West Nile Virus Emergence in Germany 2019: Looking for Hidden Human West Nile Virus Infections.

Background: Autochthonous human West Nile virus (WNV) infections were notified in the infectious disease surveillance system in Germany in 2018 for the first time and every year since then. Since clinically apparent infections are infrequent, we conducted two studies to investigate subclinical infections of this emerging disease in Germany in 2019 to detect infections not visible to surveillance based on symptomatic infections: limited-scope blood donor testing and a serosurvey among employees at two Berlin zoos with a history of demonstrated WNV infections in animals. Methods: For the zoo study, employees of the two zoos in Berlin were invited to participate in the study in late 2019. Blood samples were drawn and tested for the presence of antibodies (immunoglobulin M [IgM] and immunoglobulin G [IgG]) against WNV, and two other flaviviruses present in Germany: Usutu virus and Tick-borne encephalitis virus (TBEV). For the study in blood donors, four blood establishments with collection sites in regions with documented WNV-infected animals in 2018 and 2019 participated in the study. All donations in these regions were tested for WNV genome from July to November 2019. Results: In the enzyme-linked immunosorbent assay, none of the 70 tested zoo employees were WNV IgM-positive, 8 were WNV IgG-positive, additional 2 participants had equivocal results. All 10 were negative in the virus neutralization test (VNT) for WNV, but positive in the VNT for TBEV. None of the 4273 samples from blood donors tested in areas with WNV-infected animals was positive for WNV-RNA. Conclusion: Our results indicate that WNV circulation in Germany, though clearly documented in animals in 2019, apparently affected very few humans. Still areas with WNV-positive animals remain risk areas for human infection as well.

Longitudinal effects of ambivalent and guilt feelings on dementia family caregivers' depressive symptoms.

BACKGROUND: The world prevalence of people with dementia is increasing. Most of the care received by people with dementia is provided by family caregivers, and this prolonged activity has a significant impact on caregivers' levels of depression. Stressors and frequency of leisure are known predictors of caregivers' depressive levels. The longitudinal impact of caregivers' ambivalent and guilt feelings is unknown. METHODS: Participants were 177 family caregivers of relatives with dementia who were assessed three times during a 2-year period. In addition to demographic variables, psychological symptoms of the dementias, and frequency of leisure activities, caregivers' ambivalent feelings, guilt, and depressive symptoms were measured. The longitudinal association of changes in these variables with changes in caregivers' depressive symptoms over time was assessed using mixed linear models. RESULTS: Changes over time in the assessed variables predicted 48.05% of variance of changes over time in depressive symptoms. Even when variables strongly associated with increased depressive symptoms were controlled (lower caregivers' age and educational level, higher reaction to BPSD, and lower leisure activities), increases in ambivalence and guilt contributed to an increase of 9.22% of the variance of changes depressive symptoms over a 2-year period. The effects of ambivalent feelings on depression are indirect, mediated by guilt feelings. Cessation of caregiving do not seem to alter these findings. CONCLUSIONS: Caregivers' ambivalent and guilt feelings are significant predictors of caregivers' mental health. Caregivers may significantly benefit from early detection of ambivalent and guilt feelings and preventive strategies targeting triggers associated with ambivalent and guilt symptoms.

External quality assessment of orthohantavirus and lymphocytic choriomeningitis virus molecular detection and serology in Europe, 2021.

BackgroundRodent-borne viruses such as orthohantaviruses and arenaviruses cause considerable disease burden with regional and temporal differences in incidence and clinical awareness. Therefore, it is important to regularly evaluate laboratory diagnostic capabilities, e.g. by external quality assessments (EQA).AimWe wished to evaluate the performance and diagnostic capability of European expert laboratories to detect orthohantaviruses and lymphocytic choriomeningitis virus (LCMV) and human antibody response towards orthohantaviruses.MethodsWe conducted an EQA in 2021; molecular panels consisted of 12 samples, including different orthohantaviruses (Seoul, Dobrava-Belgrade (DOBV), Puumala (PUUV) and Hantaan orthohantavirus), LCMV and negative controls. Serological panels consisted of six human serum samples reactive to PUUV, DOBV or negative to orthohantaviruses. The EQA was sent to 25 laboratories in 20 countries.ResultsThe accuracy of molecular detection of orthohantaviruses varied (50‒67%, average 62%) among 16 participating laboratories, while LCMV samples were successfully detected in all 11 participating laboratories (91-100%, average 96%). The accuracy of serological diagnosis of acute and past orthohantavirus infections was on average 95% among 20 participating laboratories and 82% in 19 laboratories, respectively. A variety of methods was used, with predominance of in-house assays for molecular tests, and commercial assays for serological ones.ConclusionSerology, the most common tool to diagnose acute orthohantavirus infections, had a high accuracy in this EQA. The molecular detection of orthohantaviruses needs improvement while LCMV detection (performed in fewer laboratories) had 95% accuracy. Further EQAs are recommended to be performed periodically to monitor improvements and challenges in the diagnostics of rodent-borne diseases.

Cross-National Analysis of the Associations Between Familism and Self-Efficacy in Family Caregivers of People With Dementia: Effects on Burden and Depression.

Objectives: To examine the cross-national associations between familism and self-efficacy dimensions, and levels of burden and depression. Methods: Sociodemographic, familism, self-efficacy, depressive symptoms, and burden variables were measured in 349 dementia family caregivers from the US and Spain. Results: US sample: greater support from family was positively related to self-efficacy for obtaining respite and self-efficacy for controlling upsetting thoughts and behaviors. Both self-efficacy constructs were negatively related to depression. Similar findings were obtained for burden. Spanish sample: higher scores on family as referents were associated with lower scores on self-efficacy for obtaining respite; lower scores on self-efficacy for obtaining respite were associated with higher depressive symptomatology. Discussion: Study findings suggest that a significant interplay exists between the various facets of familism and self-efficacy, leading to differential caregiving outcomes. Unique cultural contexts and values derived from each country may exert distinct influences on how the caregiving role is perceived and appraised.

Sociocultural factors, guilt and depression in family caregivers of people with dementia. Kinship differences.

OBJECTIVES: This study aims to analyze the role that family obligations and social desirability have for understanding guilt and depressive symptoms in family caregivers. A theoretical model is proposed to analyze this significance based on the kinship with the person cared for. METHODS: Participants are 284 family caregivers of people with dementia divided into four kinship groups (husbands, wives, daughters and sons). Face-to-face interviews were conducted assessing sociodemographic variables, familism (family obligations), dysfunctional thoughts, social desirability, frequency and discomfort associated with problematic behaviors, guilt and depressive symptoms. Path analyses are performed to analyze the fit of the proposed model and multigroup analysis to study potential differences between kinship groups. RESULTS: The proposed model fits the data well and explains significant percentages of variance of guilt feelings and depressive symptomatology for each group. The multigroup analysis suggests that, for daughters, higher family obligations were associated with depressive symptomatology through a report of higher dysfunctional thoughts. For daughters and wives, an indirect association between social desirability and guilt was observed through reaction to problematic behaviors. CONCLUSION: The results support the need to consider the significance of sociocultural aspects such as family obligations and the desirability bias in the design and implementation of interventions for caregivers, especially for daughters. Considering that the variables that contribute to explaining caregivers' distress vary depending on the relationship with the person cared for, individualized interventions may be warranted depending on the kinship group.

Family caregivers of people with dementia in the context of the sociocultural stress and coping model: An examination of gender differences.

The study assessed gender differences in the associations between familism dimensions, dysfunctional thoughts, and resource and outcome variables in 190 Spanish dementia family caregivers. A theoretical model was tested through path analysis, obtaining an excellent fit of the model to the data. Higher scores in the familial obligations dimension were associated with lower self-efficacy for self-care and obtaining respite and leisure frequency, and higher anxious and depressive feelings, in female caregivers only. Significant between-gender differences were obtained, suggesting that female caregivers holding strong familistic values are more vulnerable to the negative consequences of caregiving compared to male caregivers.

Cross-cultural analysis of the role of ambivalent feelings for understanding caregivers' depressive symptoms.

OBJECTIVES: Behavioral and psychological symptoms of dementia (BPSD) are considered to cause ambivalent feelings in caregivers that may contribute to understanding their depressive symptoms. Transnational research is needed in order to increase our knowledge about the cross-cultural equivalence of theoretical models to understand caregivers' mental health. The aim of this study was to cross-culturally analyze the association between BPSD, ambivalent feelings and depressive symptoms in two samples of family caregivers of people with dementia from Spain and the UK. METHODS: Participants in this study were 432 caregivers who completed measures of BPSD, ambivalent feelings and depressive symptoms. The association between the assessed variables was tested through path-analysis, with differences between countries tested through multigroup analysis. RESULTS: The results suggest that the influence of BPSD on caregivers' depressive symptoms is indirect, through ambivalent feelings. The observed associations were equivalent between countries and explained a significant percentage of the variance of depressive symptoms. CONCLUSION: The findings of this study provide, for the first time, evidence of equivalent cross-cultural paths analyzing the role of ambivalent feelings for understanding caregivers' depressive symptoms. The practical implications of these results are discussed.

Seroconversion and persistence of neutralizing antibody response after yellow fever vaccination in patients with perinatally acquired HIV infection.

OBJECTIVES: To describe the dynamics of neutralizing antibody (NAbs) response after yellow fever (YF) vaccine in young adults and adolescents with perinatally acquired HIV (pHIV). DESIGN: A retrospective cross-sectional study at three time points around YF vaccination and a matched case-control comparison of NAbs titers several years after YF vaccination. METHODS: We selected patients who had both documented YF vaccination and perinatally acquired HIV (n = 46). The NAbs titers were measured in plasma samples from the following three time points: during the two years before (TP0), within the year after (TP1) and >1 year after (TP2) administration of the YF vaccine. The impact of perinatal infection was assessed by comparing pHIV YF vaccinees with 44 controls infected with HIV during adulthood. RESULTS: The median time between the YF vaccine and TP1 and TP2 was 123 days and 7.3 years, respectively. After YF vaccination, 85% of vaccinees experienced seroconversion. The proportion of pHIV patients with NAbs above the protective threshold was stable between TP1 and TP2 (91% and 86%, respectively) but levels of NAbs decreased significantly between TP1 and TP2 (P = 0.0122). The case-control analysis found slightly higher geometrical mean titers (GMT) in pHIV than patients infected during adulthood. CONCLUSIONS: Patients with pHIV showed high seroconversion rate and NAbs persistence at levels above the protective threshold after first YF vaccination. However, a decline in antibody levels over time suggests that at least one revaccination may be necessary to maintain circulating antibodies, contrary to recommendations for the general population.

Laboratory evaluation of RealStar Yellow Fever Virus RT-PCR kit 1.0 for potential use in the global yellow fever laboratory network.

BACKGROUND: Early detection of human yellow fever (YF) infection in YF-endemic regions is critical to timely outbreak mitigation. African National Laboratories chiefly rely on serological assays that require confirmation at Regional Reference Laboratories, thus delaying results, which themselves are not always definitive often due to antibody cross-reactivity. A positive molecular test result is confirmatory for YF; therefore, a standardized YF molecular assay would facilitate immediate confirmation at National Laboratories. The WHO-coordinated global Eliminate Yellow Fever Epidemics Laboratory Technical Working Group sought to independently evaluate the quality and performance of commercial YF molecular assays relevant to use in countries with endemic YF, in the absence of stringent premarket assessments. This report details a limited laboratory WHO-coordinated evaluation of the altona Diagnostics RealStar Yellow Fever Virus RT-PCR kit 1.0. METHODOLOGY AND PRINCIPAL FINDINGS: Specific objectives were to assess the assay's ability to detect YF virus strains in human serum from YF-endemic regions, determine the potential for interference and cross-reactions, verify the performance claims as stated by the manufacturer, and assess usability. RNA extracted from normal human serum spiked with YF virus showed the assay to be precise with minimal lot-to-lot variation. The 95% limit of detection calculated was approximately 1,245 RNA copies/ml [95% confidence interval 497 to 1,640 copies/ml]. Positive results were obtained with spatially and temporally diverse YF strains. The assay was specific for YF virus, was not subject to endogenous or exogenous interferents, and was clinically sensitive and specific. A review of operational characteristics revealed that a positivity cutoff was not defined in the instructions for use, but otherwise the assay was user-friendly. CONCLUSIONS AND SIGNIFICANCE: The RealStar Yellow Fever Virus RT-PCR kit 1.0 has performance characteristics consistent with the manufacturer's claims and is suitable for use in YF-endemic regions. Its use is expected to decrease YF outbreak detection times and be instrumental in saving lives.

Duration of Protection After Vaccination Against Yellow Fever: A Systematic Review and Meta-Analysis.

The duration of protection after a single dose of yellow fever vaccine is a matter of debate. To summarize the current knowledge, we performed a systematic literature review and meta-analysis. Studies on the duration of protection after 1 and ≥2 vaccine doses were reviewed. Data were stratified by time since vaccination. In our meta-analysis, we used random-effects models. We identified 36 studies from 20 countries, comprising more than 17 000 participants aged 6 months to 85 years. Among healthy adults and children, pooled seroprotection rates after single vaccination dose were close to 100% by 3 months and remained high in adults for 5 to 10 years. In children vaccinated before age 2 years, the seroprotection rate was 52% within 5 years after primary vaccination. For immunodeficient persons, data indicate relevant waning. The extent of waning of seroprotection after yellow fever vaccination depends on age and immune status at primary vaccination.

Seroconversion and antibody persistence after yellow fever vaccination in people living with HIV: impact of baseline HIV viral load and yellow fever seropositivity.

BACKGROUND: Data on seroconversion rates following yellow fever (YF) vaccine and effect of revaccination in people living with HIV (PLWH) are scarce. We aimed at determining key factors for seroconversion after YF vaccine in PLWH and the role of preexisting neutralizing antibodies (NAbs) at vaccination. METHODS: A retrospective cross-sectional study at several timepoints in two Belgian AIDS Reference Center. For each individual, plasma samples from three timepoints were selected: Timepoint 0 (TP0) in the year before administration of the YF vaccine, Timepoint 1 (TP1) in the year following the YF vaccine, Timepoint 2 (TP2) >1 year after the YF vaccine. Plasma samples were analysed for YF NAbs by plaque reduction neutralization test. The primary endpoint was the number of patients with protective levels of NAbs ≥ 1/10. A boosted immune response was defined as a 4-fold increase in serologic titres following revaccination. RESULTS: Of the 160 PLWH included, protective levels of NAbs were present in 36%, 87% and 72% of subjects at baseline, at a median of 12 months and a median of 96 months after YF vaccination, respectively. Among vaccine recipients negative for YF NAbs at baseline (n = 102), 83% seroconverted. PLWH with undetectable HIV viral load (VL) at baseline were more likely to seroconvert (P < 0·01). A booster response was observed in only 17% of subjects with baseline seropositivity (n = 10 out of 58). In multivariate analysis, undetectable HIV VL at vaccination and baseline YF seropositivity were associated with persistent levels of protective NAbs at a median of 8 years after YF vaccination. CONCLUSION: Undetectable HIV VL at baseline is associated with high rates of seroconversion. YF seropositivity before revaccination is associated with low rates of booster effect but a higher chance of long term persistent NAbs response, suggesting a benefit of revaccination in PLWH.

Caring for Relatives with Dementia in Times of COVID-19: Impact on Caregivers and Care-recipients.

OBJECTIVES: To analyze caregivers' perceived impact of the pandemic in their mental health and the well-being of the care-recipients. METHODS: Caregivers (N = 88) were asked if they had COVID-19 and about their perceptions of change of care-recipients' health conditions as well as whether their own mental health, conflicts with care-recipients and other relatives, thoughts of giving up caregiving, and feelings of coping well with the situation. RESULTS: A large percentage of caregivers perceived a worsening of care-recipients' symptoms and of their own negative emotions, an increase in the number of conflicts and thoughts of needing to give up caregiving. Having had COVID-19 and reporting higher levels of distress as well as giving up caregiving were related to perceived worsening in care-recipients well-being. Perceived increases were mainly reported by younger caregivers, those who perceived to have not coped well, and those reporting an increase in conflicts. Some caregivers perceived an increase in positive emotions. CONCLUSIONS: The pandemic has a negative impact on caregivers' perceptions about the course of their own emotions and care-recipients' well-being. CLINICAL IMPLICATIONS: Interventions are needed to train caregivers in strategies to cope with the sources of stress caused by the pandemic and to promote social support.

Laboratory capacity assessments in 25 African countries at high risk of yellow fever, August-December 2018.

INTRODUCTION: accurate and timely laboratory diagnosis of yellow fever (YF) is critical to the Eliminate Yellow Fever Epidemics (EYE) strategy. Gavi, the Vaccine Alliance recognized the need to support and build capacity in the national and regional laboratories in the Global YF Laboratory Network (GYFLN) as part of this strategy. METHODS: to better understand current capacity, gaps and needs of the GYFLN laboratories in Africa, assessments were carried out in national and regional reference laboratories in the 25 African countries at high risk for YF outbreaks that were eligible for new financial support from Gavi. RESULTS: the assessments found that the GYFLN in Africa has high capacity but 21% of specimens were not tested due to lack of testing kits or reagents and approximately 50% of presumptive YF cases were not confirmed at the regional reference laboratory due to problems with shipping. CONCLUSION: the laboratory assessments helped to document the baseline capacities of these laboratories prior to Gavi funding to support strengthening YF laboratories.

Resource-efficient internally controlled in-house real-time PCR detection of SARS-CoV-2.

BACKGROUND: The reliable detection of SARS-CoV-2 has become one of the most important contributions to COVID-19 crisis management. With the publication of the first sequences of SARS-CoV-2, several diagnostic PCR assays have been developed and published. In addition to in-house assays the market was flooded with numerous commercially available ready-to-use PCR kits, with both approaches showing alarming shortages in reagent supply. AIM: Here we present a resource-efficient in-house protocol for the PCR detection of SARS-CoV-2 RNA in patient specimens (RKI/ZBS1 SARS-CoV-2 protocol). METHODS: Two duplex one-step real-time RT-PCR assays are run simultaneously and provide information on two different SARS-CoV-2 genomic regions. Each one is duplexed with a control that either indicates potential PCR inhibition or proves the successful extraction of nucleic acid from the clinical specimen. RESULTS: Limit of RNA detection for both SARS-CoV-2 assays is below 10 genomes per reaction. The protocol enables testing specimens in duplicate across the two different SARS-CoV-2 PCR assays, saving reagents by increasing testing capacity. The protocol can be run on various PCR cyclers with several PCR master mix kits. CONCLUSION: The presented RKI/ZBS1 SARS-CoV-2 protocol represents a cost-effective alternative in times of shortages when commercially available ready-to-use kits may not be available or affordable.

Sociocultural Influences on the Feeling of Loneliness of Family Caregivers of People with Dementia: The Role of Kinship.

The extent to which familism, dysfunctional thoughts, and coping variables contribute to explaining feelings of loneliness in caregivers, controlling for kinship, is analyzed. Participants were 273 family caregivers of people with dementia. Sociodemographic variables, familism, dysfunctional thoughts, coping strategies for requesting and receiving help, perceived social support, and leisure activities were assessed. The fit of a theoretical model for explaining the effect of cultural and psychological variables on feelings of loneliness in each kinship group was tested. No significant differences in the distribution of loneliness by kinship were found. Higher levels of familism are associated with more dysfunctional thoughts, that are linked to more maladaptive strategies for coping with caring (e.g., less social support and fewer leisure activities). This in turn is associated with higher scores in the feeling of loneliness. The model bore particular relevance to the group of daughters, husbands, and sons, yet not in the case of wives. Sociocultural and coping factors associated with the caring process seem to play an important role in explaining feelings of loneliness in caregivers. Sociocultural factors associated with the care process seem to play an important role in explaining feelings of loneliness in caregivers.

Immunogenicity and duration of protection after yellow fever vaccine in people living with human immunodeficiency virus: a systematic review.

BACKGROUND: We lack the rationale on which to base the development of a yellow fever (YF) vaccination schedule for people living with human immunodeficiency virus (PLWHIV). OBJECTIVES: To report on the current evidence regarding the seroconversion rate and the duration of humoral protection after YF vaccine, as well as the impact of revaccination in PLWHIV. DATA SOURCES: MEDLINE, Google Scholar, LILACS and Cochrane CENTRAL were searched. METHODS: We selected studies on PLWHIV of all ages (including perinatally HIV-infected patients) and all settings (YF endemic and non-endemic zones). Intervention investigated was vaccination against YF, at least once after the HIV diagnosis. The research questions were the seroconversion rate, duration of humoral immunity after YF vaccine and impact of revaccination in PLWHIV. Selected studies were assessed for quality using the Newcastle-Ottawa scale. RESULTS: Ten, six and six studies were selected for the systematic review of each question, respectively. Only one study addressed the first question in perinatally HIV-infected children. The quality of the studies was assessed as Poor (n = 16), Fair (n = 2) or Good (n = 4). A meta-analysis demonstrated that 97.6% (95% CI 91.6%-100%) of the included population seroconverted. Between 1 and 10 years after YF vaccine, reported persistence of neutralizing antibodies was 72% (95% CI 53.6%-91%), and it was 62% (95% CI 45.4%-78.6%) more than 10 years after YF vaccine. No conclusions could be drawn on impact of revaccination because of the small number of patients. CONCLUSIONS: The current evidence regarding seroconversion rate, duration of humoral protection after YF vaccine and impact of revaccination in PLWHIV is limited by the low number and quality of studies. Based on the presently available data, it is difficult to rationally develop yellow fever vaccination guidelines for PLWHIV.

Serological Protection 5-6 Years Post Vaccination Against Yellow Fever in African Infants Vaccinated in Routine Programmes.

Introduction: Although effective live attenuated yellow fever (YF) vaccines have been available for over 9 decades sporadic outbreaks continue to occur in endemic regions. These may be linked to several factors including epidemiological factors such as vector and intermediate host distribution or vaccine coverage and efficacy. The World Health Organization's research priorities include gathering systematic evidence around the potential need for booster vaccination with YF vaccine whether this follows full or fractional doses in children. Knowledge on the longevity of response to YF vaccine and the implications of this response needs to be consolidated to guide future vaccination policy. Methods: We measured anti-YF IgG by microneutralization assay in a group of 481 African infants who had received YF vaccine as part of routine EPI programmes, to explore serological protection from YF 5-6 years post YF vaccination, as well as the effect of co variates. Findings: Notably, 22.2% of the cohort had undetectable antibody concentrations, with another 7.5% revealing concentrations below the threshold of seropositivity of 0.5 IU/mL. Sex, season, country and time since vaccination did not affect the longevity of antibody concentration or having antibody concentrations above a defined threshold. Conclusion: Roughly 30% of children in this cohort did not demonstrate anti-yellow fever antibody concentrations above the defined threshold of protection, with 20% having no demonstrable antibody. Knowledge on the longevity of response to YF vaccine and the implications needs to be consolidated to guide future vaccination policy.

Severe Multiorgan Failure Following Yellow Fever Vaccination.

BACKGROUND: The yellow fever (YF) vaccination is recommended by the WHO for people traveling or living in endemic areas at risk for yellow fever infections in Africa and South America. Although the live attenuated yellow fever vaccine is a safe and efficient vaccine, rare serious adverse events after vaccination have been reported. CASE PRESENTATION: We present the case of a 74-year-old male with multiorgan failure after yellow fever vaccination for a trip to Brazil. The patient required admission to the intensive care unit with a prolonged stay due to severe organ dysfunction. Five days after the YF vaccination, the patient experienced nausea, vomiting, diarrhea, and general illness. Three days later he sought medical attention and was transferred to the University Hospital Heidelberg with beginning multiorgan failure and severe septic shock, including hypotonia, tachypnea, thrombopenia, and acute renal failure the same day. Within one week after vaccination, antibodies against YF virus were already detectable and progressively increased over the next two weeks. Viral RNA was detected in serum on the day of admission, with a viral load of 1.0 × 105 copies/mL. The YF virus (YFV) RNA was also present in tracheal secretions for several weeks and could be detected in urine samples up to 20 weeks after vaccination, with a peak viral load of 1.3 × 106 copies/mL. After 20 weeks in the ICU with nine weeks of mechanical ventilation, the patient was transferred to another hospital for further recovery. CONCLUSIONS: The risk for severe adverse events due to the YF vaccination should be balanced against the risk of acquiring a severe YF infection, especially in elderly travelers.