Cost-utility analysis of increasing uptake of universal seasonal quadrivalent influenza vaccine (QIV) in children aged 6 months and older in Germany.

Seasonal influenza causes many cases and related deaths in Europe annually, despite ongoing vaccination programs for older adults and people at high-risk of complications. Children have the highest risk of infection and play a key role in disease transmission. Our cost-utility analysis, based on a dynamic transmission model, estimated the impact of increasing the current vaccination coverage with inactivated quadrivalent influenza vaccine in Germany to all (healthy and high-risk) children under 5 years of age (40% uptake), or under 18 years (40% uptake), or only high-risk children under 18 years (90% uptake). Eight influenza complications were modeled, hospitalization and death rates were based on age and risk status. All three vaccination strategies provided more health benefits than the existing vaccination situation, reducing influenza cases, complications, hospitalizations and deaths across the entire population. The strategy targeting all children under 5 years was highly cost-effective (€6/quality-adjusted life-year gained, payer perspective). The other strategies were cost saving from the payer and societal perspectives. The vaccination strategy targeting all children under 18 years was estimated to provide the most health benefits (preventing on average 1.66 million cases, 179,000 complications, 14,000 hospitalizations and 3,600 deaths due to influenza annually) and the most cost savings (annually €20.5 million and €731.3 million from payer and societal perspectives, respectively). Our analysis provides policy decision-makers with evidence supporting strategies to expand childhood influenza vaccination, to directly protect children, and indirectly all other unvaccinated age groups, in order to reduce the humanistic and economic burden on healthcare systems and society.

What is the context? Every winter, millions of people in Europe become ill due to influenza (flu), and some need to be hospitalized for complications that can sometimes lead to death.While mainly older adults and people with chronic illness are at higher risk of complications from influenza, children have the highest risk of infection and of transmitting the disease.Current vaccination policies in Europe, including Germany, target older adults and high-risk populations (pregnant women, children and other age groups with chronic diseases).What is new? This analysis simulates the effects of expanding current German vaccination programs in high-risk children to include healthy children, and of increasing vaccination coverage rates, for direct protection against infection, and to reduce the disease transmission in the rest of the population.We modeled three vaccination strategies: vaccinating 40% of all (healthy and high- risk) children under 5 years old;vaccinating 40% of all (healthy and high-risk) children under 18 years old;vaccinating 90% of high-risk children under 18 years old.What is the impact? All three strategies resulted in health gains, as more influenza cases, complications and deaths were prevented in all age groups of the population compared to the current situation.The strategies targeting both healthy and high-risk children provided the greatest health benefits. In particular, a vaccination policy targeting all children under 18 years old was predicted to provide the most health benefits as well as the highest cost savings: the increased costs of vaccination were more than offset by the savings in disease management costs as a result of having fewer influenza patients.Vaccinating healthy children against influenza is expected to significantly reduce the disease burden in the total population while saving costs, due to reduced transmission of the disease.

COVID-19 case findings and contact tracing in South German nursing homes.

BACKGROUND: The air borne SARS-CoV-2 poses a high threat to the elderly and people with underlying diseases. COVID-19 spread quickly in South German nursing homes and for this reason called for preventive measures by the German government. The aim of this paper is to showcase the testing strategies implemented by the Public Health Department Reutlingen to control the spread of COVID-19 in local nursing homes and to report the results thereof. METHODS: This study reports COVID-19 outbreaks in nursing homes in Reutlingen County and how they were dealt with through extensive testing, contact tracing, isolation and hygiene inspections. The testing strategy consisted of three phases: In phase 1 only suspected cases, in phase 2 all staff and residents, and in phase 3 all suspected cases and their contacts were tested. RESULTS: Nearly all residents (98%) and staff members (92%) of all nursing homes in Reutlingen County were tested for SARS-COV-2. 25 of 37 nursing homes had COVID-19 cases, 5 had 30-81 cases/home. 62% of the 395 nursing homes cases were residents, but less than half of them exhibited symptoms (41%). The cases uncovered in nursing homes represented 26% of all 1529 cases in Reutlingen County during the time of this study. CONCLUSIONS: Many COVID-19 cases were discovered through extensive testing, allowing for early interventions. The results shed light on the COVID-19 situation in nursing homes and allowed for individually designed preventive measures. The results also lead to a change in the German legislation. The outbreak management methods of the Public Health Department Reutlingen may also be applicable in other countries.

A Computational Model of Bacterial Population Dynamics in Gastrointestinal Yersinia enterocolitica Infections in Mice.

The complex interplay of a pathogen with its virulence and fitness factors, the host's immune response, and the endogenous microbiome determine the course and outcome of gastrointestinal infection. The expansion of a pathogen within the gastrointestinal tract implies an increased risk of developing severe systemic infections, especially in dysbiotic or immunocompromised individuals. We developed a mechanistic computational model that calculates and simulates such scenarios, based on an ordinary differential equation system, to explain the bacterial population dynamics during gastrointestinal infection. For implementing the model and estimating its parameters, oral mouse infection experiments with the enteropathogen, Yersinia enterocolitica (Ye), were carried out. Our model accounts for specific pathogen characteristics and is intended to reflect scenarios where colonization resistance, mediated by the endogenous microbiome, is lacking, or where the immune response is partially impaired. Fitting our data from experimental mouse infections, we can justify our model setup and deduce cues for further model improvement. The model is freely available, in SBML format, from the BioModels Database under the accession number MODEL2002070001.

Estimating the impact of control measures to prevent outbreaks of COVID-19 associated with air travel into a COVID-19-free country.

We aimed to estimate the risk of COVID-19 outbreaks associated with air travel to a COVID-19-free country [New Zealand (NZ)]. A stochastic version of the SEIR model CovidSIM v1.1, designed specifically for COVID-19 was utilised. We first considered historical data for Australia before it eliminated COVID-19 (equivalent to an outbreak generating 74 new cases/day) and one flight per day to NZ with no interventions in place. This gave a median time to an outbreak of 0.2 years (95% range of simulation results: 3 days to 1.1 years) or a mean of 110 flights per outbreak. However, the combined use of a pre-flight PCR test of saliva, three subsequent PCR tests (on days 1, 3 and 12 in NZ), and various other interventions (mask use and contact tracing) reduced this risk to one outbreak after a median of 1.5 years (20 days to 8.1 years). A pre-flight test plus 14 days quarantine was an even more effective strategy (4.9 years; 2,594 flights). For a much lower prevalence (representing only two new community cases per week in the whole of Australia), the annual risk of an outbreak with no interventions was 1.2% and had a median time to an outbreak of 56 years. In contrast the risks associated with travellers from Japan and the United States was very much higher and would need quarantine or other restrictions. Collectively, these results suggest that multi-layered interventions can markedly reduce the risk of importing the pandemic virus via air travel into a COVID-19-free nation. For some low-risk source countries, there is the potential to replace 14-day quarantine with alternative interventions. However, all approaches require public and policy deliberation about acceptable risks, and continuous careful management and evaluation.

Epidemiological analysis of 3,219 COVID-19 outbreaks in the state of Baden-Wuerttemberg, Germany.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has emerged as an unprecedented global crisis challenging health systems. This paper aims to assess and characterise SARS-CoV-2 outbreaks in the state of Baden-Wuerttemberg to identify groups at greatest risk, to establish early measures to curb transmission. We analysed all mandatory notified (i.e. laboratory-confirmed) coronavirus disease (COVID-19) outbreaks with more than two cases in Baden-Wuerttemberg from calendar weeks 18-49 (from 27 April to 6 December 2020). We used the following classification for settings: asylum and refugee accommodation, care homes, care facilities, day care child centres, hobby-related, hospitality, hospitals, households, other, residence halls, schools, supported housing, training schools, transportation, treatment facilities and workplace (occupational). We used R program version 3.6.3 for analysis. In our analysis, 3219 outbreaks with 22 238 individuals were included. About 48% were in household and hobby-related settings. Care homes accounted for 9.5% of outbreaks and 21.6% of cases. The median age across all settings was 43 (interquartile range (IQR) 24-63). The median age of cases in care homes was 81 (IQR 56-88). Of all reported cases in care homes, 72.1% were women. Over 30% (466/1511) of hospitalisations were among cases in care homes compared to 17.7% (268/1511) in households. Overall, 70% (500/715) of all deceased persons in outbreaks in the study period were in care homes compared to 4.2% in household settings (30/715). We observed an exponential increase in the number of notified outbreaks starting around the 41st week with N = 291 outbreaks reported in week 49. The median number of cases in outbreaks in care homes and care facilities after the 40th week was 14 (IQR 5-29) and 11 (IQR 5-20), respectively, compared to 3 (IQR 3-5) in households. We observed an increase in hospitalisations, and mortality associated with COVID-19 outbreaks in care homes after the 40th week. We found the care home demographic to be at greatest risk after the 40th week, based on the exponential increase in outbreaks, the number of cases, hospitalisations and mortality trends. Our analysis highlights the necessity of targeted, setting-specific approaches to control transmission in this vulnerable population. Regular screening of staff members and visitors' using rapid antigen point-of-care-tests could be a game-changer in curbing transmission in this setting.

Cost-effectiveness of the cell-based quadrivalent versus the standard egg-based quadrivalent influenza vaccine in Germany.

BACKGROUND: Standard influenza vaccines are produced using egg-based manufacturing methods. Through the process, the resulting egg-adapted viral strains may differ from the selected vaccine strain. Cell-derived influenza vaccine manufacturing prevents egg-adaptation of the antigen which can improve vaccine effectiveness. We evaluated the cost-effectiveness of quadrivalent cell-derived influenza vaccine (QIVc) versus an egg-based quadrivalent influenza vaccine (QIVe) in preventing seasonal influenza from German societal and payer perspectives. METHODS: Adapted version of the individual-based dynamic 4Flu transmission model was combined with a decision-tree to calculate the impact of QIVc versus QIVe on influenza over 20 seasons in Germany. Egg-adaptation, resulting in lower effectiveness of QIVe versus QIVc towards the H3N2 influenza strain, is sourced from a US retrospective study and assumed in 100% (base case) or 55% (conservative scenario) of years. Influenza-related probabilities of outpatient visits, hospitalizations, productivity loss, and mortality, with associated (dis)utilities/costs, were extracted from literature. Costs and outcomes were discounted 3.0%/year. RESULTS: Replacing QIVe with QIVc in subjects aged ≥ 9 years can annually prevent 167,265 symptomatic cases, 51,114 outpatient visits, 2,091 hospitalizations, and 103 deaths in Germany. The annual number of quality-adjusted life-years (QALYs) increased by 1,628 and healthcare costs decreased by €178 M from societal perspective. From payer perspective, the incremental cost-effectiveness ratio was €2,285 per QALY. Scenario analyses confirmed results robustness. CONCLUSIONS: The use of QIVc compared to QIVe, in the German Immunization Program, could significantly prevent outpatient visits and hospitalizations and would enable substantial savings from a societal perspective.

Estimating the risk of outbreaks of COVID-19 associated with shore leave by merchant ship crews: simulation studies for New Zealand.

AIM: We aimed to estimate the risk of COVID-19 outbreaks in a COVID-19-free destination country (New Zealand) associated with shore leave by merchant ship crews who were infected prior to their departure or on their ship. METHODS: We used a stochastic version of the SEIR model CovidSIM v1.1 designed specifically for COVID-19. It was populated with parameters for SARS-CoV-2 transmission, shipping characteristics and plausible control measures. RESULTS: When no control interventions were in place, we estimated that an outbreak of COVID-19 in New Zealand would occur after a median time of 23 days (assuming a global average for source country incidence of 2.66 new infections per 1,000 population per week, crews of 20 with a voyage length of 10 days and 1 day of shore leave per crew member both in New Zealand and abroad, and 108 port visits by international merchant ships per week). For this example, the uncertainty around when outbreaks occur is wide (an outbreak occurs with 95% probability between 1 and 124 days). The combination of PCR testing on arrival, self-reporting of symptoms with contact tracing and mask use during shore leave increased this median time to 1.0 year (14 days to 5.4 years, or a 49% probability within a year). Scenario analyses found that onboard infection chains could persist for well over 4 weeks, even with crews of only 5 members. CONCLUSION: This modelling work suggests that the introduction of SARS-CoV-2 through shore leave from international shipping crews is likely, even after long voyages. But the risk can be substantially mitigated by control measures such as PCR testing and mask use.

Immunomodulatory role of reactive oxygen species and nitrogen species during T cell-driven neutrophil-enriched acute and chronic cutaneous delayed-type hypersensitivity reactions.

Rationale: Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important regulators of inflammation. The exact impact of ROS/RNS on cutaneous delayed-type hypersensitivity reaction (DTHR) is controversial. The aim of our study was to identify the dominant sources of ROS/RNS during acute and chronic trinitrochlorobenzene (TNCB)-induced cutaneous DTHR in mice with differently impaired ROS/RNS production. Methods: TNCB-sensitized wild-type, NADPH oxidase 2 (NOX2)- deficient (gp91phox-/-), myeloperoxidase-deficient (MPO-/-), and inducible nitric oxide synthase-deficient (iNOS-/-) mice were challenged with TNCB on the right ear once to elicit acute DTHR and repetitively up to five times to induce chronic DTHR. We measured ear swelling responses and noninvasively assessed ROS/RNS production in vivo by employing the chemiluminescence optical imaging (OI) probe L-012. Additionally, we conducted extensive ex vivo analyses of inflamed ears focusing on ROS/RNS production and the biochemical and morphological consequences. Results: The in vivo L-012 OI of acute and chronic DTHR revealed completely abrogated ROS/RNS production in the ears of gp91phox-/- mice, up to 90 % decreased ROS/RNS production in the ears of MPO-/- mice and unaffected ROS/RNS production in the ears of iNOS-/- mice. The DHR flow cytometry analysis of leukocytes derived from the ears with acute DTHR confirmed our in vivo L-012 OI results. Nevertheless, we observed no significant differences in the ear swelling responses among all the experimental groups. The histopathological analysis of the ears of gp91phox-/- mice with acute DTHRs revealed slightly enhanced inflammation. In contrast, we observed a moderately reduced inflammatory immune response in the ears of gp91phox-/- mice with chronic DTHR, while the inflamed ears of MPO-/- mice exhibited the strongest inflammation. Analyses of lipid peroxidation, 8-hydroxy-2'deoxyguanosine levels, redox related metabolites and genomic expression of antioxidant proteins revealed similar oxidative stress in all experimental groups. Furthermore, inflamed ears of wild-type and gp91phox-/- mice displayed neutrophil extracellular trap (NET) formation exclusively in acute but not chronic DTHR. Conclusions: MPO and NOX2 are the dominant sources of ROS/RNS in acute and chronic DTHR. Nevertheless, depletion of one primary source of ROS/RNS exhibited only marginal but conflicting impact on acute and chronic cutaneous DTHR. Thus, ROS/RNS are not a single entity, and each species has different properties at certain stages of the disease, resulting in different outcomes.

The COVID-19 pandemic preparedness simulation tool: CovidSIM.

BACKGROUND: Efficient control and management in the ongoing COVID-19 pandemic needs to carefully balance economical and realizable interventions. Simulation models can play a cardinal role in forecasting possible scenarios to sustain decision support. METHODS: We present a sophisticated extension of a classical SEIR model. The simulation tool CovidSIM Version 1.0 is an openly accessible web interface to interactively conduct simulations of this model. The simulation tool is used to assess the effects of various interventions, assuming parameters that reflect the situation in Austria as an example. RESULTS: Strict contact reduction including isolation of infected persons in quarantine wards and at home can substantially delay the peak of the epidemic. Home isolation of infected individuals effectively reduces the height of the peak. Contact reduction by social distancing, e.g., by curfews, sanitary behavior, etc. are also effective in delaying the epidemic peak. CONCLUSIONS: Contact-reducing mechanisms are efficient to delay the peak of the epidemic. They might also be effective in decreasing the peak number of infections depending on seasonal fluctuations in the transmissibility of the disease.

Detecting the re-emergent COVID-19 pandemic after elimination: modelling study of combined primary care and hospital surveillance.

AIMS: We aimed to determine the effectiveness of surveillance using testing for SARS-CoV-2 to identify an outbreak arising from a single case of border control failure in a country that has eliminated community transmission of COVID-19: New Zealand. METHODS: A stochastic version of the SEIR model CovidSIM v1.1 designed specifically for COVID-19 was utilised. It was seeded with New Zealand population data and relevant parameters sourced from the New Zealand and international literature. RESULTS: For what we regard as the most plausible scenario with an effective reproduction number of 2.0, the results suggest that 95% of outbreaks from a single imported case would be detected in the period up to day 36 after introduction. At the time point of detection, there would be a median number of five infected cases in the community (95% range: 1-29). To achieve this level of detection, an ongoing programme of 5,580 tests per day (1,120 tests per million people per day) for the New Zealand population would be required. The vast majority of this testing (96%) would be of symptomatic cases in primary care settings and the rest in hospitals. CONCLUSIONS: This model-based analysis suggests that a surveillance system with a very high level of routine testing is probably required to detect an emerging or re-emerging SARS-CoV-2 outbreak within five weeks of a border control failure in a nation that had previously eliminated COVID-19. Nevertheless, there are plausible strategies to enhance testing yield and cost-effectiveness and potential supplementary surveillance systems such as the testing of town/city sewerage systems for the pandemic virus.

[Surgical techniques in the treatment of basal cell carcinoma-a prospective investigation]. / Chirurgische Techniken in der Therapie des Basalzellkarzinoms ­ eine prospektive Untersuchung.

BACKGROUND: Basal cell carcinomas are the most frequent epithelial skin tumors and a frequent indication for dermatological interventions. Despite the establishment of drug treatment options, surgery is still the treatment of choice. Various options are available ranging from curettage to complex dermatosurgical procedures. In addition to the main aspect of low local recurrence rates, esthetic factors and the number of procedures are also important for the choice of treatment. METHODS: In this study 347 patients with 398 basal cell carcinomas (nodular type, diameter up to 10 mm) were prospectively examined. The patients were randomized into two treatment arms: in one group the tumor was treated by ring curettage and in the other group the tumor was excised. Patients who underwent 3D histologically controlled surgery due to basal cell carcinoma during the same investigation period served as controls. RESULTS: The highest local recurrence rate was observed after curettage (14.0%), whereas the group with 3D histology had the lowest recurrence rate (0.9%, p < 0.001). In the 3D group, more re-excisions were required to achieve complete tumor clearance compared to the group who underwent excisions with serial section histology. Patients rated the esthetic outcome best after curettage. The median follow-up was 3.9 years. CONCLUSION: The choice of surgical treatment for small nodular basal cell carcinomas depends on individual circumstances. Excisions controlled by 3D histology with wound closure after complete tumor clearance showed the lowest recurrence rate in our study; however, curettage is also a possible surgical treatment option with minimal effort and an acceptable recurrence rate, which can lead to good esthetic results.

Cancer immune control needs senescence induction by interferon-dependent cell cycle regulator pathways in tumours.

Immune checkpoint blockade (ICB)-based or natural cancer immune responses largely eliminate tumours. Yet, they require additional mechanisms to arrest those cancer cells that are not rejected. Cytokine-induced senescence (CIS) can stably arrest cancer cells, suggesting that interferon-dependent induction of senescence-inducing cell cycle regulators is needed to control those cancer cells that escape from killing. Here we report in two different cancers sensitive to T cell-mediated rejection, that deletion of the senescence-inducing cell cycle regulators p16Ink4a/p19Arf (Cdkn2a) or p21Cip1 (Cdkn1a) in the tumour cells abrogates both the natural and the ICB-induced cancer immune control. Also in humans, melanoma metastases that progressed rapidly during ICB have losses of senescence-inducing genes and amplifications of senescence inhibitors. Metastatic cells also resist CIS. Such genetic and functional alterations are infrequent in metastatic melanomas regressing during ICB. Thus, activation of tumour-intrinsic, senescence-inducing cell cycle regulators is required to stably arrest cancer cells that escape from eradication.

Prognostic Impact of Perineural Invasion in Cutaneous Squamous Cell Carcinoma: Results of a Prospective Study of 1,399 Tumors.

Perineural infiltration (PNI) and desmoplasia are believed to be high-risk factors in the prognosis of squamous cell carcinoma (SCC). In the literature, dependences between PNI, de-differentiation, and desmoplasia remain unclear. The aim of this study was to analyze the respective prognostic impact of these factors in regard to local recurrence and metastasis. Between 2005 and 2015, 1,399 unselected primary SCCs of 1,434 patients were diagnosed. If a patient had multiple tumors, the tumor with the highest risk profile was selected. Histological sections of all tumors with a tumor thickness of ≥6 mm and desmoplastic SCC with a tumor thickness of 2.1-5.9 mm were re-examined for PNI. Median follow-up was 36.5 months. PNI was present exclusively within tumors of the desmoplastic type (14.5%). PNI was present significantly more often in patients developing lymph node metastasis (3% all non-desmoplastic SCC, 17% desmoplastic SCC, and 29% desmoplastic SCC with PNI) and local recurrence (3%, 26%, and 64%) and associated with overall tumor-specific death (4%, 25%, and 54%). Using a multivariate model of disease recurrence, tumor thickness ≥6 mm, tumor horizontal size ≥20 mm, immunosuppression, desmoplasia, and PNI remained significant factors. In conclusion, PNI was found to be an additional marker indicative of an unfavorable prognosis and an independent high-risk factor within the desmoplastic type of SCC.

Assessing direct and indirect effects of pediatric influenza vaccination in Germany by individual-based simulations.

Children have a high burden of influenza and play a central role in spreading influenza. Routinely vaccinating children against influenza may, thus, not only reduce their disease burden, but also that of the general population, including the elderly who frequently suffer severe complications. Using the published individual-based tool 4Flu, we simulated how pediatric vaccination would change infection incidence in Germany. Transmission of four influenza strains was simulated in 100,000 individuals with German demography and contact structure. After initialization with the recorded trivalent influenza vaccination coverage for 20 years (1997-2016), all vaccinations were switched to quadrivalent influenza vaccine (QIV). Scenarios where vaccination coverage of children (0.5-17-year-old) was increased from the current value (4.3%) to a maximum of 10-60% were compared to baseline with unchanged coverage, averaging results of 1,000 pairs of simulations over a 20-year evaluation period (2017-2036). Pediatric vaccination coverage of 10-60% annually prevented 218-1,732 (6.3-50.5%) infections in children, 204-1,961 (2.9-28.2%) in young adults and 95-868 (3.1-28.9%) in the elderly in a population of 100,000 inhabitants; overall, 34.1% of infections in the total population (3.7 million infections per year in Germany) can be prevented if 60% of all children are vaccinated annually. 4.4-4.6 vaccinations were needed to prevent one infection among children; 1.7-1.8 were needed to prevent one in the population. Enhanced pediatric vaccination prevents many infections in children and even more in young adults and the elderly.