrug-Resistant (PDR) if resistant to all classes. Results One-hundred-twenty-four infections (15% CA, 52% HA, 33% HCA) were observed in 111 patients. Urinary tract infections, pneumonia and spontaneous bacterial peritonitis were the more frequent. Forty-seven percent of infections were caused by Gram-negative bacteria. Fifty-one percent of the isolates were multi-resistant to antibiotic therapy (76% MDR, 21% XDR, 3% PDR): the use of antibiotic prophylaxis (OR = 8.4; 95%CI = 1.03-76; P = 0,05) and current/recent contact with the healthcare-system (OR = 3.7; 95%CI = 1.05-13; P = 0.04) were selected as independent predictors. The failure of the empirical antibiotic therapy was progressively more frequent according to the degree of resistance. The therapy was inappropriate in the majority of HA and HCA infections. Conclusions Multi-resistant infections are increasing in hospitalized cirrhotic patients. A better knowledge of the epidemiological characteristics is important to improve the efficacy of empirical antibiotic therapy. The use of preventive measures aimed at reducing the spread of multi-resistant bacteria is also essential.

Reconstitution of Intestinal CD4 and Th17 T Cells in Antiretroviral Therapy Suppressed HIV-Infected Subjects: Implication for Residual Immune Activation from the Results of a Clinical Trial

Introduction During HIV infection the severe depletion of intestinal CD4+ T-cells is associated with microbial translocation, systemic immune activation, and disease progression. This study examined intestinal and peripheral CD4+ T-cell subsets reconstitution under combined antiretroviral therapy (cART), and systemic immune activation markers. Methods This longitudinal single-arm pilot study evaluates CD4+ T cells, including Th1 and Th17, in gut and blood and soluble markers for inflammation in HIV-infected individuals before (M0) and after eight (M8) months of cART. From January 2010 to December 2011, 10 HIV-1 naïve patients were screened and 9 enrolled. Blood and gut CD4+ T-cells subsets and cellular immune activation were determined by flow-cytometry and plasma soluble CD14 by ELISA. CD4+ Th17 cells were detected in gut biopsies by immunohistochemistry. Microbial translocation was measured by limulus-amebocyte-lysate assay to detect bacterial lipopolysaccharide (LPS) and PCR Real Time to detect plasma bacterial 16S rDNA. Results Eight months of cART increased intestinal CD4+ and Th17 cells and reduced levels of T-cell activation and proliferation. The magnitude of intestinal CD4+ T-cell reconstitution correlated with the reduction of plasma LPS. Importantly, the magnitude of Th17 cells reconstitution correlated directly with blood CD4+ T-cell recovery. Conclusion Short-term antiretroviral therapy resulted in a significant increase in the levels of total and Th17 CD4+ T-cells in the gut mucosa and in decline of T-cell activation. The observation that pre-treatment levels of CD4+ and of CD8+ T-cell activation are predictors of the magnitude of Th17 cell reconstitution following cART provides further rationale for an early initiation of cART in HIV-infected individuals. Trial Registration ClinicalTrials.gov NCT02097381

An empirical broad spectrum antibiotic therapy in health-care-associated infections improves survival in patients with cirrhosis: A randomized trial

Early diagnosis and appropriate treatment of infections in cirrhosis are crucial because of their high morbidity and mortality. Multidrug‐resistant (MDR) infections are on the increase in health care settings. Health‐care–associated (HCA) infections are still frequently treated as community‐acquired with a detrimental effect on survival. We aimed to prospectively evaluate in a randomized trial the effectiveness of a broad spectrum antibiotic treatment in patients with cirrhosis with HCA infections. Consecutive patients with cirrhosis hospitalized with HCA infections were enrolled. After culture sampling, patients were promptly randomized to receive a standard or a broad spectrum antibiotic treatment (NCT01820026). The primary endpoint was in‐hospital mortality. Efficacy, side effects, and the length of hospitalization were considered. Treatment failure was followed by a change in antibiotic therapy. Ninety‐six patients were randomized and 94 were included. The two groups were similar for demographic, clinical, and microbiological characteristics. The prevalence of MDR pathogens was 40% in the standard versus 46% in the broad spectrum group. In‐hospital mortality showed a substantial reduction in the broad spectrum versus standard group (6% vs. 25%; P = 0.01). In a post‐hoc analysis, reduction of mortality was more evident in patients with sepsis. The broad spectrum showed a lower rate of treatment failure than the standard therapy (18% vs. 51%; P = 0.001). Length of hospitalization was shorter in the broad spectrum (12.3 ± 7 days) versus standard group (18 ± 15 days; P = 0.03). Five patients in each group developed a second infection during hospitalization with a similar prevalence of MDR (50% broad spectrum vs. 60% standard). Conclusions: A broad spectrum antibiotic therapy as empirical treatment in HCA infections improves survival in cirrhosis. This treatment was significantly effective, safe, and cost saving. (Hepatology 2016;63:1632‐1639)

An empirical broad spectrum antibiotic therapy in Healthcare‐Associated infections improves survival in cirrhotics: A randomized trial

Early diagnosis and appropriate treatment of infections in cirrhosis are crucial because of their high morbidity and mortality. Multidrug‐resistant (MDR) infections are on the increase in health care settings. Health‐care–associated (HCA) infections are still frequently treated as community‐acquired with a detrimental effect on survival. We aimed to prospectively evaluate in a randomized trial the effectiveness of a broad spectrum antibiotic treatment in patients with cirrhosis with HCA infections. Consecutive patients with cirrhosis hospitalized with HCA infections were enrolled. After culture sampling, patients were promptly randomized to receive a standard or a broad spectrum antibiotic treatment (NCT01820026). The primary endpoint was in‐hospital mortality. Efficacy, side effects, and the length of hospitalization were considered. Treatment failure was followed by a change in antibiotic therapy. Ninety‐six patients were randomized and 94 were included. The two groups were similar for demographic, clinical, and microbiological characteristics. The prevalence of MDR pathogens was 40% in the standard versus 46% in the broad spectrum group. In‐hospital mortality showed a substantial reduction in the broad spectrum versus standard group (6% vs. 25%; P = 0.01). In a post‐hoc analysis, reduction of mortality was more evident in patients with sepsis. The broad spectrum showed a lower rate of treatment failure than the standard therapy (18% vs. 51%; P = 0.001). Length of hospitalization was shorter in the broad spectrum (12.3 ± 7 days) versus standard group (18 ± 15 days; P = 0.03). Five patients in each group developed a second infection during hospitalization with a similar prevalence of MDR (50% broad spectrum vs. 60% standard). Conclusions: A broad spectrum antibiotic therapy as empirical treatment in HCA infections improves survival in cirrhosis. This treatment was significantly effective, safe, and cost saving. (Hepatology 2016;63:1632‐1639)