Sera from different age cohorts in Belgium show limited cross-neutralization between the mumps vaccine and outbreak strains

ObjectivesMumps used to affect children between 2 and 15 years old. The mumps–measles–rubella (MMR) vaccine is available, with vaccine coverage rate of about 85% after two vaccine doses. Recently new mumps outbreaks have emerged in highly vaccinated populations; the causes for these new outbreaks are yet unknown. We tested if a difference in seroneutralizing capacity against the vaccine and wild-type viruses existed and if waning immunity could be detected.MethodsIn this study, 570 serum samples (age group 2–3 years (n = 96), 8–9 years (n = 95), 13–14 years (n = 94), 18–20 years (n = 96), 24–26 years (n = 92) and 50 + years (n = 97)) in Belgium were tested in the rapid fluorescent foci inhibition test for their neutralizing capacity against the vaccine and wild-type viruses.ResultsNeutralizing antibodies against the vaccine strain were present in 84% (81/97) of the 2–3-year, 74% (70/95) of the 8–9-year, 81% (76/94) of the 13–14-year, 76% (73/96) of the 18–20-year, 67% (62/92) of the 24–26-year and 77% (75/97) of the 50+-year age group serum samples. For all age groups, only about half of these serum samples were also positive for the wild-type virus. The geometric mean titres for the vaccine and wild-type virus for all younger age groups, except for 24–26 years, were significantly different, demonstrating poor in vitro cross-neutralization.ConclusionsA possible contribution of antigenic differences between the genotype A and G mumps virus as well as other immune factors, in addition to lower-than-optimal vaccination coverage and waning immunity, could explain the poor in vitro cross-neutralization and should be further studied.     

‘Test n Treat’ (TnT): a cluster randomized feasibility trial of on-site rapid Chlamydia trachomatis tests and treatment in ethnically diverse,sexually active teenagers attending technical colleges

ObjectivesWe conducted a cluster-randomized feasibility trial of 90-minute Chlamydia trachomatis tests and same day on-site treatment (‘Test n Treat/TnT’) in six technical colleges in London, England, to assess TnT uptake rates; follow-up rates; prevalence of C. trachomatis at baseline and 7 months; time to treatment; acceptability of TnT.MethodsParticipants completed questionnaires and provided genitourinary samples at baseline and 7 months. Participants were informed that baseline samples would not be tested for 7 months and were advised to get screened independently. Colleges were randomly allocated 1:1 to intervention (TnT) or control (no TnT).One month and 4 months post recruitment, participants at intervention colleges were texted invitations for on-site free C. trachomatis tests. A purposive sample of students who did/did not attend for screening were interviewed (n = 26).ResultsFive hundred and nine sexually active students were recruited: median age 17.9 years, 47% male, 50% black ethnicity, 55% reporting two or more sexual partners in the previous year. TnT uptake was 13% (33/259; 95% CI 8.9–17.4%) at 1 month and 10% (26/259; 6.7–14.4%) at 4 months with overall C. trachomatis positivity 5.1% (3/59; 1.1–14.2%). Follow-up at 7 months was 62% (317/509) for questionnaires and 52% (264/509) for samples. C. trachomatis prevalence was 6.2% (31/503) at baseline and 6.1% (16/264) at 7 months. Median time from test to treatment was 15 h. Interviews suggested low test uptake was associated with not feeling at risk, perceptions of stigma, and little knowledge of sexually transmitted infections (STIs).ConclusionsDespite high C. trachomatis rates at baseline and follow-up, uptake of testing was low. Like many countries, England urgently needs better sex education, including making STI testing routine/normal.Trial registration ISRCTN58038795     

Developing a risk prediction model for 30-day unplanned hospitalization in patients receiving outpatient parenteral antimicrobial therapy

ObjectivesOutpatient parenteral antimicrobial therapy (OPAT) is increasingly used to treat a wide range of infections. However, there is risk of hospital readmissions. The study aim was to develop a prediction model for the risk of 30-day unplanned hospitalization in patients receiving OPAT.MethodsUsing a retrospective cohort design, we retrieved data on 1073 patients who received OPAT over 2 years (January 2015 to January 2017) at a large teaching hospital in Sheffield, UK. We developed a multivariable logistic regression model for 30-day unplanned hospitalization, assessed its discrimination and calibration abilities, and internally them validated using bootstrap resampling.ResultsThe 30-day unplanned hospitalization rate was 11% (123/1073). The main indication for hospitalization was worsening or nonresponse of infection (52/123, 42%). The final regression model consisted of age (adjusted odds ratio (aOR), 1.18 per decade; 95% confidence interval (CI), 1.04–1.34), Charlson comorbidity score (aOR, 1.11 per unit increase; 95% CI, 1.00–1.23), prior hospitalizations in past 12 months (aOR, 1.30 per admission; 95% CI, 1.17–1.45), concurrent intravenous antimicrobial therapy (aOR, 1.89; 95% CI, 1.03–3.47) and endovascular infection (aOR, 3.51; 95% CI, 1.49–8.28). Mode of OPAT treatment was retained in the model as a confounder. The model had adequate concordance (c-statistic 0.72; 95% CI 0.67–0.77) and calibration (Hosmer-Lemeshow p 0.546; calibration slope 0.99; 95% CI 0.78–1.21), and low degree of optimism (bootstrap optimism corrected c-statistic, 0.70).ConclusionsWe identified a set of six important predictors of unplanned hospitalization based on readily available data. The prediction model may help improve OPAT outcomes through better identification of high-risk patients and provision of tailored care.     

Variable performance of different commercial systems for testing carbapenem susceptibility of KPC carbapenemase-producing Escherichia coli

ObjectivesThe aim was to evaluate different methods for testing carbapenem susceptibility of Escherichia coli producing KPC-type carbapenemase.MethodsSusceptibility to imipenem, meropenem and ertapenem was assayed using the reference broth microdilution method and several commercial methods (Vitek2, MicroScan, Etest, MIC Test Strip) starting from the same bacterial suspension. Susceptibility to imipenem and meropenem was also tested by Sensititre and disc diffusion (Bio-Rad). Results were interpreted according to EUCAST clinical breakpoints. Essential agreement (EA), category agreement (CA) and error rates were calculated as described by the International Organization for Standardization (ISO) guidelines and also considering the new EUCAST definitions. Genotypic diversity of isolates was evaluated with a RAPD profiling protocol.ResultsOf 54 KPC-positive E. coli isolates, 5.6%, 7.4% and 0% were susceptible standard dosing regimen (S), 55.6%, 72.2% and 0% susceptible increased exposure (I), and 38.9%, 20.4% and 100.0% resistant (R) to imipenem, meropenem and ertapenem, respectively, using the reference broth microdilution method. CA lower than 90% were observed with all systems for imipenem and meropenem using both the ISO and the modified EUCAST criteria. With ertapenem, CA >90% was observed with all methods except Vitek2. RAPD profiling revealed a remarkable genotypic diversity of the isolates, supporting that results were not biased by an oligoclonal nature of the collection.ConclusionsCommercial methods can be unreliable for testing susceptibility to carbapenems of KPC-producing E. coli. Susceptibility should be confirmed by reference broth microdilution.     

Operational models and criteria for incorporating microbial whole genome sequencing in hospital microbiology – A systematic literature review

BackgroundMicrobial whole genome sequencing (WGS) has many advantages over standard microbiological methods. However, it is not yet widely implemented in routine hospital diagnostics due to notable challenges.ObjectivesThe aim was to extract managerial, financial and clinical criteria supporting the decision to implement WGS in routine diagnostic microbiology, across different operational models of implementation in the hospital setting.MethodsThis was a systematic review of literature identified through PubMed and Web of Science. English literature studies discussing the applications of microbial WGS without limitation on publication date were eligible. A narrative approach for categorization and synthesis of the sources identified was adopted.ResultsA total of 98 sources were included. Four main alternative operational models for incorporating WGS in clinical microbiology laboratories were identified: full in-house sequencing and analysis, full outsourcing of sequencing and analysis and two hybrid models combining in-house/outsourcing of the sequencing and analysis components. Six main criteria (and multiple related sub-criteria) for WGS implementation emerged from our review and included cost (e.g. the availability of resources for capital and operational investment); manpower (e.g. the ability to provide training programmes or recruit trained personnel), laboratory infrastructure (e.g. the availability of supplies and consumables or sequencing platforms), bioinformatics requirements (e.g. the availability of valid analysis tools); computational infrastructure (e.g. the availability of storage space or data safety arrangements); and quality control (e.g. the existence of standardized procedures).ConclusionsThe decision to incorporate WGS in routine diagnostics involves multiple, sometimes competing, criteria and sub-criteria. Mapping these criteria systematically is an essential stage in developing policies for adoption of this technology, e.g. using a multicriteria decision tool. Future research that will prioritize criteria and sub-criteria that were identified in our review in the context of operational models will inform decision-making at clinical and managerial levels with respect to effective implementation of WGS for routine use. Beyond WGS, similar decision-making challenges are expected with respect to future integration of clinical metagenomics.     

Peripheral Immunotype Correlates with Minimal Residual Disease Status and Is Modulated by Immunomodulatory Drugs in Multiple Myeloma

Data indicate reversal of immune dysfunction with active treatment; however, the precise contribution of specific immune effector and immune suppressor components to achieve a minimal residual disease (MRD) state and immunomodulatory drug–mediated immunomodulatory effects in multiple myeloma (MM) patients remains poorly understood. In this prospective proof-of-principle study we sought to determine the dynamic alterations in natural killer (NK), NK-T, and T cells, including maturation and activating/inhibitory repertoire associated with MRD^pos versus MRD^neg status after autologous stem cell transplantation (ASCT) and during lenalidomide-based maintenance therapy. Of the 46MM patients enrolled, 36 had bone marrow MRD assessment 60+ days post-ASCT, 30 had longitudinal blood immunotyping during maintenance (pretherapy and after cycles 1, 3, and 6), and 20 had both MRD assessment and longitudinal immunotyping. Multicolor flow cytometry was used for MRD and immunotyping. Although the absolute number of NK cells was significantly lower in patients with MRD^pos response, phenotypically NK cells in these patients displayed higher expression of activating receptors KIRDS4 and decreased expression of inhibitory molecules NKG2A compared with the MRD^neg group. Furthermore, we observed significantly lower frequencies of T cells displaying KIR3DL1 in MRD^pos versus MRD^neg patients. Longitudinal immunotyping during lenalidomide maintenance showed loss of mature NK effector function, augmentation of NK-T effector function, and acquisition of PD1 independent anergic state. Our findings also suggest skewing of T cells toward an exhausted state during the maintenance phase in MRD^pos patients. Put together, these observations provide a distinctive signature for MRD^neg and MRD^pos groups. These data support exploration of immune profiling in prospective clinical trials according to MRD-defined responses to identify patients that may benefit from maintenance intensification/modification or maintenance withdrawal.     

Peripheral Blood versus Bone Marrow from Unrelated Donors: Bone Marrow Allografts Have Improved Long-Term Overall and Graft-versus-Host Disease-Free,Relapse-Free Survival

Peripheral blood (PB) and bone marrow (BM) from unrelated donors can serve as a graft source for hematopoietic cell transplantation (HCT). Currently, PB is most commonly used in roughly 80% of adult recipients. Determining the long-term impact of graft source on outcomes would inform this decision. Data collected by the Center for International Blood and Marrow Transplant Research from 5200 adult recipients of a first HCT from an 8/8 or 7/8 HLA antigen-matched unrelated donor for treatment of acute leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome between 2001 and 2011 were analyzed to determine the impact of graft source on graft-versus-host disease (GVHD) relapse-free survival (GRFS), defined as freedom from grade III/IV acute GVHD, chronic GVHD requiring immunosuppressive therapy, relapse, and death, and overall survival. GRFS at 2 years was superior in BM recipients compared with PB recipients (16%; 95% confidence interval [CI], 14% to 18% versus 10%; 95% CI, 8% to 11%; P <.0001) in the 8/8 HLA-matched cohort and 7/8 HLA-matched cohort (11%; 95% CI, 8% to 14% versus 5%; 95% CI, 4% to 7%; P?=?.001). With 8/8 HLA-matched unrelated donors, overall survival at 5 years was superior in recipients of BM (43%; 95% CI, 40% to 46% versus 38%; 95% CI, 36% to 40%; P?=?.014). The inferior 5-year survival in the PB cohort was attributable to a higher frequency of deaths while in remission compared with the BM cohort. For recipients of 7/8 HLA-matched grafts, survival at 5 years was similar in BM recipients and PB recipients (32% versus 29%; P?=?.329). BM grafts are associated with improved long-term GRFS and overall survival in recipients of matched unrelated donor HCT and should be considered the unrelated allograft of choice, when available, for adults with acute leukemia, chronic myelogenous leukemia, and myelodysplastic syndrome.