[The COVID-19 Pandemic as an Opportunity and Challenge for Registries in Health Services Research: Lessons Learned from the Lean European Open Survey on SARS-CoV-2 Infected Patients (LEOSS)]. / Die COVID-19 Pandemie als Herausforderung und Chance für Register in der Versorgungsforschung: Erfahrungen aus Lean European Open Survey on SARS-CoV-2 Infected Patients (LEOSS).

OBJECTIVE: The Coronavirus Disease-2019 (COVID-19) pandemic has brought opportunities and challenges, especially for health services research based on routine data. In this article we will demonstrate this by presenting lessons learned from establishing the currently largest registry in Germany providing a detailed clinical dataset on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infected patients: the Lean European Open Survey on SARS-CoV-2 Infected Patients (LEOSS). METHODS: LEOSS is based on a collaborative and integrative research approach with anonymous recruitment and collection of routine data and the early provision of data in an open science context. The only requirement for inclusion was a SARS-CoV-2 infection confirmed by virological diagnosis. Crucial strategies to successfully realize the project included the dynamic reallocation of available staff and technical resources, an early and direct involvement of data protection experts and the ethics committee as well as the decision for an iterative and dynamic process of improvement and further development. RESULTS: Thanks to the commitment of numerous institutions, a transsectoral and transnational network of currently 133 actively recruiting sites with 7,227 documented cases could be established (status: 18.03.2021). Tools for data exploration on the project website, as well as the partially automated provision of datasets according to use cases with varying requirements, enabled us to utilize the data collected within a short period of time. Data use and access processes were carried out for 97 proposals assigned to 27 different research areas. So far, nine articles have been published in peer-reviewed international journals. CONCLUSION: As a collaborative effort of the whole network, LEOSS developed into a large collection of clinical data on COVID-19 in Germany. Even though in other international projects, much larger data sets could be analysed to investigate specific research questions through direct access to source systems, the uniformly maintained and technically verified documentation standard with many discipline-specific details resulted in a large valuable data set with unique characteristics. The lessons learned while establishing LEOSS during the current pandemic have already created important implications for the design of future registries and for pandemic preparedness and response.

Clinical and pharmacoeconomic evaluation of antifungal prophylaxis with continuous micafungin in patients undergoing allogeneic stem cell transplantation: A six-year cohort analysis.

BACKGROUND: Patients undergoing allogeneic stem cell transplantation (aSCT) are at high risk to develop an invasive fungal disease (IFD). Optimisation of antifungal prophylaxis strategies may improve patient outcomes and reduce treatment costs. OBJECTIVES: To analyse the clinical and economical impact of using continuous micafungin as antifungal prophylaxis. PATIENTS/METHODS: We performed a single-centre evaluation comparing patients who received either oral posaconazole with micafungin as intravenous bridging as required (POS-MIC) to patients who received only micafungin (MIC) as antifungal prophylaxis after aSCT. Epidemiological, clinical and direct treatment cost data extracted from the Cologne Cohort of Neutropenic Patients (CoCoNut) were analysed. RESULTS: Three hundred and thirteen patients (97 and 216 patients in the POS-MIC and MIC groups, respectively) were included into the analysis. In the POS-MIC and MIC groups, median overall length of stay was 42 days (IQR: 35-52 days) vs 40 days (IQR: 35-49 days; p = .296), resulting in median overall costs of €42,964 (IQR: €35,040-€56,348) vs €43,291 (IQR: €37,281 vs €51,848; p = .993), respectively. Probable/proven IFD in the POS-MIC and MIC groups occurred in 5 patients (5%) vs 3 patients (1%; p = .051), respectively. The Kaplan-Meier analysis showed improved outcome of patients in the MIC group at day 100 (p = .037) and day 365 (p < .001) following aSCT. CONCLUSIONS: Our study results demonstrate improved outcomes in the MIC group compared with the POS-MIC group, which can in part be explained by a tendency towards less probable/proven IFD. Higher drug acquisition costs of micafungin did not translate into higher overall costs.

HEnRY: a DZIF LIMS tool for the collection and documentation of biomaterials in multicentre studies.

BACKGROUND: Well-characterized biomaterials of high quality have great potential for acceleration and quality improvement in translational biomedical research. To improve accessibility of local sample collections, efforts have been made to create central biomaterial banks and catalogues. Available technical solutions for creating professional local sample catalogues and connecting them to central systems are cost intensive and/or technically complex to implement. Therefore, the Translational Thematic Unit HIV of the German Center for Infection Research (DZIF) developed a Laboratory Information and Management System (LIMS) called HIV Engaged Research Technology (HEnRY) for implementation into the Translational Platform HIV (TP-HIV) at the DZIF and other research networks. RESULTS: HEnRY is developed at the University Hospital of Cologne. It is an advanced LIMS to manage processing and storage of samples and aliquots of different sample types. Features include: monitoring of stored samples and associated information data selection via query tools or Structured Query Language (SQL) preparation of summary documents, including scannable search lists centralized management of the practical laboratory part of multicentre studies (e.g. import of drawing schemes and sample processing steps), preparation of aliquot shipments, including associated documents to be added to shipments unique and secure identification of aliquots through use of customizable Quick Response (QR) code labels directly from HEnRY support of aliquot data transmission to central registries. In summary, HEnRY offers all features necessary for a LIMS software. In addition, the structure of HEnRY provides sufficient flexibility to allow the implementation in other research areas. CONCLUSION: HEnRY is a free biobanking tool published under the MIT license. While it was developed to support HIV research in Germany, the feature set and language options, allow much broader applications and make this a powerful free research tool.

Chlorhexidine-containing dressings in the prevention of central venous catheter-related bloodstream infections: A cost and resource utilization analysis.

BACKGROUND: A recent study reported a reduction in probable/definite central venous catheter (CVC)-related bloodstream infections (CRBSIs) in neutropenic high-risk patients using CVC dressings with a chlorhexidine-containing gel pad. METHODS: Based on published data, a health-economic analysis was performed to analyze the economic effect of using CVC dressings with a chlorhexidine-containing gel pad compared to non-chlorhexidine control dressings. A micro-costing approach was used to determine CRBSI-related direct treatment cost factors. RESULTS: Between February 2012 and September 2014, 356 patients (178 patients in both groups) were analyzed. Distribution of probable and definite CRBSI in the chlorhexidine group and control group were 12 (7%) vs 18 (10%) and 9 (5%) vs 21 (12%), respectively (P = .011). Median overall length of stay (25 vs 27.5 days; P = .630) and days on treatment with antibacterials (10 vs 12 days; P = .140) were similar between the chlorhexidine and control groups. The most important cost driver in both groups was treatment on general ward (€4275 [US$ 5173], interquartile range [IQR]: €592 - €6504 [US$ 716 - US$ 7871] vs €4560 [US$ 5518], IQR: €1227 - €8567 [US$ 1485 - US$ 10,367]; P = .120), resulting in median overall direct treatment costs of €13,881 (US$ 16,798) [IQR: €10,922 - €25,457 (US$ 13,217 - US$ 30,807) vs €13,929 [US$ 16,856] [IQR: €11,295 - €23,561 (US$ 13,669 - US$ 28,512); P = .640]). CONCLUSION: Our study shows similar results in overall direct treatment costs, meaning that higher acquisition costs of chlorhexidine-containing dressings did not translate into higher costs. Expenses were primarily outweighed by a lower rate of probable/definite CRBSI and reduced associated costs.

A cohort study on breakthrough invasive fungal infections in high-risk patients receiving antifungal prophylaxis.

OBJECTIVES: Antifungal prophylaxis is recommended for haematological patients at high risk of invasive fungal infections (IFIs). Incidence, optimal therapeutic management and outcome of breakthrough IFIs (bIFIs) are largely unknown. METHODS: To assess bIFI incidence, treatment and outcomes, data on patients undergoing AML remission-induction and consolidation chemotherapy and from allogeneic HSCT recipients on antifungal prophylaxis with itraconazole, micafungin or posaconazole were extracted from the Cologne Cohort of Neutropenic Patients (CoCoNut). bIFIs were classified according to revised EORTC/MSG criteria. RESULTS: From January 2004 to April 2013, 250 AML patients with 329 hospitalizations and 409 HSCT patients with 496 hospitalizations were identified. In AML patients, there were 16 (6.4%) proven or probable bIFIs and 44 (17.6%) possible bIFIs. In HSCT patients, there were 14 (3.4%) proven or probable bIFIs and 37 (9.0%) possible bIFIs. Proven cases included five candidaemias, two mucormycoses, three aspergilloses and one fusariosis. The most frequent choice for bIFI treatment was liposomal amphotericin B in AML patients (21/60; 35.0%) and continuation of posaconazole prophylaxis in HSCT patients (16/51; 31.4%). In HSCT recipients, survival on day 365 was significantly lower in bIFI patients (AML, 63.3% versus 70.0%; P = 0.297; HSCT, 49.0% versus 66.8%; P = 0.012). Comparison of continuation of prophylaxis versus switch of antifungal class as first-line treatment showed no significant difference regarding response to treatment and survival. CONCLUSIONS: Rates of bIFIs observed in our population were comparable to previous data. There was no clear shift towards rare species, as previously reported. A high variety of treatment approaches was observed.

Sensor and software use for the glycaemic management of insulin-treated type 1 and type 2 diabetes patients.

Lowering glucose levels, while avoiding hypoglycaemia, can be challenging in insulin-treated patients with diabetes. We evaluated the role of ambulatory glucose profile in optimising glycaemic control in this population. Insulin-treated patients with type 1 and type 2 diabetes were recruited into a prospective, multicentre, 100-day study and randomised to control (n = 28) or intervention (n = 59) groups. The intervention group used ambulatory glucose profile, generated by continuous glucose monitoring, to assess daily glucose levels, whereas the controls relied on capillary glucose testing. Patients were reviewed at days 30 and 45 by the health care professional to adjust insulin therapy. Comparing first and last 2 weeks of the study, ambulatory glucose profile-monitored type 2 diabetes patients (n = 28) showed increased time in euglycaemia (mean ± standard deviation) by 1.4 ± 3.5 h/day (p = 0.0427) associated with reduction in HbA1c from 77 ± 15 to 67 ± 13 mmol/mol (p = 0.0002) without increased hypoglycaemia. Type 1 diabetes patients (n = 25) showed reduction in hypoglycaemia from 1.4 ± 1.7 to 0.8 ± 0.8 h/day (p = 0.0472) associated with a marginal HbA1c decrease from 75 ± 10 to 72 ± 8 mmol/mol (p = 0.0508). Largely similar findings were observed comparing intervention and control groups at end of study. In conclusion, ambulatory glucose profile helps glycaemic management in insulin-treated diabetes patients by increasing time spent in euglycaemia and decreasing HbA1c in type 2 diabetes patients, while reducing hypoglycaemia in type 1 diabetes patients.

A cost and resource utilization analysis of micafungin bridging for hemato-oncological high-risk patients undergoing allogeneic stem cell transplantation.

BACKGROUND: Intravenous bridging strategies increase exposure of antifungal prophylaxis in high-risk hematological patients. The cost-effectiveness of such strategies has not been analyzed. METHODS: A recent study compared the impact of oral posaconazole (POS) and oral posaconazole with intravenous micafungin bridging (POS-MIC) as prophylactic antifungal regimens in patients undergoing allogeneic stem cell transplantation (aSCT). Based on data from the Cologne Cohort of Neutropenic Patients (CoCoNut), a health economic evaluation of direct treatment costs was performed to analyze the economic impact of micafungin bridging. Analysis was undertaken based on current guidelines for the German societal perspective with an annual discount rate of 5%, whereby indirect costs were disregarded due to the severity of the underlying disease. Sensitivity analysis of cost calculation with different discount rates was performed to improve robustness of our health economic evaluation. RESULTS: A retrospective case-control analysis of patients undergoing aSCT between 05/2006 and 07/2011 was performed; 106 patients each in the POS and POS-MIC group were included. In the POS and POS-MIC group, mean costs per patient for the treatment on bone marrow transplant ward were €27,228 (95% CI: €24,932-€29,525) vs. €27,894 (95% CI: €26,414-€29,375; P = 0.629), for diagnostic measures €2124 (95% CI: €1823-€2425) vs. €1269 (95% CI: €1168-€1370; P ≤ 0.001), for laboratory findings €10,612 (95% CI: €9681-€11,544) vs. €8836 (95% CI: €8198-€9475; P = 0.002), and for overall antifungal treatment €6105 (95% CI: €4703-€7508) vs. €6943 (95% CI: €5393-€8493; P = 0.428), resulting in mean overall costs per patient of €60,304 (95% CI: €53,969-€66,639) vs. €58,089 (95% CI: €51,736-64,442; P = 0.625). CONCLUSIONS: Our health economic evaluation shows micafungin bridging in aSCT patients did not result in excess cost. Higher acquisition costs of antifungal prophylaxis were balanced by a reduced incidence of possible IFD and lower costs for empirical, preemptive, and targeted antifungal therapy as well as lower costs for diagnostic measures and laboratory tests in the micafungin bridging group.

Low-grade proteinuria is highly prevalent in HIV-positive patients on antiretroviral treatment.

OBJECTIVES: HIV-positive patients are at an increased risk for chronic kidney disease. However, these data mainly derive from cohorts with a high percentage of African-American patients, representing a specific ethnical risk group for chronic kidney disease. The aim of this study was to estimate the prevalence and risk factors specifically for early signs of kidney dysfunction in a large, predominantly white cohort of HIV patients. DESIGN: Cross-sectional study. METHODS: Prevalence of low-grade proteinuria was measured by quantitative analysis of urinary protein-to-creatinine ratio (cutoff >70 mg/g) and further differentiated by assessing α1-microglobulin (tubular proteinuria) and albumin-to-creatinine ratio (glomerular proteinuria) of HIV patients attending the University Hospital in Cologne, Germany. Together with standard and HIV-related laboratory findings and medical history, risk factors for each form of proteinuria were identified using multivariate forward selection. RESULTS: Of 945 enrolled patients, 55% were identified with low-grade proteinuria, 41% with tubular proteinuria, and 20% with glomerular proteinuria. Older age was a risk factor for all forms of proteinuria in multivariate analysis. Low-grade proteinuria was also associated with concomitant diabetes and exposure to nucleoside reverse transcriptase inhibitor [anytime during HIV infection, not tenofovir (TDF)-specific], whereas tubular proteinuria was linked to current and any exposure to nucleoside reverse transcriptase inhibitor (TDF-specific). Further risk factors for glomerular proteinuria were hypertension and diabetes in this cohort. CONCLUSION: Low-grade, glomerular and tubular proteinuria are highly prevalent in this large white HIV cohort. Older age represents a nonmodifiable risk factor for all forms of proteinuria. Glomerular proteinuria is associated with modifiable cardiovascular, but not HIV-related risk factors, whereas tubular proteinuria is linked to TDF exposure.

Developments in the prediction of type 1 diabetes mellitus, with special reference to insulin autoantibodies.

The prodromal phase of type 1 diabetes is characterised by the appearance of multiple islet-cell related autoantibodies (Aab). The major target antigens are islet-cell antigen, glutamic acid decarboxylase (GAD), protein-tyrosine phosphatase-2 (IA-2) and insulin. Insulin autoantibodies (IAA), in contrast to the other autoimmune markers, are the only beta-cell specific antibodies. There is general consensus that the presence of multiple Aab (> or = 3) is associated with a high risk of developing diabetes, where the presence of a single islet-cell-related Aab has usually a low predictive value. The most commonly used assay format for the detection of Aab to GAD, IA-2 and insulin is the fluid-phase radiobinding assay. The RBA does not identify or measure Aab, but merely detects its presence. However, on the basis of molecular studies, disease-specific constructs of GAD and IA-2 have been employed leading to somewhat improved sensitivity and specificity of the RBA. Serological studies have shown epitope restriction of IAA that can differentiate diabetes-related from unrelated IAA, but current assays do not distinguish between disease-predictive and non-predictive IAA or between IAA and insulin antibodies (IA). More recently, phage display technology has been successful in identifying disease-specific anti-idiotopes of insulin. In addition, phage display has facilitated the in vitro production of antibodies with high affinity. Identification of disease-specific anti-idiotopes of insulin should enable the production of a high affinity reagent against the same anti-idiotope. Such a development would form the basis of a disease-specific radioimmunoassay able to identify and measure particular idiotypes, rather than merely detect and titrate IAA.

Distinct idiotypes of insulin autoantibody in autoimmune polyendocrine syndrome type 2 and childhood onset type 1 diabetes.

Insulin autoantibodies (IAA) are present in type 1 diabetes (T1D) and other autoimmune diseases. The differences in the IAA epitopes in various clinical diseases have not been evaluated. We used phage display to select phagotopes specific to IAA from a newly diagnosed T1D child (designated FPP) and from an adult-onset T1D subject with autoimmune polyendocrine syndrome type 2 (APS-II). The phagotopes randomly selected were tested as antiidiotope reagents to displace human radiolabeled insulin in the microfiltration radiobinding assay using IAA(+) sera from T1D subjects and insulin antibody (IA(+)) sera from insulin-treated type 2 diabetes subjects. The DNA of the phagotopes selected from the FPP and APS sera revealed consensus amino acid sequences of GRG and LGKRS, respectively. Phagotope FPP-10 displaced insulin binding in 90% of IAA(+) subjects but not in the IA(+) or the APS subject. Phagotope APS-4 was able to displace insulin binding from the APS subject but not in the IAA(+) or IA(+) subjects. We have demonstrated antiidiotope reagents able to distinguish childhood-onset T1D-associated IAA(+) from adult-onset T1D (APS-II-associated IAA(+)) that are different from their specificity for human insulin and from its antiidiotope amino acid sequence.