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Infections with hypervirulent Klebsiella pneumoniae (hvKp) commonly presents with primary liver infection, bacteremia, and metastatic abscesses. Here, we present 2 cases of severe community-acquired pulmonary infections by hvKp in patients in the Netherlands without recent travel history. Both bacterial isolates are closely related to an archetype ST23 hvKp reference isolate. Based on these findings, surveillance programs on hvKp may consider to include isolates from community-acquired pneumonia by K. pneumoniae.

Infections with hypervirulent Klebsiella pneumoniae (hvKp) commonly presents with primary liver infection, bacteremia, and metastatic abscesses. Here, we present 2 cases of severe community-acquired pulmonary infections by hvKp in patients in the Netherlands without recent travel history. Both bacterial isolates are closely related to an archetype ST23 hvKp reference isolate. Based on these findings, surveillance programs on hvKp may consider to include isolates from community-acquired pneumonia by K. pneumoniae.

Background Invasive pulmonary aspergillosis typically occurs in an immunocompromised host. For almost a century, influenza has been known to set up for bacterial superinfections, but recently patients with severe influenza were also reported to develop invasive pulmonary aspergillosis. We aimed to measure the incidence of invasive pulmonary aspergillosis over several seasons in patients with influenza pneumonia in the intensive care unit (ICU) and to assess whether influenza was an independent risk factor for invasive pulmonary aspergillosis. Methods We did a retrospective multicentre cohort study. Data were collected from adult patients with severe influenza admitted to seven ICUs across Belgium and The Netherlands during seven influenza seasons. Patients were older than 18 years, were admitted to the ICU for more than 24 h with acute respiratory failure, had pulmonary infiltrates on imaging, and a confirmed influenza infection based on a positive airway PCR test (influenza cohort). We used logistic regression analyses to determine if influenza was independently associated with invasive pulmonary aspergillosis in non-immunocompromised (ie, no European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group [EORTC/MSG] host factor) influenza-positive patients (influenza case group) compared with nonimmunocompromised patients with severe community-acquired pneumonia who had a negative airway influenza PCR test (control group). Findings Data were collected from patients admitted to the ICU between Jan 1, 2009, and June 30, 2016. Invasive pulmonary aspergillosis was diagnosed in 83 (19%) of 432 patients admitted with influenza (influenza cohort), a median of 3 days after admission to the ICU. The incidence was similar for influenza A and B. For patients with influenza who were immunocompromised, incidence of invasive pulmonary aspergillosis was as high as 32% (38 of 117 patients), whereas in the non-immunocompromised influenza case group, incidence was 14% (45 of 315 patients). Conversely, only 16 (5%) of 315 patients in the control group developed invasive pulmonary aspergillosis. The 90-day mortality was 51% in patients in the influenza cohort with invasive pulmonary aspergillosis and 28% in the influenza cohort without invasive pulmonary aspergillosis (p=0.0001). In this study, influenza was found to be independently associated with invasive pulmonary aspergillosis (adjusted odds ratio 5.19; 95% CI 2.63-10.26; p

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To investigate the incidence and risk factors of immune reconstitution inflammatory syndrome (IRIS) associated with toxoplasmic encephalitis (TE) in patients starting combination antiretroviral therapy (cART). A historical multicenter cohort study. We included all HIV-infected patients diagnosed with toxoplasmic encephalitis in six Dutch hospitals between 1996 and 2016. Diagnosis of TE-IRIS was made using predefined IRIS criteria. We distinguished paradoxical TE-IRIS (worsening of underlying treated infection) from unmasking TE-IRIS (unmasking of subclinical infection after start of cART). We compared CD4 cell count, plasma viral load and timing of cART initiation between patients with and without paradoxical TE-IRIS. A total of 211 toxoplasmic encephalitis cases were included. Among 143 cases at risk for paradoxical TE-IRIS, we identified five cases of paradoxical TE-IRIS (3.5%). In six other cases, we could not differentiate paradoxical TE-IRIS from recurrence of disease due to inadequate secondary Toxoplasma prophylaxis. There was no difference in time between start of toxoplasmic encephalitis treatment and cART initiation for patients who did or did not develop paradoxical TE-IRIS (P = 0.50). Within the group of 2228 patients who started cART while having a CD4 cell count below 200 × 10 cells/l and receiving adequate primary prophylaxis, we identified eight cases of unmasking TE-IRIS (0.36%). Unmasking TE-IRIS could not be differentiated from a newly occurring toxoplasmic encephalitis in six other patients, as they were not receiving adequate primary prophylaxis against Toxoplasma. Unmasking TE-IRIS was rare in this cohort, whereas paradoxical TE-IRIS did occur more often. We found no relationship between the timing of cART initiation and the occurrence of paradoxical TE-IRIS

Contains fulltext : 206779.pdf (Publisher’s version ) (Open Access) BACKGROUND: The objective of this study was to assess the cumulative incidence of invasive candidiasis (IC) in intensive care units (ICUs) in Europe. METHODS: A multinational, multicenter, retrospective study was conducted in 23 ICUs in 9 European countries, representing the first phase of the candidemia/intra-abdominal candidiasis in European ICU project (EUCANDICU). RESULTS: During the study period, 570 episodes of ICU-acquired IC were observed, with a cumulative incidence of 7.07 episodes per 1000 ICU admissions, with important between-center variability. Separated, non-mutually exclusive cumulative incidences of candidemia and IAC were 5.52 and 1.84 episodes per 1000 ICU admissions, respectively. Crude 30-day mortality was 42%. Age (odds ratio [OR] 1.04 per year, 95% CI 1.02-1.06, p < 0.001), severe hepatic failure (OR 3.25, 95% 1.31-8.08, p 0.011), SOFA score at the onset of IC (OR 1.11 per point, 95% CI 1.04-1.17, p 0.001), and septic shock (OR 2.12, 95% CI 1.24-3.63, p 0.006) were associated with increased 30-day mortality in a secondary, exploratory analysis. CONCLUSIONS: The cumulative incidence of IC in 23 European ICUs was 7.07 episodes per 1000 ICU admissions. Future in-depth analyses will allow explaining part of the observed between-center variability, with the ultimate aim of helping to improve local infection control and antifungal stewardship projects and interventions.

BACKGROUND: Progression of liver-related disease is accelerated in individuals coinfected with HIV and hepatitis C virus (HCV). Because the life expectancy of HIV-infected drug users (DUs) improved after the widespread use of highly active antiretroviral therapy (HAART), HCV-related death is likely to become more important. To disentangle the effects of HCV and HIV, we compared the overall and cause-specific mortality between HCV/HIV-infected DUs and HCV-infected DUs and DUs without HCV or HIV, followed up between 1985 and 2006. METHODS: A total of 1295 participants in the Amsterdam Cohort Study were included. Cause-specific hazard ratios (CHRs) were estimated for the eras before ( or =1997) within and among serologic groups. RESULTS: The risk of dying decreased for most causes of death > or =1997; this decrease was not the same for the different serologic groups. Among HCV/HIV-coinfected DUs, the risk of hepatitis/liver-related death did not substantially change over time (CHR = 0.87, 95% confidence interval [CI]: 0.21 to 3.58), whereas the risk of AIDS-related mortality decreased. Compared with DUs solely infected with HCV, HCV/HIV-coinfected DUs were at increased risk of dying from hepatitis/liver-related disease (CHR = 7.15, 95% CI: 1.98 to 25.8), other natural causes (CHR = 3.09, 95% CI: 1.41 to 6.79), and nonnatural causes (CHR = 2.30, 95% CI: 1.07 to 4.95) in the HAART era. CONCLUSIONS: HCV/HIV-coinfected DUs remain at increased risk of dying from hepatitis/liver-related death in the HAART era compared with HCV-monoinfected DUs. This risk did not change in HCV/HIV-coinfected DUs after HAART was introduced, suggesting that in the HAART era, HIV continues to accelerate HCV disease progression. Efforts should be made to establish effective treatment for HCV infection in HCV/HIV-coinfected individuals

OBJECTIVES: To investigate the impact of harm-reduction programmes on HIV and hepatitis C virus (HCV) incidence among ever-injecting drug users (DU) from the Amsterdam Cohort Studies (ACS). METHODS: The association between use of harm reduction and seroconversion for human immunodeficiency virus (HIV) and/or hepatitis C virus (HCV) was evaluated using Poisson regression. A total of 714 DU were at risk for HIV and/or HCV during follow-up. Harm reduction was measured by combining its two most important components--methadone dose and needle exchange programme (NEP) use--and looking at five categories of participation, ranging from no participation (no methadone in the past 6 months, injecting drug use in the past 6 months and no use of NEP) to full participation (> or = 60 mg methadone/day and no current injecting or > or = 60 mg methadone/day and current injecting but all needles exchanged). RESULTS: Methadone dose or NEP use alone were not associated significantly with HIV or HCV seroconversion. However, with combination of these variables and after correction for possibly confounding variables, we found that full participation in a harm reduction programme (HRP) was associated with a lower risk of HIV and HCV infection in ever-injecting drug users (DU), compared to no participation [incidence rate ratio 0.43 (95% CI 0.21-0.87) and 0.36 (95% CI 0.13-1.03), respectively]. CONCLUSIONS: In conclusion, we found that full participation in HRP was associated with a lower incidence of HCV and HIV infection in ever-injecting DU, indicating that combined prevention measures--but not the use of NEP or methadone alone--might contribute to the reduction of the spread of these infections

Injecting drug users (DU) are at high risk for hepatitis C virus (HCV) and HIV infections. To examine the prevalence and incidence of these infections over a 20-year period (1985-2005), the authors evaluated 1276 DU from the Amsterdam Cohort Studies who had been tested prospectively for HIV infection and retrospectively for HCV infection. To compare HCV and HIV incidences, a smooth trend was assumed for both curves over calendar time. Risk factors for HCV seroconversion were determined using Poisson regression. Among ever-injecting DU, the prevalence of HCV antibodies was 84.5% at study entry, and 30.9% were co-infected with HIV. Their yearly HCV incidence dropped from 27.5/100 person years (PY) in the 1980s to 2/100 PY in recent years. In multivariate analyses, ever-injecting DU who currently injected and borrowed needles were at increased risk of HCV seroconversion (incidence rate ratio 29.9, 95% CI 12.6, 70.9) compared to ever-injecting DU who did not currently inject. The risk of HCV seroconversion decreased over calendar time. The HCV incidence in ever-injecting DU was on average 4.4 times the HIV incidence, a pattern seen over the entire study period. The simultaneous decline of both HCV and HIV incidence probably results from reduced risk behavior at the population level.

Background: Effective screening programs are urgently needed to provide undiagnosed hepatitis C virus (HCV)-infected individuals with therapy. This systematic review of characteristics and outcomes of screening programs for HCV focuses on strategies to identify HCV risk groups hidden in the general population. Methods: We conducted a comprehensive search of MEDLINE and EMBASE databases for articles published between 1991-2010, including studies that screened the general population using either a newly developed (nonintegrated) screening program or one integrated in existing health care facilities. Look-back studies, prevalence studies, and programs targeting high-risk groups in care (e.g., current drug users) were excluded. Results: After reviewing 7052 studies, we identified 67 screening programs: 24 nonintegrated; 41 programs integrated in a variety of health care facilities (e.g., general practitioner); and 2 programs with both integrated and nonintegrated strategies. Together, these programs identified approximately 25,700 HCV-infected individuals. In general, higher HCV prevalence was found in programs in countries with intermediate to high HCV prevalence, in psychiatric clinics, and in programs that used a prescreening selection based on HCV risk factors. Only 6 programs used a comparison group for evaluation purposes, and 1 program used theory about effective promotion for screening. Comparison of the programs and their effectiveness was hampered by lack of reported data on program characteristics, clinical follow-up, and type of diagnostic test. Conclusions: A prescreening selection based on risk factors can increase the efficiency of screening in low-prevalence populations, and we need programs with comparison groups to evaluate effectiveness. Also, program characteristics such as type of diagnostic test, screening uptake, and clinical outcomes should be reported systematically

The largest population of people at risk for HCV-infection is injecting drug users (DU). We hypothesize that recurrent exposure to HCV, by continuing risk behavior, influences the development of an HCV-specific T-cell response. Therefore, we studied the association between repeated exposure to and the height and focus of the HCV-specific T-cell response in HCV antibody-positive injecting DU (n=18) with ongoing risk behavior ('high-risk'), 9 with and 9 without detectable HCV-RNA), and 9 never-injecting DU ('low-risk', HCV-RNA+). Both total HCV-specific T-cell response, as well as the T-cell response against HCV nonstructural proteins, were significantly higher in injecting compared to never-injecting DU. Interestingly, the high-risk HCV-RNA¯ had no measurable CD4(+) T-cell response to Core protein, compared to detectable responses to Core in the HCV-RNA+ group. Thus, both ongoing risk behavior and presence of HCV-RNA affect the HCV-specific T-cell response in both magnitude and specificity, which may have implications for vaccine development.

Background & Aims Most studies of progression of chronic hepatitis C virus (cHCV) infection were conducted in hospital settings and were therefore biased for patients with severe disease. We evaluated the long-term outcomes of hepatitis C virus (HCV) infection among injecting drug users, recruited from outside the hospital setting, and examined the effect of cHCV on mortality after seroconversion. Methods We studied data from 106 seroconverters with a documented or estimated date of HCV seroconversion. Cox proportional hazards analysis was used to determine the effect of HCV persistence, compared with HCV clearance, on survival after HCV seroconversion. The median follow-up time was 14.8 years (interquartile range, 7.8–19.6). Results cHCV infection developed in 71 of the subjects (67%; 95% confidence interval [CI], 57%–76%); 33 subjects died. One HCV-related death was observed 23 years after HCV seroconversion. Most causes of death were non-natural (n = 12) or acquired immune deficiency syndrome–related (n = 8). The effect of cHCV on mortality was nonproportional over time. When survival time was analyzed separately for 0–5 years, >5—10 years, and >10 years after HCV seroconversion, the age-adjusted hazard ratios for cHCV were 0.59 (95% CI, 0.16–2.20), 1.76 (95% CI, 0.36–8.53), and 8.28 (95% CI, 1.10–64.55), respectively, compared with resolved HCV infection. Conclusions cHCV infection does not affect overall mortality in the first decade after seroconversion, compared with individuals who resolve HCV infection; however, during the second decade after infection, individuals with cHCV have an increased risk for all-cause mortality. Mortality from liver-related causes was low but might have been masked by competing mortality.

Background Although hepatitis C virus (HCV) treatment has shown to be effective, uptake of treatment among active drug users is still low. The Drug Users Treatment for Chronic Hepatitis-C project aims to offer active drug users in Amsterdam HCV testing and treatment using a multidisciplinary approach. Methods The study population comprises drug users participating in the Amsterdam Cohort Studies and drug users referred to the Drug Users Treatment for Chronic Hepatitis-C unit. Drug users were offered HCV testing and, if chronically infected, medical and psychiatric screening and HCV treatment. Various specialists collaborated to provide optimal care. We assessed test-uptake and treatment-uptake and outcomes. Results Four hundred and ninety-seven Amsterdam Cohort Studies drug users were offered HCV testing: 449 out of 497 (90%) accepted. HCV antibodies were found in 267 out of 449 (60%): 183 out of 267 (69%) were HCV-viremic and 49 out of 183 (27%) were HIV-co-infected. Of the 134 HCV-monoinfected patients, 102 (76%) initiated additional medical screening and 44 started treatment by 1 July 2009. Sixty-two drug users referred from methadone clinics were also HCV-monoinfected, of whom 14 started treatment by 1 July 2009. In total 58 persons were treated: 16 (27%) with genotype 1 or 4, 42 (72%) with genotype 2 or 3. Eighty-four percent used methadone, 97% used drugs (heroin, cocaine or amphetamine) at least once in the 6 months before treatment, 19% were active injectors. Sixty-two percent used alcohol, 41% had psychiatric disease other than substance abuse. Of the 57 individuals with sufficient follow-up, 37 (65%) achieved sustained virological response. Conclusion In a multidisciplinary setting, HIV-negative drug users with chronic HCV infection can be treated successfully despite active drug or alcohol use and psychiatric diseases. Therefore, access to HCV therapy using an integrated approach should be increased for this population. Eur J Gastroenterol Hepatol 23:23-31 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

Background: Opioid substitution treatment seems to improve adherence to highly active antiretroviral therapy (HAART) in drug users (DU). DU in Amsterdam receive methadone within a harm reduction programme. We hypothesized that not only receiving methadone, but joining this complete comprehensive programme would improve HAART adherence. Methods: Included were 102 HIV-positive DU attending the Amsterdam Cohort Study (ACS), reporting HAART use at multiple visits between 1999 and 2009. Non-adherence was defined as taking less than 95% of medication in the past 6 months (self-reported). Harm reduction intensity (HR) was measured by combining injecting drug use, methadone dosage and needle exchange, in different levels of participation, ranging from no/incomplete HR, complete HR to low or no dependence on HR. We studied the association between non-adherence and harm reduction intensities with logistic regression models adjusted for repeated measurements. Results: Non-adherence was reported in 11.9% of ACS visits. Non-injecting DU with low dependence on HR were less adherent than DU with complete HR (aOR 1.78; CI 95% 1.00-3.16), although there was no overall effect of HR. No difference was demonstrated in adherence between DU with complete HR and incomplete HR. Unsupervised housing (no access to structural support at home) (aOR 2.58; CI 95% 1.40-4.73) and having a steady partner (aOR 0.48; CI 95% 0.24-0.96) were significantly associated with respectively more and less non-adherence. Conclusions: In Amsterdam, still-injecting DU who are exposed to systematic and integrated care, although not practising complete harm reduction, can be just as adherent to HAART as DU who make use of complete harm reduction and non-injecting DU with no dependence on harm reduction. These findings suggest the importance of a systematic and comprehensive support system including supervised housing and social and medical support to increase HAART adherence rates amongst all HIV-infected DU. When such programmes are introduced in settings where injecting drug use is highly prevalent, access to HAART for drug users in these settings can and should be increased. (C) 2011 Elsevier B.V. All rights reserved

Background: Since the association between hepatitis C virus (HCV)-specific T-cell responses both pretreatment and during interferon-a based therapy and viral clearance is unresolved, a combined analysis of distinctive T-cell characteristics (proliferation and interferon-gamma production) is important to clarify this issue. Methods: Peripheral blood mononuclear cells (PBMC) collected in 22 chronic HCV infected patients at pretreatment and at week 4 during pegIFN-alpha/ribavirin therapy, were stimulated with overlapping peptide pools in a [H-3]-thymidine assay, an interferon-gamma-ELISA, and a sensitive 12-day T-cell expansion assay. Results: Compared to the [H-3]-thymidine proliferation and interferon-gamma secretion assays, the 12-day T-cell expansion assay was more sensitive in detecting T-cell responses. No significant association was demonstrated between pre-treatment HCV-specific CD4(+) or CD8(+) T-cell responses and either a sustained virological response (SVR) or a rapid virological response (RVR). However, a skewing of individual responses towards the non-structural antigens was observed. During pegIFN-a/ribavirin therapy, HCV-specific CD4(+) and CD8(+) T-cells declined similarly in both SVR/RVR and non-SVR/non-RVR patients. Conclusion: No correlation was found between the magnitude of pre-treatment HCV-specific T-cell responses and the outcome of pegIFN-a/ribavirin therapy in terms of SVR and RVR. Moreover, the magnitude of HCV-specific T-cell responses declined in all patients early during treatment. (C) 2010 Elsevier B.V. All rights reserved.

Background/Aims:This study investigates the occurrence of HCV reinfection and superinfection among HCV seroconverters participating in the Amsterdam Cohort Studies among drug users from 1985 through 2005. Methods: HCV seroconverters (n = 59) were tested for HCV RNA at five different time points: the last visit before seroconversion (t = -1), the first visit after seroconversion (t = 1), six months after (t = 2) and one year after (t = 3) seroconversion, and the last visit prior to November 2005 (t = 4). If HCV RNA was present, part of the NS5B region was amplified and sequenced. Additional phylogenetic analysis and cloning was performed to establish HCV reinfection and superinfection. Results: Multiple HCV infections were detected in 23/59 (39%) seroconverters; 7 had HCV reinfections, 14 were superinfected, and 2 had reinfection followed by superinfection. At the moment of HCV reinfection, 7/9 seroconverters were HIV-negative: persistent HCV reinfection developed in both HIV-positive cases but also in 4/7 HIV-negative cases. In total, we identified 93 different HCV infections, varying from 1 to 4 infections per seroconverter. Multiple HCV infections were observed in 10/24 seroconverters with spontaneous HCV clearance (11 reinfections, 3 superinfections) and in 13/35 seroconverters without viral clearance (20 superinfections). Conclusions: HCV reinfection and superinfection are common among actively injecting drug users. This might further complicate the development of an effective HCV vaccine. (C) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved