Detection of opsonizing antibodies directed against a recently circulating Bordetella pertussis strain in paired plasma samples from symptomatic and recovered pertussis patients.

Correlates of protection (CoPs) against the highly contagious respiratory disease whooping cough, caused by Bordetella pertussis, remain elusive. Characterizing the antibody response to this pathogen is essential towards identifying potential CoPs. Here, we evaluate levels, avidity and functionality of B. pertussis-specific-antibodies from paired plasma samples derived from symptomatic and recovered pertussis patients, as well as controls. Natural infection is expected to induce protective immunity. IgG levels and avidity to nine B. pertussis antigens were determined using a novel multiplex panel. Furthermore, opsonophagocytosis of a B. pertussis clinical isolate by neutrophils was measured. Findings indicate that following infection, B. pertussis-specific antibody levels of (ex-) pertussis patients waned, while the avidity of antibodies directed against the majority of studied antigens increased. Opsonophagocytosis indices decreased upon recovery, but remained higher than controls. Random forest analysis of all the data revealed that 28% of the opsonophagocytosis index variances could be explained by filamentous hemagglutinin- followed by pertussis toxin-specific antibodies. We propose to further explore which other B. pertussis-specific antibodies can better predict opsonophagocytosis. Moreover, other B. pertussis-specific antibody functions as well as the possible integration of these functions in combination with other immune cell properties should be evaluated towards the identification of CoPs against pertussis

Gender differences in the use of cardiovascular interventions in HIV-positive persons; the D:A:D Study

Peer reviewe

Non-AIDS defining cancers in the D:A:D Study-time trends and predictors of survival : a cohort study

BACKGROUND:Non-AIDS defining cancers (NADC) are an important cause of morbidity and mortality in HIV-positive individuals. Using data from a large international cohort of HIV-positive individuals, we described the incidence of NADC from 2004-2010, and described subsequent mortality and predictors of these.METHODS:Individuals were followed from 1st January 2004/enrolment in study, until the earliest of a new NADC, 1st February 2010, death or six months after the patient's last visit. Incidence rates were estimated for each year of follow-up, overall and stratified by gender, age and mode of HIV acquisition. Cumulative risk of mortality following NADC diagnosis was summarised using Kaplan-Meier methods, with follow-up for these analyses from the date of NADC diagnosis until the patient's death, 1st February 2010 or 6 months after the patient's last visit. Factors associated with mortality following NADC diagnosis were identified using multivariable Cox proportional hazards regression.RESULTS:Over 176,775 person-years (PY), 880 (2.1%) patients developed a new NADC (incidence: 4.98/1000PY [95% confidence interval 4.65, 5.31]). Over a third of these patients (327, 37.2%) had died by 1st February 2010. Time trends for lung cancer, anal cancer and Hodgkin's lymphoma were broadly consistent. Kaplan-Meier cumulative mortality estimates at 1, 3 and 5 years after NADC diagnosis were 28.2% [95% CI 25.1-31.2], 42.0% [38.2-45.8] and 47.3% [42.4-52.2], respectively. Significant predictors of poorer survival after diagnosis of NADC were lung cancer (compared to other cancer types), male gender, non-white ethnicity, and smoking status. Later year of diagnosis and higher CD4 count at NADC diagnosis were associated with improved survival. The incidence of NADC remained stable over the period 2004-2010 in this large observational cohort.CONCLUSIONS:The prognosis after diagnosis of NADC, in particular lung cancer and disseminated cancer, is poor but has improved somewhat over time. Modifiable risk factors, such as smoking and low CD4 counts, were associated with mortality following a diagnosis of NADC

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

Cellular and humoral immunity after infection with B. pertussis : the role of age, antigen and vaccination history

Pertussis (whooping cough), is a bacterial disease of the respiratory tract, caused by the human pathogen Bordetella pertussis. Vaccination against pertussis has dramatically lowered pertussis incidence and mortality rates; however pertussis still occurs. The duration of immunity to B. pertussis after infection is longer than after vaccination, with presently used acellular pertussis (aP) vaccines comparing less favourably than first generation whole-cell pertussis (wP) vaccines. The current upsurge of pertussis in the overall population questions the prevalence and functionality of immunity to B. pertussis throughout age groups. To study B. pertussis specific -humoral and cell mediated- immune responses, elicited by a natural infection, we set up a clinical study called the SKI study (“Specifieke Kinkhoest Immuniteit”). This study, conducted between 2008 and 2012, comprised of ~300 symptomatic (ex-) pertussis cases of all age categories, included at a known time after infection, and ~90 household controls. We aimed to profoundly extend our knowledge on waning immunity to B. pertussis and on the impact that aging and vaccination history may have. In the field of serology, we developed a biexponential decay model to compare several infection-induced immunoglobulin (Ig) levels specific to various B. pertussis antigens (Ptx, FHA, Prn, Fim2/3 and OMV) in all SKI-cases. The decay model revealed that antigen type and age group were major factors determining variation in levels and kinetics of Ig (sub) classes. Vaccination history also played a substantial role, illustrated by poor recognition of antigens by unvaccinated (pre-) elderly and by reversed IgG3/IgG4 ratio’s in responsiveness of wP versus aP primed youngsters. Next, we asked if the prevalence of pertussis reinfections could be estimated based on single point Ig levels to Ptx in ex-symptomatic cases, years after a proven pertussis episode. We showed that an IgG-Ptx based cut-off method and a two-component mixture analysis were both unreliable for reinfection prevalence estimation. Applying a novel two-dimensional profile using both IgG-Ptx and IgA-Ptx data, a more certified reinfection prevalence was obtained, confirming that although reinfections do occur, natural pertussis infection provides (ex) cases with a relatively long period of protection to renewed infection. Our subsequent investigations addressed research questions regarding the levels, decay, specificity, functionality and age- or cohort dependency of B. pertussis specific cellular immune mechanisms, as observed after natural infection. For these studies memory B (Bmem) and T (Tmem) cells were analysed in sub-cohorts of SKI participants. Age was found to affect Bmem and Tmem cell responses differently; levels of specific Bmem cells increased with age while various functions and features of specific Tmem cells were lost with age. Remarkably, youngsters and adults being primed with wP vaccines in infancy showed similar Th1/Th2 cytokine ratio’s in their post-infection responses. An aP pre-school booster (associated with Th2 immunity) in another youngster group, also wP-primed in infancy, enhanced this ratio. The T cell responses from the aP boosted youngsters showed striking resemblances to the adult responses, indicating that both chronological age and/or a totting up of antigen exposure may drive maturation of responses that could lead to T cell exhaustion

Cellular and humoral immunity after infection with B. pertussis : the role of age, antigen and vaccination history

Pertussis (whooping cough), is a bacterial disease of the respiratory tract, caused by the human pathogen Bordetella pertussis. Vaccination against pertussis has dramatically lowered pertussis incidence and mortality rates; however pertussis still occurs. The duration of immunity to B. pertussis after infection is longer than after vaccination, with presently used acellular pertussis (aP) vaccines comparing less favourably than first generation whole-cell pertussis (wP) vaccines. The current upsurge of pertussis in the overall population questions the prevalence and functionality of immunity to B. pertussis throughout age groups. To study B. pertussis specific -humoral and cell mediated- immune responses, elicited by a natural infection, we set up a clinical study called the SKI study (“Specifieke Kinkhoest Immuniteit”). This study, conducted between 2008 and 2012, comprised of ~300 symptomatic (ex-) pertussis cases of all age categories, included at a known time after infection, and ~90 household controls. We aimed to profoundly extend our knowledge on waning immunity to B. pertussis and on the impact that aging and vaccination history may have. In the field of serology, we developed a biexponential decay model to compare several infection-induced immunoglobulin (Ig) levels specific to various B. pertussis antigens (Ptx, FHA, Prn, Fim2/3 and OMV) in all SKI-cases. The decay model revealed that antigen type and age group were major factors determining variation in levels and kinetics of Ig (sub) classes. Vaccination history also played a substantial role, illustrated by poor recognition of antigens by unvaccinated (pre-) elderly and by reversed IgG3/IgG4 ratio’s in responsiveness of wP versus aP primed youngsters. Next, we asked if the prevalence of pertussis reinfections could be estimated based on single point Ig levels to Ptx in ex-symptomatic cases, years after a proven pertussis episode. We showed that an IgG-Ptx based cut-off method and a two-component mixture analysis were both unreliable for reinfection prevalence estimation. Applying a novel two-dimensional profile using both IgG-Ptx and IgA-Ptx data, a more certified reinfection prevalence was obtained, confirming that although reinfections do occur, natural pertussis infection provides (ex) cases with a relatively long period of protection to renewed infection. Our subsequent investigations addressed research questions regarding the levels, decay, specificity, functionality and age- or cohort dependency of B. pertussis specific cellular immune mechanisms, as observed after natural infection. For these studies memory B (Bmem) and T (Tmem) cells were analysed in sub-cohorts of SKI participants. Age was found to affect Bmem and Tmem cell responses differently; levels of specific Bmem cells increased with age while various functions and features of specific Tmem cells were lost with age. Remarkably, youngsters and adults being primed with wP vaccines in infancy showed similar Th1/Th2 cytokine ratio’s in their post-infection responses. An aP pre-school booster (associated with Th2 immunity) in another youngster group, also wP-primed in infancy, enhanced this ratio. The T cell responses from the aP boosted youngsters showed striking resemblances to the adult responses, indicating that both chronological age and/or a totting up of antigen exposure may drive maturation of responses that could lead to T cell exhaustion

Implementing Individually Tailored Prescription of Physical Activity in Routine Clinical Care: Protocol of the Physicians Implement Exercise = Medicine (PIE=M) Development and Implementation Project.

Contains fulltext : 229883.pdf (publisher's version ) (Open Access)BACKGROUND: The prescription of physical activity (PA) in clinical care has been advocated worldwide. This "exercise is medicine" (E=M) concept can be used to prevent, manage, and cure various lifestyle-related chronic diseases. Due to several challenges, E=M is not yet routinely implemented in clinical care. OBJECTIVE: This paper describes the rationale and design of the Physicians Implement Exercise = Medicine (PIE=M) study, which aims to facilitate the implementation of E=M in hospital care. METHODS: PIE=M consists of 3 interrelated work packages. First, levels and determinants of PA in different patient and healthy populations will be investigated using existing cohort data. The current implementation status, facilitators, and barriers of E=M will also be investigated using a mixed-methods approach among clinicians of participating departments from 2 diverse university medical centers (both located in a city, but one serving an urban population and one serving a more rural population). Implementation strategies will be connected to these barriers and facilitators using a systematic implementation mapping approach. Second, a generic E=M tool will be developed that will provide tailored PA prescription and referral. Requirements for this tool will be investigated among clinicians and department managers. The tool will be developed using an iterative design process in which all stakeholders reflect on the design of the E=M tool. Third, we will pilot-implement the set of implementation strategies, including the E=M tool, to test its feasibility in routine care of clinicians in these 2 university medical centers. An extensive learning process evaluation will be performed among clinicians, department managers, lifestyle coaches, and patients using a mixed-methods design based on the RE-AIM framework. RESULTS: This project was approved and funded by the Dutch grant provider ZonMW in April 2018. The project started in September 2018 and continues until December 2020 (depending on the course of the COVID-19 crisis). All data from the first work package have been collected and analyzed and are expected to be published in 2021. Results of the second work package are described. The manuscript is expected to be published in 2021. The third work package is currently being conducted in clinical practice in 4 departments of 2 university medical hospitals among clinicians, lifestyle coaches, hospital managers, and patients. Results are expected to be published in 2021. CONCLUSIONS: The PIE=M project addresses the potential of providing patients with PA advice to prevent and manage chronic disease, improve recovery, and enable healthy ageing by developing E=M implementation strategies, including an E=M tool, in routine clinical care. The PIE=M project will result in a blueprint of implementation strategies, including an E=M screening and referral tool, which aims to improve E=M referral by clinicians to improve patients' health, while minimizing the burden on clinicians