Mathematical modeling of pneumococcal transmission dynamics in response to PCV13 infant vaccination in Germany predicts increasing IPD burden due to serotypes included in next-generation PCVs.

INTRODUCTION: Two next-generation pneumococcal conjugate vaccines (PCVs), a 15- and a 20-valent PCV (PCV15 and PCV20), have recently been licensed for use in adults, and PCV15 has also been licensed in children. We developed a dynamic transmission model specific for Germany, with the aim to predict carriage prevalence and invasive pneumococcal disease (IPD) burden for serotypes included in these vaccines. METHODS: The model allows to follow serotype distributions longitudinally both in the absence and presence of PCV vaccinations. We considered eight age cohorts and seven serotype groups according to the composition of different pneumococcal vaccines. This comprises the additional serotypes contained in PCV15 and PCV20 but not in PCV13. RESULTS: The model predicted that by continuing the current vaccine policy (standard vaccination with PCV13 in children and with PPSV23 in adults) until 2031, IPD case counts due to any serotype in children <2 years of age will remain unchanged. There will be a continuous decrease of IPD cases in adults aged 16-59y, but a 20% increase in adults ≥60y. Furthermore, there will be a steady decrease of the proportion of carriage and IPD due to serotypes included in PCV7 and PCV13 over the model horizon and a steady rise of non-PCV13 serotypes in carriage and IPD. The highest increase for both pneumococcal carriage and absolute IPD case counts was predicted for serotypes 22F and 33F (included in both PCV15 and PCV20) and serotypes 8, 10A, 11A, 12F, and 15B (included in PCV20 only), particularly in older adults. Between 2022 and 2031, serotypes included in PCV20 only are expected to cause 19.7-25.3% of IPD cases in adults ≥60y. CONCLUSIONS: We conclude that introduction of next-generation PCVs for adults may prevent a substantial and increasing proportion of adult IPDs, with PCV20 having the potential to provide the broadest protection against pneumococcal disease.

Pneumococcal vaccination rates in immunocompromised patients in Germany: A retrospective cohort study to assess sequential vaccination rates and changes over time.

BACKGROUND: Pneumococcal vaccination is recommended by the German Standing Committee on Vaccination (STIKO) for infants, elderly 60+ years and patients at risk. In 2016, a sequential pneumococcal vaccination schedule (conjugate vaccine followed by polysaccharide vaccine 6-12 months later) supplemented this recommendation for immunocompromised patients ≥2 years of age. Previous research showed low pneumococcal vaccination rates (pnc-VR) in this vulnerable group. Moreover, no evidence is available on adherence to the newer sequential schedule. This study aimed to analyze the development of pnc-VRs in immunocompromised patients and rates of sequential vaccinations according to the STIKO recommendations. METHODS: Using a representative health claims database, we assigned incident immunocompromised patients ≥2 years of age to one of two successive cohorts to observe trends over time: cohort A (first diagnosis of immunocompromised condition between 01/2013 and 12/2014), and cohort B (first diagnosis between 01/ 2015 and 12/2017). Pnc-VR within two years after first diagnosis and cumulative pnc-VR was compared among both cohorts. In cohort B, we assessed sequential pnc-VR within 15 months of the first vaccination. For additional analyses, patients were stratified by age, gender and immunocompromising condition. RESULTS: Cohort A and B comprised 193,521 and 289,279 patients, respectively. Overall pnc-VR increased over time from 4.3% (cohort A; 95%-confidence interval: 4.3%-4.4%) to 6.0% (cohort B; 5.9%-6.1%), with highest pnc-VRs in men ≥60 years (11.3%: 11.1%-11.6%) and HIV patients (15.2%: 13.1%-17.4%). Cumulative pnc-VRs in cohort B were higher in any quarter following diagnosis when compared with cohort A. Overall sequential pnc-VR in cohort B was 4.0% (3.7%-4.3%), with a higher rate observed in patients aged 16-59 (6.8%: 6.0%-7.7%) vs. patients aged ≥60 years (3.1%: 2.8%-3.4%). CONCLUSION: While some improvements were seen over time, pnc-VRs remain very low in immunocompromised patients, as did sequential vaccination rates. Current recommendations to protect immunocompromised patients from pneumococcal infections are not being sufficiently implemented.

Population-based incidence and mortality of community-acquired pneumonia in Germany.

BACKGROUND: Little information on the current burden of community-acquired pneumonia (CAP) in adults in Germany is available. METHODS: We conducted a retrospective cohort study using a representative healthcare claims database of approx. 4 million adults to estimate the incidence rates (IR) and associated mortality of CAP in 2015. IR and mortality were stratified by treatment setting, age group, and risk group status. A pneumonia coded in the primary diagnosis position or in the second diagnosis position with another pneumonia-related condition coded in the primary position was used as the base cases definition for the study. Sensitivity analyses using broader and more restrictive case definitions were also performed. RESULTS: The overall IR of CAP in adults ≥18 years was 1,054 cases per 100,000 person-years of observation. In adults aged 16 to 59 years, IR for overall CAP, hospitalized CAP and outpatient CAP was 551, 96 and 466 (with a hospitalization rate of 17%). In adults aged ≥60 years, the respective IR were 2,032, 1,061 and 1,053 (with a hospitalization rate of 52%). If any pneumonia coded in the primary or secondary diagnosis position was considered for hospitalized patients, the IR increased 1.5-fold to 1,560 in the elderly ≥60 years. The incidence of CAP hospitalizations was substantially higher in adults ≥18 years with at-risk conditions and high-risk conditions (IR of 608 and 1,552, respectively), compared to adults without underlying risk conditions (IR 108). High mortality of hospitalized CAP in adults ≥18 was observed in-hospital (18.5%), at 30 days (22.9%) and at one-year (44.5%) after CAP onset. Mortality was more than double in older adults in comparison to younger patients. CONCLUSION: CAP burden in older adults and individuals with underlying risk conditions was high. Maximizing uptake of existing vaccines for respiratory diseases may help to mitigate the disease burden, especially in times of strained healthcare resources.

Vaccination rate and adherence of tick-borne encephalitis vaccination in Germany.

BACKGROUND: Tick-borne encephalitis (TBE) is an arboviral infection of the central nervous system. As there is no causal treatment of TBE, disease prevention by vaccination is especially important. Immunization consists of a three-dose primary vaccination schedule, followed by regular booster doses. In Germany, the Standing Committee on Vaccination (STIKO) at the Robert Koch-Institute recommends TBE vaccination for all those at high risk of contracting TBE. This includes individuals living in, traveling to and/or working in risk areas, and being exposed to ticks. To our knowledge, there are currently no reliable data on TBE vaccination rates in Germany available. METHODS: This retrospective cohort study based on anonymized German health claims data was conducted to determine vaccination rates of TBE primary immunization in 2012 to 2015 by federal state, compliance with the vaccination schedule, and TBE vaccination uptake for the 2011 birth cohort. Vaccination protection rates for each federal state were simulated based on a compartmental model. RESULTS: Vaccination rates of an initiated primary immunization ranged from about 3% in the southern federal states to <1% in the northern federal states. Across all federal states, compliance with the vaccination schedule decreased with each subsequent vaccination. Slightly higher TBE vaccination uptake was determined in the 2011 birth cohort, as compared to the German school entry health examination statistics in 2017. Simulated vaccination protection rates for each federal state ranged from 10% in Hamburg to 51% in Baden-Wuerttemberg. CONCLUSIONS: While there was an overall low vaccination uptake and a discrepancy between areas of high vs. low TBE risk, this study also indicates a concerning decline in vaccination compliance. Vaccinating physicians should address the importance of adherence upon initiation of TBE vaccination.

Pneumococcal vaccination rates in immunocompromised patients-A cohort study based on claims data from more than 200,000 patients in Germany.

BACKGROUND: The German Committee on Vaccination recommends pneumococcal vaccination for infants, seniors 60+ years and patients at risk with defined underlying diseases. Aim of this study was to assess the pneumococcal vaccination rate (pnc-VR) in patients with certain incident inherited or acquired immunodeficiency or immunosuppression and to understand who vaccinates these patients who are particularly at high risk to develop a pneumococcal infection. METHODS: We conducted a cohort study in patients aged 2 years or older, with a first episode of a "high-risk" condition between January 2013 and December 2014 based on a representative sample of German claims data. Pnc-VR was calculated as the proportion of patients receiving any pneumococcal vaccine within two years after first episode of "high-risk" condition. Further analyses cover pnc-VR stratified by high risk conditions and region, time to vaccination, and physician specialty administering the pneumococcal vaccination. RESULTS: The study population comprised 204,088 incident "high-risk" patients (56% female). The overall pnc-VR within two years was 4.4% (95%-confidence interval: 4.3%-4.5%). Within specific high-risk conditions, we found the highest vaccination rate of 11.5% (10.1%-13.0%) among patients starting immunosuppressants with underlying rheumatoid arthritis followed by 9.9% (7.8%-12.4%) in HIV patients. Stratification by region revealed a slightly higher vaccination rate in Eastern (6.5%: 6.0%-6.9%) compared to Western Germany (4.2%: 4.1-4.3%). Median time to vaccination within the first two years in vaccinated patients was 332.5 days (Q1 142 days, Q3 528 days). The majority of patients (92.6%) got vaccinated by a general practitioner. CONCLUSION: Although these vulnerable patients need protection most, our study suggests that the overall pnc-VR after a first episode of a high-risk condition for pneumococcal disease is very low and vaccination is far too late. To prevent pneumococcal disease in patients at high risk, further efforts are needed to increase awareness and improve the timeliness of pneumococcal vaccination.

Estimating the cost-effectiveness of a sequential pneumococcal vaccination program for adults in Germany.

INTRODUCTION: In Germany, a 23-valent polysaccharide pneumococcal vaccine (PPSV23) is recommended for elderly (60+) and patients 16+ with chronic diseases not associated with immune suppression. For all other patients at risk, sequential immunization with a 13-valent pneumococcal conjugate vaccine (PCV13) first, followed by PPSV23 is recommended. Repeated vaccination with PPSV23 is recommended every 6 years after individual assessment by the physician. This was adopted into the vaccination directive with binding reimbursement and funding. However, additional voluntary services allow statutory health insurances to differentiate from each other. Aim of this study is to estimate the cost-effectiveness of voluntary service scenarios compared to the strategy in place to support informed decision making. METHODS: A microsimulation framework with Markov-type process of a population susceptible to pneumococcal disease over a lifetime horizon was developed to compare effectiveness and cost-effectiveness of different vaccination strategies. We simulated 1,000 iterations for seven scenarios. Assumptions were derived from published literature and probabilistic sensitivity analysis was run to show the robustness of the model. RESULTS: Our study indicates that all voluntary service strategies could prevent further clinical cases compared to the existing policy. Depending on the scenario, 48-142 invasive pneumococcal disease (IPD), 24,000-45,000 hospitalized all-cause nonbacteremic pneumonia (NBP), 15,000-45,000 outpatient NBP cases, and 4,000-8,000 deaths could be avoided on average. This refers to potential savings of €115 Mio. - €187 Mio. for medical and non-medical costs. Additional costs per patient for the payer are €2.48 to €7.13 and for the society €2.20 to €6.85. The ICER per LYG ranged from €3,662 to €23,061 (payer) and €3,258 to €29,617 (societal). All but one scenario was cost-effective in ≥60% of the generated 1,000 simulations. CONCLUSION: Compared to the vaccination strategy in place, the different hypothetical scenarios can be considered cost-effective and suitable as additional voluntary services.

Evaluation of Adjusted and Unadjusted Indirect Comparison Methods in Benefit Assessment. A Simulation Study for Time-to-event Endpoints.

BACKGROUND: With the Act on the Reform of the Market for Medicinal Products (AMNOG) in Germany, pharmaceutical manufacturers are obliged to submit a dossier demonstrating added benefit of a new drug compared to an appropriate comparator. Underlying evidence was planned for registration purposes and therefore often does not meet the appropriate comparator as defined by the Federal Joint Committee (G-BA). For this reason AMNOG allows indirect comparisons to assess the extent of added benefit. OBJECTIVES: The aim of this study is to evaluate the characteristics and applicability of adjusted indirect comparison described by Bucher and Matching-Adjusted Indirect Comparison (MAIC) in various situations within the early benefit assessment according to §35a Social Code Book 5. In particular, we consider time-to-event endpoints. METHODS: We conduct a simulation study where we consider three different scenarios: I) similar study populations, II) dissimilar study populations without interactions and III) dissimilar study populations with interactions between treatment effect and effect modifiers. We simulate data from a Cox model with Weibull distributed survival times. Desired are unbiased effect estimates. We compare the power and the proportion of type 1 errors of the methods. RESULTS: I) Bucher and MAIC perform equivalently well and yield unbiased effect estimates as well as proportions of type 1 errors below the significance level of 5 %. II) Both Bucher and MAIC yield unbiased effect estimates, but Bucher shows a higher power for detection of true added benefit than MAIC. III) Only MAIC, but not Bucher yields unbiased effect estimates. When using robust variance estimation MAIC yields a proportion of type 1 error close to 5 %. In general, power of all methods for indirect comparisons is low. An increasing loss of power for the indirect comparisons can be observed as the true treatment effects decrease. CONCLUSION: Due to the great loss of power and the potential bias for indirect comparisons, head-to-head trials using the appropriate comparator as defined by the Federal Joint Committee should be conducted whenever possible. However, indirect comparisons are needed if no such direct evidence is available. To conduct indirect comparisons in case of a present common comparator and similar study populations in the trials to be compared, both Bucher and MAIC can be recommended. In case of using adjusted effect measures (such as Hazard Ratio), the violation of the similarity assumption has no relevant effect on the Bucher approach as long as interactions between treatment effect and effect modifiers are absent. Therefore Bucher can still be considered appropriate in this specific situation. In the authors' opinion, MAIC can be considered as an option (at least as sensitivity analysis to Bucher) if such interactions are present or cannot be ruled out. Nevertheless, in practice MAIC is potentially biased and should always be considered with utmost care.

Examining patient preferences in the treatment of rheumatoid arthritis using a discrete-choice approach.

BACKGROUND: Biological disease-modifying antirheumatic drugs (bDMARDs) used in second-line treatment of rheumatoid arthritis (RA) are administered parenterally. However, so-called targeted synthetic DMARDs (tsDMARDs) - developed more recently - offer alternative (ie, oral) administration forms in second-line treatment. Since bDMARDs and tsDMARDs can be regarded as equal in terms of efficacy, the present study examines whether such characteristics as route of administration drive RA patients' treatment choice. This may ultimately suggest superiority of some second-line DMARDs over equally effective options, at least according to RA-patient preferences. OBJECTIVE: The current study assessed the importance of oral administration among other treatment characteristics differing between available second-line DMARDs for RA patients' preferences using a discrete-choice experiment (DCE). MATERIALS AND METHODS: The DCE involved scenarios of three hypothetical treatment options in a d-efficient design with varying levels of key attributes (route and frequency of administration, time till onset of drug effect, combination therapy, possible side effects), as defined by focus groups. Further patient characteristics were recorded by an accompanying questionnaire. In the DCE, patients were asked to choose best and worst options (best-worst scaling). Results were analyzed by count analysis and adjusted regression analysis. RESULTS: A total of 1,588 subjects completed the DCE and were eligible for final analyses. Across all characteristics included in the DCE, "oral administration" was most desired and "intravenous infusion" was most strongly rejected. This was followed by "no combination with methotrexate" being strongly preferred and "intake every 1-2 weeks" being strongly rejected. On average, levels of route of administration showed strongest influences on patients' decisions in post hoc bootstrapping analysis. CONCLUSION: According to the results, an oral DMARD that does not have to be combined with methotrexate and is not administered (only) every 1-2 weeks appears a highly favorable treatment option for patients with RA. DMARDs meeting these preferences may increase compliance and adherence in RA treatment.

Efficacy of PPV23 in Preventing Pneumococcal Pneumonia in Adults at Increased Risk--A Systematic Review and Meta-Analysis.

BACKGROUND: Pneumococcal community-acquired pneumonia (pCAP) is the most frequent form of pneumonia. The elderly and adults with underlying diseases are at an increased risk of developing pCAP. The 23-valent pneumococcal polysaccharide vaccine (PPV23) was licensed over 30 years ago and is recommended as the standard intervention in many countries across the globe, although its efficacy continues to be debated. We performed a meta-analysis of randomized controlled trials (RCTs) to investigate the effect of PPV23 for preventing pCAP in adults ≥60 years of age. METHODS: An existing Cochrane Review was updated to Oct 2014 using a systematic literature search to select appropriate RCTs. DerSimonian and Laird random-effects meta-analyses were performed and odd ratios (OR) with 95%-confidence intervals (CI) and p-values were calculated for the descriptive analyses. Reasons for heterogeneity were explored by subgroup analyses. RESULTS: Meta-analysis of PPV23 efficacy included four studies. Three of them did not demonstrate efficacy for PPV23. The body of evidence indicated statistically significant heterogeneity (I2 = 78%, p = 0.004) that could be explained by subgroup analysis by "study setting". Further effect modifiers for pCAP were "continent of trial" (p<0.01), and "method of pneumococcal diagnostics" (p = 0.001). Subgroup analyses revealed that the only study showing efficacy for PPV23 was an outlier. Overall, the validity of the meta-analytic PPV23 efficacy assessment was confirmed by the meta-analysis of all-cause CAP including six studies. DISCUSSION: Inconsistencies in PPV23 treatment effects to prevent pCAP could solely be explained by one outlier study that was performed in nursing homes in Japan. The effect modifier "method of pneumococcal diagnostics" should be interpreted carefully, since methodological weaknesses are not restricted to one special method only, which would justify the exclusion of certain studies. Overall, we conclude from our meta-analysis that to date there is no proof that PPV23 can prevent pCAP in a general, community-dwelling elderly population.

Difference between real and perceived power of dermoscopical methods for detection of malignant melanoma.

Clear proceedings in detection of malignant melanoma and monitoring of melanocytic nevi (MN) have been achieved by dermoscopy in recent years: sensitivity to 95% is possible for experts. Does patients' confidence in methods for detection of malignant melanoma most important for adherence in follow-up reflect this diagnostic power? A self-administered survey was performed in 210 consecutive patients at 13 private dermatological practices and the department of Dermatology of the University of Regensburg. Confidence was assessed by a 5-step ordinal scale ranging from 1 to 5 (higher values indicate higher confidence) and willingness-to-pay (wtp) as health-economic instrument for naked-eye inspection (NEI), handheld dermoscopy (HHD), digital dermoscopy (DD), and teledermoscopy (TD); additional, wtp for a hypothetical method promising 100% accuracy. Data of 143 patients (response rate 69.5%; mean age 37 years, 58% female) could be analysed. Mean confidence was 1.9 0.9 for NEI, 2.8 0.9 for HHD, 4.5 0.7 for DD, and 4.7 0.5 for TD. Mean wtp per examination was 0.64% 1.1 of monthly income for NEI, 1.1% 1.9 for HHD, 2.8% 3.3 for DD, 3.1% 4.6 for TD, and 5.0% 7.8 for hypothetical method. Differences between methods were statistically significant. Compared to the hypothetical method, NEI achieved only 14.9%, HHD 24.8%, DD 58.4%, and TD 60% of maximum confidence. This study was performed without any influence on routine information for patients. Results therefore represent patients' actual knowledge of dermoscopical methods in daily dermatological practices. Patients' confidence was highest for TD, HHD was clearly underestimated. Willingness-to-pay in HHD, DD, and TD was at least 40% below a hypothetical method promising 100% accuracy. Better information about diagnostic accuracy of methods available is necessary to increase patients' knowledge and confidence.

Treatment of atopic dermatitis and impact on quality of life: a review with emphasis on topical non-corticosteroids.

Atopic dermatitis (AD) is a chronic skin disease with increasing prevalence and rising costs. Stigmatisation and pruritus are only some aspects of potential quality-of-life (QOL) impairments. AD is not curable and repeated treatments are often necessary. At present, treatment with topically-applied corticosteroids is state-of-the-art for mild to moderate flare-ups. However, many patients are worried about the use of corticosteroids due to the widespread fear of adverse effects. In this review the present literature is analysed concerning impact on quality of life for topically-applicable alternatives to the state-of-the-art treatment. For comparison reasons, data from other treatment modalities are additionally given. Characteristics of studies were analysed using 'general' (year and mode of publication, type and aim of study, number of patients, and clinical measurement) and 'QOL specific' criteria (type and number of QOL measurements including relevance for study aim and age group, validation in used language, sensitivity to change, and improvement at end of study). QOL data are published only in the minority of studies evaluating treatment efficacy and do not cover the variety of possible therapies. Data are available for tacrolimus, pimecrolimus, UVA/UVB combination and UVB narrowband (topical non-corticosteroidal treatments), as well as for topical corticosteroids, cyclosporin, and inpatient treatment. All studies provided a marked improvement in quality of life after therapy. One study assessed quality of life after a treatment-free follow-up period obtaining a clear increase in impact on quality of life. Since studies used different QOL measurements and vary in inclusion criteria, treatment schedules and presentation of results, a comparison of QOL improvement is not recommended. A single randomised study compared topically applied non-corticosteroidal treatment (UVA/UVB combination) with another treatment modality (cyclosporin) and found no difference in QOL improvement. At present, there is a clear lack of controlled randomised studies evaluating different active treatment modalities and their impact on quality of life. Consensus meetings are desirable to formulate guidelines for the selection and correct use of QOL measurements. Patients' fear of side effects (e.g. concerning corticosteroids) should be integrated in QOL questionnaires for evaluation of possible compliance problems and real costs. Since relapse after treatment is frequent in AD, QOL measurements should also be performed after a treatment-free follow-up period. At present, we can not answer the question 'which treatment best improves quality of life in AD?'.

Dead Sea treatment - principle for outpatient use in atopic dermatitis: safety and efficacy of synchronous balneophototherapy using narrowband UVB and bathing in Dead Sea salt solution.

Safety and efficacy of this new treatment modality for out-patients were evaluated by an uncontrolled multicenter trial under GCP-conditions. Patients had to undergo 3-5 treatment sessions per week up to 35 in total. SCORAD (SC) was assessed at baseline, after 20 and 35 sessions. For patients with early study withdrawal the last-observation-carry-forward-principle was used. 615 intention-to-treat (itt)- (baseline SC: 59.4) and 143 according-to-protocol (atp)-patients (baseline SC: 60.1) could be analysed. 289 patients (47%) (baseline SC: 59.1) underwent less than 35 sessions. Main reasons were: lack of time (16%), non-compliance (12%), good improvement (7%), lack of efficacy (6%), intercurrent disease (4%) and side effects (3%). Mean number of sessions in atp-group was 35, in itt 26, and in patients with early study withdrawal 15.8. SC decreased in atp-group to 37.5 (itt: 44.5/patients with early study withdrawal: 46.1) after 20 sessions and to 27.1 (35.2/42.6) at end of treatment. Relative SC-improvement was statistically significant in atp- (55%), itt-group (41%), and in patients with early study withdrawal (26%). Most frequent side effects were: erythema in 7.3%, burning of skin due to salt solution in 3.6%. Safety and efficacy could be proven in both atp- and itt-group. A marked difference in efficacy between atp and itt underlines the importance of evaluating itt-data providing a more realistic assessment of a treatment modality in practice. This treatment is especially recommended for patients with chronic type of AD, high compliance and time free for therapy.