Positive Impact of [18F]FDG-PET/CT on Mortality in Patients With Staphylococcus aureus Bacteremia Explained by Immortal Time Bias.

BACKGROUND: Several studies have suggested that in patients with Staphylococcus aureus bacteremia (SAB) [18F] fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG-PET/CT) improves outcome. However, these studies often ignored possible immortal time bias. METHODS: Prospective multicenter cohort study in 2 university and 5 non-university hospitals, including all patients with SAB. [18F]FDG-PET/CT was performed on clinical indication as part of usual care. Primary outcome was 90-day all-cause mortality. Effect of [18F]FDG-PET/CT was modeled with a Cox proportional hazards model using [18F]FDG-PET/CT as a time-varying variable and corrected for confounders for mortality (age, Charlson score, positive follow-up cultures, septic shock, and endocarditis). Secondary outcome was 90-day infection-related mortality (assessed by adjudication committee) using the same analysis. In a subgroup-analysis, we determined the effect of [18F]FDG-PET/CT in patients with high risk of metastatic infection. RESULTS: Of 476 patients, 178 (37%) underwent [18F]FDG-PET/CT. Day-90 all-cause mortality was 31% (147 patients), and infection-related mortality was 17% (83 patients). The confounder adjusted hazard ratio (aHR) for all-cause mortality was 0.50 (95% confidence interval [CI]: .34-.74) in patients that underwent [18F]FDG-PET/CT. Adjustment for immortal time bias changed the aHR to 1.00 (95% CI .68-1.48). Likewise, after correction for immortal time bias, [18F]FDG-PET/CT had no effect on infection-related mortality (cause specific aHR 1.30 [95% CI .77-2.21]), on all-cause mortality in patients with high-risk SAB (aHR 1.07 (95% CI .63-1.83) or on infection-related mortality in high-risk SAB (aHR for 1.24 [95% CI .67-2.28]). CONCLUSIONS: After adjustment for immortal time bias [18F]FDG-PET/CT was not associated with day-90 all-cause or infection-related mortality in patients with SAB.

Autopsy Study Defines Composition and Dynamics of the HIV-1 Reservoir after Allogeneic Hematopoietic Stem Cell Transplantation with CCR5Δ32/Δ32 Donor Cells.

Allo-HSCT with CCR5Δ32/Δ32 donor cells is the only curative HIV-1 intervention. We investigated the impact of allo-HSCT on the viral reservoir in PBMCs and post-mortem tissue in two patients. IciS-05 and IciS-11 both received a CCR5Δ32/Δ32 allo-HSCT. Before allo-HSCT, ultrasensitive HIV-1 RNA quantification; HIV-1-DNA quantification; co-receptor tropism analysis; deep-sequencing and viral characterization in PBMCs and bone marrow; and post-allo-HSCT, ultrasensitive RNA and HIV-1-DNA quantification were performed. Proviral quantification, deep sequencing, and viral characterization were done in post-mortem tissue samples. Both patients harbored subtype B CCR5-tropic HIV-1 as determined genotypically and functionally by virus culture. Pre-allo-HSCT, HIV-1-DNA could be detected in both patients in bone marrow, PBMCs, and T-cell subsets. Chimerism correlated with detectable HIV-1-DNA LTR copies in cells and tissues. Post-mortem analysis of IciS-05 revealed proviral DNA in all tissue biopsies, but not in PBMCs. In patient IciS-11, who was transplanted twice, no HIV-1-DNA could be detected in PBMCs at the time of death, whereas HIV-1-DNA was detectable in the lymph node. In conclusion, shortly after CCR5Δ32/Δ32, allo-HSCT HIV-1-DNA became undetectable in PBMCs. However, HIV-1-DNA variants identical to those present before transplantation persisted in post-mortem-obtained tissues, indicating that these tissues play an important role as viral reservoirs.

Incidence of invasive pneumococcal disease in immunocompromised patients: A systematic review and meta-analysis.

BACKGROUND: Invasive pneumococcal disease (IPD) is associated with high morbidity and mortality, with immunocompromised patients (ICPs) at particular risk. Therefore, guidelines recommend pneumococcal vaccination for these patients. However, guidelines are scarcely underpinned with references to incidence studies of IPD in this population. This, potentially results in unawareness of the importance of vaccination and low vaccination rates. The objective of this systematic review and meta-analysis was to assess the incidence of IPD in ICPs. METHODS: We systematically searched PubMed and Embase to identify studies in English published before December 6th, 2017 that included terms related to 'incidence', 'rate', 'pneumococcal', 'pneumoniae', 'meningitis', 'septicemia', or 'bacteremia'. We focused on patients with HIV, transplantation and chronic inflammatory diseases. RESULTS: We included 45 studies in the systematic review reporting an incidence or rate of IPD, defined as isolation of Streptococcus pneumoniae from a normally sterile site. Random effects meta-analysis of 38 studies showed a pooled IPD incidence of 331/100,000 person years in patients with HIV in the late-antiretroviral treatment era in non-African countries, and 318/100,000 in African countries; 696 and 812/100,000 in patients who underwent an autologous or allogeneic stem cell transplantation, respectively; 465/100,000 in patients with a solid organ transplantation; and 65/100,000 in patients with chronic inflammatory diseases. In healthy control cohorts, the pooled incidence was 10/100,000. DISCUSSION: ICPs are at increased risk of contracting IPD, especially those with HIV, and those who underwent transplantation. Based on our findings, we recommend pneumococcal vaccination in immunocompromised patients. PROSPERO REGISTRATION: ID: CRD42016048438.

Characterization of Hepatitis C Virus (HCV) Envelope Diversification from Acute to Chronic Infection within a Sexually Transmitted HCV Cluster by Using Single-Molecule, Real-Time Sequencing.

In contrast to other available next-generation sequencing platforms, PacBio single-molecule, real-time (SMRT) sequencing has the advantage of generating long reads albeit with a relatively higher error rate in unprocessed data. Using this platform, we longitudinally sampled and sequenced the hepatitis C virus (HCV) envelope genome region (1,680 nucleotides [nt]) from individuals belonging to a cluster of sexually transmitted cases. All five subjects were coinfected with HIV-1 and a closely related strain of HCV genotype 4d. In total, 50 samples were analyzed by using SMRT sequencing. By using 7 passes of circular consensus sequencing, the error rate was reduced to 0.37%, and the median number of sequences was 612 per sample. A further reduction of insertions was achieved by alignment against a sample-specific reference sequence. However, in vitro recombination during PCR amplification could not be excluded. Phylogenetic analysis supported close relationships among HCV sequences from the four male subjects and subsequent transmission from one subject to his female partner. Transmission was characterized by a strong genetic bottleneck. Viral genetic diversity was low during acute infection and increased upon progression to chronicity but subsequently fluctuated during chronic infection, caused by the alternate detection of distinct coexisting lineages. SMRT sequencing combines long reads with sufficient depth for many phylogenetic analyses and can therefore provide insights into within-host HCV evolutionary dynamics without the need for haplotype reconstruction using statistical algorithms.IMPORTANCE Next-generation sequencing has revolutionized the study of genetically variable RNA virus populations, but for phylogenetic and evolutionary analyses, longer sequences than those generated by most available platforms, while minimizing the intrinsic error rate, are desired. Here, we demonstrate for the first time that PacBio SMRT sequencing technology can be used to generate full-length HCV envelope sequences at the single-molecule level, providing a data set with large sequencing depth for the characterization of intrahost viral dynamics. The selection of consensus reads derived from at least 7 full circular consensus sequencing rounds significantly reduced the intrinsic high error rate of this method. We used this method to genetically characterize a unique transmission cluster of sexually transmitted HCV infections, providing insight into the distinct evolutionary pathways in each patient over time and identifying the transmission-associated genetic bottleneck as well as fluctuations in viral genetic diversity over time, accompanied by dynamic shifts in viral subpopulations.

Difference in Aortic Stiffness Between Treated Middle-Aged HIV Type 1-Infected and Uninfected Individuals Largely Explained by Traditional Cardiovascular Risk Factors, With an Additional Contribution of Prior Advanced Immunodeficiency.

BACKGROUND: Patients with HIV, even with suppressed viremia on combination antiretroviral therapy, are at increased risk for cardiovascular disease. The underlying pathophysiology remains to be clarified. Aortic stiffness, known to be associated with cardiovascular disease in the general population, was investigated in a cohort of HIV type 1 (HIV 1)-infected and similar but uninfected individuals. METHODS: Aortic stiffness was assessed by measuring pulse wave velocity (PWV) with an Arteriograph. Five hundred seven HIV-uninfected and 566 HIV 1-infected individuals, predominantly with suppressed viremia on combination antiretroviral therapy, aged ≥45 years, participating in the ongoing AGEhIV Cohort Study were included in the analysis. Multivariable linear regression was used to investigate whether HIV was independently associated with aortic stiffness, adjusting for traditional cardiovascular risk factors. RESULTS: Study groups were comparable in demographics; smoking and hypertension were more prevalent in HIV-infected participants. PWV was higher in the HIV-infected group (7.9 vs. 7.7 m/s, P = 0.004). After adjustment for mean arterial pressure, age, gender, and smoking, HIV status was not significantly associated with aortic stiffness. In HIV-infected participants, having a nadir CD4 T-cell count ≤100 cells per cubic millimeter was independently associated with a higher PWV. CONCLUSIONS: The increased aortic stiffness in HIV-infected participants was largely explained by a higher prevalence of traditional cardiovascular risk factors, particularly smoking. Although HIV itself was not independently associated with higher aortic stiffness, a prior greater degree of immunodeficiency was. This suggests a detrimental effect of immunodeficiency on the aortic wall, possibly mediated by inflammation.

Genetic characterization of multiple hepatitis C virus infections following acute infection in HIV-infected men who have sex with men.

OBJECTIVE: High rates of hepatitis C virus (HCV) reinfections among HIV-infected men who have sex with men (MSM) following clearance of a primary infection suggest absence of protective immunity. Here, we investigated the incidence of HCV super and reinfections in 85 HIV-infected MSM with incident HCV infection. DESIGN AND METHODS: Serial sequencing of a fragment of NS5B and the HCV envelope was used to longitudinally characterize the virus. If the primary genotype was still present at the most recent viremic time point, as indicated by the NS5B sequence analysis, serial envelope 2/hypervariable region 1 (E2/HRV1) sequence analysis was performed to distinguish a new infection with the same genotype (clade switch) from intrahost evolution. Incidence rate and cumulative incidence of secondary infections were estimated, and the effect of the primary genotype (1a versus non1) on the risk of acquiring a second infection with the same genotype was determined using Cox proportional-hazards analysis. RESULTS: Among 85 patients with a median follow-up of 4.8 years, incidence rate of secondary infections was 5.39 cases/100 person-years (95% confidence interval 3.34-8.26). Cumulative incidence of genotype switches was markedly higher than the cumulative incidence of clade switches (26.7 versus 4.8% at 5 years, respectively). In patients with HCV-1a as primary infection, the risk for acquiring another HCV-1a infection was reduced compared to those with a primary non-HCV-1a subsequently acquiring HCV-1a (hazard ratio 0.25, 95% confidence interval 0.07-0.93). CONCLUSION: Risk of acquiring a secondary infection with the primary genotype was strikingly reduced compared with the risk of acquiring a secondary infection with a different genotype.

[Osteonecrosis as late complication in HIV-infected patients]. / Osteonecrose als late complicatie bij hiv-geïnfecteerde patiënten.

Osteonecrosis of the femoral head was diagnosed in a 22-year-old woman and a 46-year-old man, both with HIV infection . Both had groin pain and impaired mobility. Conservative treatment did not relieve the pain. Both patients underwent a surgical procedure, i.e. core decompression and total hip replacement. In HIV-infected patients, osteonecrosis, i.e. avascular necrosis is an increasingly common problem in view of current longer life expectancy. The incidence of osteonecrosis is higher in HIV-infected patients than in the general population. Osteonecrosis should be included in differential diagnosis of groin or hip pain in HIV-positive patients. This may enable more rapid diagnosis and reduce the need for surgery.

Health-related quality of life and posttraumatic stress disorder among survivors of left-sided native valve endocarditis.

BACKGROUND: The long-term prognosis of endocarditis is described primarily in relation to clinical outcome measures-for example, such complications as cerebrovascular accident, cardiac failure, need for cardiac surgery, relapse rate, and mortality. To our knowledge, to date, no studies have examined the health-related quality of life and the prevalence of long-term persistence of physical symptoms for survivors of left-sided native valve endocarditis. METHODS: We conducted a prospective follow-up study of patients treated for left-sided native valve endocarditis from 1 November 2000 through 31 October 2003 in 23 hospitals in the Netherlands. Of 86 patients eligible to participate, 55 completed questionnaires administered 3 m and 12 m after discharge; an additional 12 patients completed questionnaires 12 m after discharge only, making a total of 67 patients in our study. Persistence of symptoms and employment status were recorded. The health-related quality of life was measured by using the Dutch version of the Medical Outcomes Study Short Form 36-item health survey and the Posttraumatic Stress Disorder questionnaire. RESULTS: Three months after the end of antimicrobial treatment, 41 (75%) of 55 patients still had physical symptoms. Twelve months after the end of antimicrobial treatment, 36 (54%) of 67 patients still had physical symptoms. Before the episode of endocarditis, 30 (81%) of 37 patients aged < or =60 years were employed and working. At 3 m follow-up, 16 (52%) of 31 patients returned to work, and at 12 m follow-up, 24 (65%) of 37 patients were working. One year after discharge, the health-related quality of life was impaired in 5 of 8 dimensions, compared with age-adjusted standard values, and 7 (11%) of 64 patients suffered from posttraumatic stress disorder. CONCLUSIONS: A year after discharge, most survivors of left-sided native valve endocarditis still had persisting symptoms and a seriously diminished quality of life, and 11% of patients suffered from posttraumatic stress disorder.

High incidence of asymptomatic syphilis in HIV-infected MSM justifies routine screening.

BACKGROUND: Recently, the incidence of syphilis has risen, mainly among men having sex with men (MSM), many of whom are coinfected with HIV. Current guidelines recommend at least yearly syphilis testing in this group. In this study, we assessed the yield of routine syphilis screening in outpatient HIV-patients. METHODS: From March through June 2003, syphilis serology was routinely performed in HIV-infected patients visiting our outpatient clinic. Serology was repeated six months later. Positive test results of the first episode were compared to historical test results (retrospective analysis). Test results of the second episode were compared to test results from the first episode (prospective analysis). Case records of all patients with a new infection were reviewed for symptomatic disease or testing because of syphilis contacts, versus asymptomatic disease. RESULTS: In the retrospective analysis, 1,105 patients were included. In 68 patients, 81 syphilis infections were identified, of which 33% asymptomatic. 77/81 infections were acquired between 2000 and 2003, resulting in a total incidence of 2.7/100 person years (PY) of follow-up, and 0.9/100 PY for asymptomatic disease. In MSM, the incidence rate was 4.6/100 and 1.5/100 PY respectively. In the prospective analysis, 1,010 patients were included. Seventeen patients, all MSM, had a new or recurrent syphilis infection, of whom 4 asymptomatic, accounting for a total event rate of 3.5/100 PY. In MSM, the event rate was 6.2/100 PY, with an incidence of asymptomatic disease of 1.4/100 PY. CONCLUSION: Routine screening for syphilis identifies significant numbers of asymptomatic syphilis infection in HIV-infected MSM.

Current features of infective endocarditis in elderly patients: results of the International Collaboration on Endocarditis Prospective Cohort Study.

BACKGROUND: Elderly patients are emerging as a population at high risk for infective endocarditis (IE). However, adequately sized prospective studies on the features of IE in elderly patients are lacking. METHODS: In this multinational, prospective, observational cohort study within the International Collaboration on Endocarditis, 2759 consecutive patients were enrolled from June 15, 2000, to December 1, 2005; 1056 patients with IE 65 years or older were compared with 1703 patients younger than 65 years. Risk factors, predisposing conditions, origin, clinical features, course, and outcome of IE were comprehensively analyzed. RESULTS: Elderly patients reported more frequently a hospitalization or an invasive procedure before IE onset. Diabetes mellitus and genitourinary and gastrointestinal cancer were the major predisposing conditions. Blood culture yield was higher among elderly patients with IE. The leading causative organism was Staphylococcus aureus, with a higher rate of methicillin resistance. Streptococcus bovis and enterococci were also significantly more prevalent. The clinical presentation of elderly patients with IE was remarkable for lower rates of embolism, immune-mediated phenomena, or septic complications. At both echocardiography and surgery, fewer vegetations and more abscesses were found, and the gain in the diagnostic yield of transesophageal echocardiography was significantly larger. Significantly fewer elderly patients underwent cardiac surgery (38.9% vs 53.5%; P < .001). Elderly patients with IE showed a higher rate of in-hospital death (24.9% vs 12.8%; P < .001), and age older than 65 years was an independent predictor of mortality. CONCLUSIONS: In this large prospective study, increasing age emerges as a major determinant of the clinical characteristics of IE. Lower rates of surgical treatment and high mortality are the most prominent features of elderly patients with IE. Efforts should be made to prevent health care-associated acquisition and improve outcomes in this major subgroup of patients with IE.

Prognostic value of serial C-reactive protein measurements in left-sided native valve endocarditis.

BACKGROUND: The clinical course of left-sided native valve infective endocarditis varies from uncomplicated disease to fulminant infection. Although several factors are known to affect clinical outcome, it is difficult to predict morbidity and mortality in individual patients. The objective of this study was to determine the value of serial C-reactive protein (CRP) measurements as a predictor of clinical outcome. METHODS: One hundred twenty-three consecutive patients who fulfilled the Duke criteria for definite left-sided native valve infective endocarditis were prospectively enrolled. Poor outcome was defined as serious infectious complications or death. Patients were followed up for 12 weeks after the end of antimicrobial therapy. Multivariate analysis was used to examine the relative importance of the CRP level as a predictor of poor outcome after adjusting for age, abscess, multivalvular involvement, and Staphylococcus aureus infection. RESULTS: After 1 week of therapy, the adjusted odds ratio for poor outcome was 10.3 (95% confidence interval, 2.2-49.4) for patients with CRP levels in the highest tertile (>122 mg/L [to convert to nanomoles per liter, multiply by 9.524]) vs the lowest tertile (1-69 mg/L). A low percentage decline during the first week of treatment was statistically significantly associated with a higher risk of poor outcome (logistic regression coefficient, 1.1; P = .009). At no point in time did CRP level predict the need for cardiac surgery. CONCLUSION: High CRP level after 1 week of treatment and a slow percentage decline in CRP level during the first week of treatment are indicators of poor clinical outcome.

Post-exposure prophylaxis.

The mean risk of acquiring HIV after an occupational exposure, injecting drug use or sexual exposure varies from < 0.1 to 3%. A high plasma HIV-RNA of the source increases the risk of each of the exposures. Other factors, such as the volume of the inoculum involved to which the individual was exposed, other sexually transmitted diseases and ruptures of mucous membranes are associated with a higher risk of HIV transmission. Based on the calculated risk, post-exposure prophylaxis (PEP) should be recommended. In the Netherlands, prescription of PEP in the occupational setting is a standard procedure and has proved to be feasible. This was associated with a high percentage (62%) of mild and reversible toxicity and a small percentage (2%) of serious adverse events related to antiretroviral drugs, i.e. nephrolithiasis (due to indinavir) and toxic hepatitis (due to nevirapine). In The Netherlands so far no HIV-seroconversions have been recorded after an occupational accident.