Andrea Gori

Risk of clinical progression among patients with immunological nonresponse despite virological suppression after combination antiretroviral treatment

Background:It is unclear whether lack of immunological response despite viral suppression and relatively preserved CD4+ T-cell count is associated with increased risk of AIDS or severe non-AIDS events. Methods:Patients initiating first combination antiretroviral therapy (cART) were studied from first viral load 80 copies/ml or less up to AIDS, serious non-AIDS events (malignancies, severe infections, acute kidney injury, cardiovascular events, liver decompensation) or death. Follow-up was right censored if viral load was more than 500. Immunological nonresponse (INR) was defined as current CD4+ cell count less than 120% pre-cART. A Poisson regression analysis was used to investigate the association between INR and the outcome. Results:Three thousand, three hundred and seventy-eight patients were followed for a median of 32 months (interquartile range: 15–67). Two hundred and twenty-two events (32 deaths, 39 AIDS-defining events, 48 malignancies, 32 severe infections, 47 acute kidney injuries, 12 cardiovascular events, 12 other nonfatal events) were observed. The rate of clinical events among INR and immunological responders was 4.41 [95% confidence interval (CI) 3.38–5.74] and 1.84 (95% CI 1.58–2.15) per 100 person years of follow-up, respectively, accounting for a crude rate ratio of 2.39 (95% CI 1.77–3.25; P < 0.001). INR remained an independent predictor of clinical progression after adjusting for baseline characteristics, including pre-cART CD4+ cell count (adjusted rate ratio 2.93; 95% CI 2.06–4.16, P < 0.001) or current CD4+ cell count (adjusted rate ratio 1.94; 95% CI 1.39–2.72, P < 0.001). The association did not vary by pre-cART CD4+ cell counts (P for interaction = 0.93) Conclusion:INR are at higher risk of severe clinical events than responders. The association was consistent across different CD4+ cell counts at cART initiation and was only partially explained by current CD4+ cell count. INR could be a marker of immune system malfunctioning, not completely captured by absolute CD4+ cell count.

Imported ciprofloxacin-resistant Neisseria meningitidis.

To the Editor: Emergence and spread of antimicrobial drug resistance in community-acquired infections is a global threat. Resistance of Neisseria meningitidis raises concern because of severity of disease caused by this organism and the need for immediate treatment of infected patients. We report an imported case of meningococcal disease caused by fluoroquinolone-resistant N. meningitidis. The patient, a previously healthy, unvaccinated 43-year-old man who had traveled internationally, was hospitalized because of high fever, neck stiffness, and a diffuse petechial rash. Signs and symptoms were observed 24 hours after he had returned to Italy from a 10-day business trip during February–March 2009, to New Delhi and Chennai in India and a stopover of a few hours in Frankfurt, Germany. Microscopic examination of cerebrospinal fluid showed gram-negative diplococci and culture documented N. meningitidis serogroup A. The strain was characterized as serotype 4,21 subtype P1.9 by using monoclonal antibodies. Multilocus sequence typing performed at the National Reference Laboratory for Invasive Meningococcal Diseases in Rome characterized the strain as sequence type (ST)-4789 and belonging to clonal complex ST-5/subgroup III. Antimicrobial drug susceptibility was determined by using an agar dilution test, and MICs were determined by using an agar disk-diffusion test (Etest; AB Biodisk, Solna, Sweden) and standard techniques. The strain was resistant to ciprofloxacin, levofloxacin, and trimethoprim/sulfamethoxazole and susceptible to penicillin, ampicillin, ceftriaxone, chloramphenicol, rifampin, and azithromycin. MICs for ciprofloxacin, levofloxacin, penicillin, ampicillin, and ceftriaxone were 0.25, 0.25, 0.03, 0.12, and <0.016 mg/L, respectively (Figure). The patient recovered after treatment with ceftriaxone. Figure Antimicrobial drug–susceptibility test, showing resistance to levofloxacin (LEV, lower strip), ciprofloxacin (CIP, upper strip), and nalidixic acid (NA, disk) for the strain of Neisseria meningitidis isolated from the patient. Before results of antimicrobial drug–susceptibility testing were available, 15 adult contacts of the patient received ciprofloxacin as chemoprophylaxis according to public health recommendations in Italy. After positive test results, all contacts were offered repeat chemoprophylaxis with rifampin; 13 of them accepted. A diagnosis of meningitis and results of antibiograms were sent to the patient’s place of employment in India and to the airport manager in Frankfurt. However, we were not able to assess what chemoprophylaxis was given to the patient’s fellow employees and air travel contacts. No secondary cases have been detected so far in Italy. Sporadic cases of infection with N. meningitidis (mainly serogroup B) with reduced susceptibility to ciprofloxacin have been reported in Europe, North and South America, and Australia since 2000 (1–4). Ciprofloxacin-resistant N. meningitidis of serogroup A caused an outbreak of meningococcal meningitis in Delhi, India, in 2005 and a recurrence in 2006 (5). Although the patient reported in our study had no known contact in India with patients who had meningococcal disease, multilocus sequencing typing analysis showed that the isolate had the same sequence type as isolates from the epidemic in India (5,6). We report isolation of an imported, ciprofloxacin-resistant strain of N. meningitidis isolated from a patient with meningococcal disease. During the past 2 years, 182 strains of N. meningitidis have been sent to the Istituto Superiore di Sanita; all were susceptible to ciprofloxacin and MICs ranged from 0.002 mg/L to 0.006 mg/L (National Reference Laboratory for Invasive Meningococcal Diseases, pers. comm.) Serogroup A N. meningitidis accounted for only 1 of these strains; serogroups B and C are the most common groups in Italy. In contrast, group A meningococci are the major cause of meningitis outbreaks worldwide, especially in Africa and Asia. To date, spread of ciprofloxacin resistance in serogroup A appears to be limited to India because a recent report of antimicrobial drug susceptibility of N. meningitidis in the meningitis belt of Africa during 2000–2006 showed no evidence of ciprofloxacin resistance (7). Temporal correlation and epidemiologic features strongly suggest that transmission of N. meningitidis to our patient occurred during his journey to India. Meningococcal disease is rarely imported because onset of symptoms is often rapid and severe. Nonetheless, the enormous increase in global trade and travel and shortening of international travel time may increase the risk for spread of infectious diseases and drug-resistant organisms. In addition, carriage of N. meningitidis in the nasopharynx of otherwise healthy persons can occur. Emergence of fluoroquinolone resistance in some countries raises concerns about current chemoprophylaxis recommendations for meningococcal disease. Ciprofloxacin is widely used for postexposure prophylaxis of close contacts of infected persons because it is simple to use (single oral dose) and lacks toxicity. However, patients and their contacts should be questioned about possible recent travel. When transmission of N. meningitidis is suspected in regions where fluoroquinolone resistance has been found (New Delhi, India, and North Dakota and western Minnesota in the United States), alternative chemoprophylaxis such as rifampin or ceftriaxone should be used. Emergence of autochthonous ciprofloxacin-resistant N. meningitidis is possible in countries where fluoroquinolones are widely used. In vitro drug susceptibility testing is not routinely and uniformly used in all settings because treatment or chemoprophylaxis are usually started before antibiogram results are available. Our case demonstrates that drug susceptibility testing should be encouraged and routinely performed for all isolates. Local and worldwide surveillance for antimicrobial drug–resistant N. meningitidis is crucial for determining antimicrobial drug resistance trends and future recommendations for chemoprophylaxis and treatment.

Cohort Profile: Standardized Management of Antiretroviral Therapy Cohort (MASTER Cohort)

Cohort Profile: Standardized Management of Antiretroviral Therapy Cohort (MASTER Cohort) Carlo Torti, Elena Raffetti,* Francesco Donato, Francesco Castelli, Franco Maggiolo, Gioacchino Angarano, Francesco Mazzotta, Andrea Gori, Laura Sighinolfi, Angelo Pan, Roberto Cauda, Alfredo Scalzini, Eugenia Quiros-Roldan, Paola Nasta, Giampietro Gregis, Simone Benatti, Simona Digiambenedetto, Nicoletta Ladisa, Mariarosaria Giralda, Annalisa Saracino, Filippo Castelnuovo, Massimo Di Pietro, Sergio Lo Caputo, Giuseppe Lapadula, Silvia Costarelli, Silvia Lorenzotti, Nicola Mazzini, Giuseppe Paraninfo, Salvatore Casari, Emanuele Focà, Chiara Pezzoli, Massimiliano Fabbiani, Laura Monno, Piera Pierotti, Claudio Ble, Sebastiano Leone, Maria Concetta Postorino, Chiara Fornabaio, Fabio Zacchi, Alessia Zoncada and Giampiero Carosi Unità di Malattie Infettive e Tropicali, Dipartimento di Scienze Mediche e Chirurgiche, Università Magna Grecia di Catanzaro, Catanzaro, Italia, Unità di Igiene, Epidemiologia e Sanità Pubblica, Università degli Studi di Brescia, Brescia, Italia, Divisione Universitaria di Malattie Infettive Spedali Civili di Brescia-Università degli Studi di Brescia, Brescia, Italia, Malattie Infettive Ospedale Papa Giovanni XXIII, Bergamo, Italia, Clinica di Malattie Infettive Policlinico di Bari, Bari, Italia, Malattie Infettive S.M. Annunziata, Firenze, Italia, Malattie Infettive Ospedale San Gerardo di Monza, Monza, Italia, Malattie Infettive Nuovo Polo Ospedaliero di Cona, Ferrara, Italia, Malattie Infettive Istituti Ospitalieri di Cremona, Cremona, Italia, Clinica di Malattie Infettive Policlinico A. Gemelli-Università Cattolica di Roma, Roma, Italia, Divisione Ospedaliera di Malattie Infettive Spedali Civili, Brescia, Italia and Fondazione Malattie Infettive e Salute Internazionale, Brescia, Italia

Physiological response of the cold-water coral Desmophyllum dianthus to thermal stress and ocean acidification

Rising temperatures and ocean acidification driven by anthropogenic carbon emissions threaten both tropical and temperate corals. However, the synergistic effect of these stressors on coral physiology is still poorly understood, in particular for cold-water corals. This study assessed changes in key physiological parameters (calcification, respiration and ammonium excretion) of the widespread cold-water coral Desmophyllum dianthus maintained for ∼8 months at two temperatures (ambient 12 °C and elevated 15 °C) and two pCO2 conditions (ambient 390 ppm and elevated 750 ppm). At ambient temperatures no change in instantaneous calcification, respiration or ammonium excretion rates was observed at either pCO2 levels. Conversely, elevated temperature (15 °C) significantly reduced calcification rates, and combined elevated temperature and pCO2 significantly reduced respiration rates. Changes in the ratio of respired oxygen to excreted nitrogen (O:N), which provides information on the main sources of energy being metabolized, indicated a shift from mixed use of protein and carbohydrate/lipid as metabolic substrates under control conditions, to less efficient protein-dominated catabolism under both stressors. Overall, this study shows that the physiology of D. dianthus is more sensitive to thermal than pCO2 stress, and that the predicted combination of rising temperatures and ocean acidification in the coming decades may severely impact this cold-water coral species.

Limited Genetic Connectivity between Gorgonian Morphotypes along a Depth Gradient.

Gorgonian species show a high morphological variability in relation to the environment in which they live. In coastal areas, parameters such as temperature, light, currents, and food availability vary significantly with depth, potentially affecting morphology of the colonies and the structure of the populations, as well as their connectivity patterns. In tropical seas, the existence of connectivity between shallow and deep populations supported the hypothesis that the deep coral reefs could potentially act as (reproductive) refugia fostering re-colonization of shallow areas after mortality events. Moreover, this hypothesis is not so clear accepted in temperate seas. Eunicella singularis is one of the most common gorgonian species in Northwestern Mediterranean Sea, playing an important role as ecosystem engineer by providing biomass and complexity to the coralligenous habitats. It has a wide bathymetric distribution ranging from about 10 m to 100 m. Two depth-related morphotypes have been identified, differing in colony morphology, sclerite size and shape, and occurrence of symbiotic algae, but not in mitochondrial DNA haplotypes. In the present study the genetic structure of E. singularis populations along a horizontal and bathymetric gradient was assessed using microsatellites and ITS1 sequences. Restricted gene flow was found at 30–40 m depth between the two Eunicella morphotypes. Conversely, no genetic structuring has been found among shallow water populations within a spatial scale of ten kilometers. The break in gene flow between shallow and deep populations contributes to explain the morphological variability observed at different depths. Moreover, the limited vertical connectivity hinted that the refugia hypothesis does not apply to E. singularis. Re-colonization of shallow water populations, occasionally affected by mass mortality events, should then be mainly fueled by larvae from other shallow water populations.

Heterotrophy promotes the re-establishment of photosynthate translocation in a symbiotic coral after heat stress

Symbiotic scleractinian corals are particularly affected by climate change stress and respond by bleaching (losing their symbiotic dinoflagellate partners). Recently, the energetic status of corals is emerging as a particularly important factor that determines the corals’ vulnerability to heat stress. However, detailed studies of coral energetic that trace the flow of carbon from symbionts to host are still sparse. The present study thus investigates the impact of heat stress on the nutritional interactions between dinoflagellates and coral Stylophora pistillata maintained under auto- and heterotrophy. First, we demonstrated that the percentage of autotrophic carbon retained in the symbionts was significantly higher during heat stress than under non-stressful conditions, in both fed and unfed colonies. This higher photosynthate retention in symbionts translated into lower rates of carbon translocation, which required the coral host to use tissue energy reserves to sustain its respiratory needs. As calcification rates were positively correlated to carbon translocation, a significant decrease in skeletal growth was observed during heat stress. This study also provides evidence that heterotrophic nutrient supply enhances the re-establishment of normal nutritional exchanges between the two symbiotic partners in the coral S. pistillata, but it did not mitigate the effects of temperature stress on coral calcification.

Risk of Severe Non AIDS Events Is Increased among Patients Unable to Increase their CD4+ T-Cell Counts >200+/μl Despite Effective HAART

Background Immunological non-response (INR) despite virological suppression is associated with AIDS-defining events/death (ADE). Little is known about its association with serious non-AIDS-defining events (nADE). Methods Patients highly-active antiretroviral therapy (HAART) with <200 CD4+/μl and achieving HIV-RNA <50 copies/ml within 12 (±3) months were categorized as INR if CD4+ T-cell count at year 1 was <200/μl. Predictors of nADE (malignancies, severe infections, renal failure—ie, estimated glomerular filtration rate <30 ml/min, cardiovascular events and liver decompensation) were assessed using multivariable Cox models. Follow-up was right-censored in case of HAART discontinuation or confirmed HIV-RNA>50. Results 1221 patients were observed for a median of 3 (IQR: 1.3-6.1) years. Pre-HAART CD4+ were 77/μl (IQR: 28-142) and 56% of patients had experienced an ADE. After 1 year, CD4+ increased to 286 (IQR: 197-387), but 26.1% of patients were INR. Thereafter, 86 nADE (30.2% malignancies, 27.9% infectious, 17.4% renal, 17.4% cardiovascular, 7% hepatic) were observed, accounting for an incidence of 1.83 events (95%CI: 1.73-2.61) per 100 PYFU. After adjusting for measurable confounders, INR had a significantly greater risk of nADE (HR 1.65; 95%CI: 1.06-2.56). Older age (per year, HR 1.03; 95%CI: 1.01-1.05), hepatitis C co-infection (HR 2.09; 95%CI: 1.19-3.7), a history of previous nADE (HR 2.16; 95%CI: 1.06-4.4) and the occurrence of ADE during the follow-up (HR 2.2; 95%CI: 1.15-4.21) were other independent predictors of newly diagnosed nADE. Conclusions Patients failing to restore CD4+ to >200 cells/μl run a greater risk of serious nADE, which is intertwined or predicted by AIDS progression. Improved management of this fragile population and innovative therapy able to induce immune-reconstitution are urgently needed. Also, our results strengthen the importance of earlier diagnosis and HAART introduction.

Real-life data on potential drug-drug interactions in patients with chronic hepatitis C viral infection undergoing antiviral therapy with interferon-free DAAs in the PITER Cohort Study

Background There are few real-life data on the potential drug-drug interactions (DDIs) between anti-HCV direct-acting antivirals (DAAs) and the comedications used. Aim To assess the potential DDIs of DAAs in HCV-infected outpatients, according to the severity of liver disease and comedication used in a prospective multicentric study. Methods Data from patients in 15 clinical centers who had started a DAA regimen and were receiving comedications during March 2015 to March 2016 were prospectively evaluated. The DDIs for each regimen and comedication were assigned according to HepC Drug Interactions (www.hep-druginteractions.org). Results Of the 449 patients evaluated, 86 had mild liver disease and 363 had moderate-to-severe disease. The use of a single comedication was more frequent among patients with mild liver disease (p = 0.03), whereas utilization of more than three drugs among those with moderate-to-severe disease (p = 0.05). Of the 142 comedications used in 86 patients with mild disease, 27 (20%) may require dose adjustment/closer monitoring, none was contraindicated. Of the 322 comedications used in 363 patients with moderate-to-severe liver disease, 82 (25%) were classified with potential DDIs that required only monitoring and dose adjustments; 10 (3%) were contraindicated in severe liver disease. In patients with mild liver disease 30% (26/86) used at least one drug with a potential DDI whereas of the 363 patients with moderate-to-severe liver disease, 161 (44%) were at risk for one or more DDI. Conclusions Based on these results, we can estimate that 30–44% of patients undergoing DAA and taking comedications are at risk of a clinically significant DDI. This data indicates the need for increased awareness of potential DDI during DAA therapy, especially in patients with moderate-to-severe liver disease. For several drugs, the recommendation related to the DDI changes from “dose adjustment/closer monitoring”, in mild to moderate liver disease, to “the use is contraindicated” in severe liver disease.

Simplification to a dual regimen with darunavir/ritonavir plus lamivudine or emtricitabine in virologically-suppressed HIV-infected patients.

Journal of Infection - In Press.Proof corrected by the author Available online since mercredi 7 septembre 2016

Infections during extracorporeal membrane oxygenation: epidemiology, risk factors, pathogenesis and prevention

Extracorporeal membrane oxygenation (ECMO) is a life support technique used in patients with respiratory and/or cardiac failure. The ECMO circuit consists of vascular cannulae, a pump and an artificial lung. Infections are among the most common complications associated with ECMO and have a significant impact on the mortality rate. Here we present a narrative literature review regarding the epidemiology, risk factors, pathogenesis and prevention of infectious complications during ECMO support. The prevalence of hospital-acquired infections during ECMO is 10-12% and their occurrence is likely to be more frequent compared with other critically ill patients. Coagulase-negative staphylococci, Candida spp., Enterobacteriaceae and Pseudomonas aeruginosa are the most frequently involved pathogens. A high incidence of ventilator-associated pneumonia was reported (24.4 cases/1000 ECMO days), with a major role unexpectedly played by Enterobacteriaceae. The infectious risk was shown to increase along the duration of the ECMO run, which represents the most important risk factor for the development of infections. Other ECMO-specific factors predisposing to infections include the severity of illness in ECMO patients, the high risk of bacterial translocation from the gut, and ECMO-related impairment of the immune system. Another important issue could be microbial colonisation of catheters, ECMO cannulae and the oxygenator, which is consistent with most commonly observed aetiologies.