SARS-CoV-2-specific cellular and humoral immunity after bivalent BA.4/5 COVID-19-vaccination in previously infected and non-infected individuals.

Knowledge is limited as to how prior SARS-CoV-2 infection influences cellular and humoral immunity after booster-vaccination with bivalent BA.4/5-adapted mRNA-vaccines, and whether vaccine-induced immunity may indicate subsequent infection. In this observational study, individuals with prior infection (n = 64) showed higher vaccine-induced anti-spike IgG-antibodies and neutralizing titers, but the relative increase was significantly higher in non-infected individuals (n = 63). In general, both groups showed higher neutralizing activity towards the parental strain than towards Omicron-subvariants BA.1, BA.2 and BA.5. In contrast, CD4 or CD8 T cell levels towards spike from the parental strain and the Omicron-subvariants, and cytokine expression profiles were similar irrespective of prior infection. Breakthrough infections occurred more frequently among previously non-infected individuals, who had significantly lower vaccine-induced spike-specific neutralizing activity and CD4 T cell levels. In summary, we show that immunogenicity after BA.4/5-bivalent vaccination differs between individuals with and without prior infection. Moreover, our results may help to improve prediction of breakthrough infections.

Retrospective study of the incidence, risk factors, treatment outcomes of bacterial infections at uncommon sites in cirrhotic patients.

BACKGROUND: Bacterial infections (BI) negatively affect the natural course of cirrhosis. The most frequent BI are urinary tract infections (UTI), pneumonia, and spontaneous-bacterial peritonitis (SBP). AIM: To assess the relevance of bacterial infections beyond the commonly recognized types in patients with cirrhosis and to investigate their relationship with other clinical variables. METHODS: We retrospectively analyzed patients with cirrhosis and BI treated between 2015 and 2018 at our tertiary care center. BIs were classified as typical and atypical, and clinical as well as laboratory parameters were compared between the two groups. RESULTS: In a cohort of 488 patients with cirrhosis, we identified 225 typical BI (95 UTI, 73 SBP, 72 pulmonary infections) and 74 atypical BIs, predominantly cholangitis and soft tissue infections (21 each), followed by intra-abdominal BIs (n = 9), cholecystitis (n = 6), head/throat BIs (n = 6), osteoarticular BIs (n = 5), and endocarditis (n = 3). We did not observe differences concerning age, sex, or etiology of cirrhosis in patients with typical vs atypical BI. Atypical BIs were more common in patients with more advanced cirrhosis, as evidenced by Model of End Stage Liver Disease (15.1 ± 7.4 vs 12.9 ± 5.1; P = 0.005) and Child-Pugh scores (8.6 ± 2.5 vs 8.0 ± 2; P = 0.05). CONCLUSION: Atypical BIs in cirrhosis patients exhibit a distinct spectrum and are associated with more advanced stages of the disease. Hence, the work-up of cirrhosis patients with suspected BI requires detailed work-up to elucidate whether typical BI can be identified.

Antiparasitic stewardship: a call to action.

Tweetable abstract There is an urgent need to consider antiparasitic drugs in global efforts to achieve and implement equitable and sustainable antimicrobial stewardship initiatives worldwide.

A multi-pronged approach to improve blood culture diagnostics in different clinical departments: a single-centre experience.

PURPOSE: Blood culture (BC) diagnostics are influenced by many factors. We performed a targeted interdisciplinary analysis to analyse effects of various measures on BC diagnostics performance. METHODS: A diagnostic stewardship initiative was conducted at two intervention and two control wards in a German tertiary level hospital. The initiative comprised staff training on the correct indications and sampling for BC, implementation of information cards, labels to identify the collection site, regular BC bottle feedback including the number of bottles, filling volumes and identified pathogens; and the use of a specific sampling device (BD Vacutainer®). Before and after the interventions, two three-month measurement periods were performed, as well as a one-month follow-up period to assess the sustainability of the conducted measures. RESULTS: In total, 9362 BC bottles from 787 patients were included in the analysis. The number of BCs obtained from peripheral venous puncture could be increased at both intervention wards (44.0 vs. 22.2%, 58.3 vs. 34.4%), while arterial sampling could be reduced (30.6 vs. 4.9%). A total of 134 staff members were fully trained. The intervention led to a considerable increase in BC knowledge (from 62.4 to 79.8% correct answers) with differences between the individual professional groups. Relevant reduced contamination rates could be detected at both intervention wards. CONCLUSIONS: As knowledge on the correct BC sampling and strategies to reduce contamination varies considerably between clinical departments and healthcare professionals, a targeted training should be adapted to the specific needs of the individual professional groups. An additional filling device is not necessary.

Hemophagocytic lymphohistiocytosis-how common and how severe is it as a complication of malaria? Retrospective case series and review of the literature.

BACKGROUND: Infection-associated secondary hemophagocytic lymphohistiocytosis (sHLH) is a potentially life-threatening hyperinflammatory condition caused by various infectious diseases. Malaria has rarely been described as trigger. The aim of this study is to collect data on frequency, clinical spectrum, and outcome of sHLH induced by malaria. METHODS: We collected case numbers on malaria and malaria-associated sHLH from specialized centers in Germany from 2015 to 2022. In addition, we conducted a literature search on published cases of malaria-associated sHLH and systematically analyzed the literature regarding clinical and diagnostic criteria. RESULTS: We obtained data from 13 centers treating 1461 malaria cases with different Plasmodium species, of which 5 patients (0.34%) also were diagnosed with sHLH. The literature search revealed detailed case reports from further 51 patients and case series comprising the description of further 24 patients with malaria-associated sHLH. Most cases (48/80; 60%) were reported from Asia. The median time interval between onset of malaria symptoms and hospital admission was 7 days. Severe complications of sHLH were documented in 36% (20/56) of patients, including two patients with multiple organ failure in our case series. Only 41% (23/56) of patients received specific treatment for sHLH, nevertheless the mortality rate (CFR) of 5% is lower compared to the CFR reported for sHLH triggered by other infectious diseases (e.g., 25% in sHLH due to EBV infection). CONCLUSION: Malaria-associated sHLH appears to have a comparatively good prognosis but may still represent an underdiagnosed and potentially fatal complication of malaria, especially in resource-poor settings.

Development of prevalence and incidence of non-tuberculous mycobacteria in German laboratories from 2016 to 2020.

Numbers of non-tuberculous mycobacteria (NTM) pulmonary diseases (PD) have been repeatedly reported as increasing over the last decades, particularly in Europe. Sound epidemiological data are however missing for most European regions. This study calculated prevalence and incidence of NTM recovered from patients' lungs in Germany, the largest Central European country, over a five-year period. It furthermore determined regional particularities of NTM species and results from susceptibility testing. 22 German NTM laboratories provided their mycobacteriological diagnostic data of 11,430 NTM isolates recovered from 5998 pulmonary patients representing 30% of all notified NTM-PD cases of Germany from 2016 to 2020. NTM incidence and prevalence were calculated for every study year. The presented epidemiological indicators are particularly reliant as TB surveillance data were used as a reference and TB notification reaches almost 100% in Germany. Laboratory incidence and prevalence of NTM recovered from respiratory samples ranged from 4.5-4.9 and from 5.3-5.8/100,000 for the population of Germany, respectively, and did not change over the five-year study period. Prevalence and incidence were stable also when stratifying for facultative pathogenic NTM, M. avium/intracellulare complex (MAIC), and M. abscessus/chelonae complex (MABSC). The proportion of NTM with drug susceptibility testing (DST) increased from 27.3% (2016) to 43.8% (2020). The unchanging laboratory NTM prevalence/incidence in Germany represents a "ceiling" of possible NTM-PD notification when diagnostic strategies do not change in the coming years. A notable increase in NTM-DST may indicate better notification of NTM-PD and/or awareness of new clinical guidelines but still remains below clinical needs.

Differences in SARS-CoV-2 specific humoral and cellular immune responses after contralateral and ipsilateral COVID-19 vaccination.

BACKGROUND: Individual doses of dual-dose vaccine-regimens are sequentially administered into the deltoid muscle, but little attention has so far been paid to the immunological effects of choosing the ipsilateral or the contralateral side for the second dose. METHODS: In an observational study, 303 previously naive individuals were recruited, who received the second dose of the COVID-19 vaccine BNT162b2 on either the ipsilateral (n = 147) or the contralateral side (n = 156). Spike-specific IgG, IgG-avidity, and neutralizing antibodies were quantified using ELISA and a surrogate assay 2 weeks after dose 2. A subgroup of 143 individuals (64 ipsilateral, 79 contralateral) was analysed for spike-specific CD4 and CD8 T-cells using flow-cytometry. FINDINGS: Median spike-specific IgG-levels did not differ after ipsilateral (4590 (IQR 3438) BAU/ml) or contralateral vaccination (4002 (IQR 3524) BAU/ml, p = 0.106). IgG-avidity was also similar (p = 0.056). However, neutralizing activity was significantly lower after contralateral vaccination (p = 0.024). Likewise, median spike-specific CD8 T-cell levels were significantly lower (p = 0.004). Consequently, the percentage of individuals with detectable CD8 T-cells was significantly lower after contralateral than after ipsilateral vaccination (43.0% versus 67.2%, p = 0.004). Spike specific CD4 T-cell levels were similar in both groups, but showed significantly higher CTLA-4 expression after contralateral vaccination (p = 0.011). These effects were vaccine-specific, as polyclonally stimulated T-cell levels did not differ. INTERPRETATION: Both ipsilateral and contralateral vaccination induce a strong immune response, but secondary boosting is more pronounced when choosing vaccine administration-routes that allows for drainage by the same lymph nodes used for priming. Higher neutralizing antibody activity and higher levels of spike-specific CD8 T-cells may have implications for protection from infection and severe disease and support general preference for ipsilateral vaccination. FUNDING: Financial support was provided in part by the State chancellery of the Saarland to M.S.

Recipient-Reported Reactogenicity of Different SARS-CoV-2 Vaccination Regimens among Healthcare Professionals and Police Staff in Germany.

The rapid availability of effective vaccines against SARS-CoV-2 was key during the COVID-19 pandemic. However, vaccine hesitancy and relatively low vaccine coverage rates among the general population and particularly vulnerable populations such as healthcare staff reduced the potential benefits of these vaccines. During the early phase of the pandemic, fear of vaccine-related adverse events was common among individuals who refused vaccination. Between March and May 2021, we comparatively assessed the self-reported reactogenicity of different SARS-CoV-2 prime-boost regimens using mRNA-based (BNT162b2 and mRNA-1273) and vector-based vaccines (ChAdOx1 nCoV-19) in (a) healthcare workers (HCW), and (b) police staff from southwest Germany. The majority of participants (71.8%; 1564/2176) received a homologous vaccination. Among HCW, 75.0% were female, whereas 70.0% of police staff were male. The most frequently reported reactions following the first vaccine administration were pain at the injection site (77.94%; 1696/2176), tiredness (51.75%; 1126/2176), and headache (40.44%; 880/2176), which were more commonly reported by HCW as compared to police staff. In homologous, mRNA-based and heterologous vaccination schedules, more reactions were reported after the second vaccine dose. We conclude that the frequency and intensity of self-perceived vaccine reactogenicity may differ between specific population groups and might be mitigated by tailored communication strategies.

Occurrence, resistance patterns, and management of carbapenemase-producing bacteria in war-wounded refugees from Ukraine.

We analyzed consecutive clinical cases of infections due to carbapenemase-producing gram-negative bacteria detected in war-wounded patients from Ukraine who were treated at one university medical center in southwest Germany between June and December 2022. The isolates of multiresistant gram-negative bacteria were subjected to a thorough microbiological characterization and whole genome sequencing (WGS). We identified five war-wounded Ukrainian patients who developed infections with New Delhi metallo-ß-lactamase 1-positive Klebsiella pneumoniae. Two isolates also carried OXA-48 carbapenemases. The bacteria were resistant to novel antibiotics, such as ceftazidime/avibactam and cefiderocol. The used treatment strategies included combinations of ceftazidime/avibactam + aztreonam, colistin, or tigecycline. WGS suggested transmission during primary care in Ukraine. We conclude that there is an urgent need for thorough surveillance of multiresistant pathogens in patients from war zones.

The state of infectious disease training in Germany before introduction of the new board certification in internal medicine and infectious diseases: past experience and future expectations.

PURPOSE: Recently, the German Medical Association introduced a new board certification in Internal Medicine and Infectious Diseases (ID). Accompanying, current experience with ID training and expectations for the new curriculum were assessed. METHODS: After the development of a digital survey covering four main areas with 59 questions, it was distributed via the German Society for Infectious Diseases (DGI) and other networks following a snowball principle. Participation was carried out digitally in a web-based application. RESULTS: Between December 2021 and February 2022, 300 datasets were included. 38.9% (114/293) of respondents had completed the additional training in ID. Of those, 54.0% (61/113) were concerned about recognition of previous training certification in the future after the establishment of the new sub-specialization. Overall, 78.5% (135/172) of respondents were satisfied or rather satisfied with the qualification gained through their training, but 8.7% (15/172) felt poorly prepared by their ID training. With regard to the inclusion of microbiology or antimicrobial stewardship (AMS) training into the new ID training curriculum, 84.6% (254/300) and 87.7% (263/300) of participants, respectively, desired an integration. Only 30.8% (53/172) felt sufficiently supported by their employer regarding childcare and 51.7% (89/172) reported missing support for scientific commitment. CONCLUSION: Overall, ID training in Germany seems satisfactory so far, but there is uncertainty about future recognition. Participants find that AMS and microbiology training should be integrated into new ID training curricula. New concepts regarding the compatibility of childcare and career as well as the support of scientific commitment seem essential to attract young professionals to the field.

Comparative immunogenicity and reactogenicity of heterologous ChAdOx1-nCoV-19-priming and BNT162b2 or mRNA-1273-boosting with homologous COVID-19 vaccine regimens.

Comparative analyses of the immunogenicity and reactogenicity of homologous and heterologous SARS-CoV-2 vaccine-regimens will inform optimized vaccine strategies. Here we analyze the humoral and cellular immune response following heterologous and homologous vaccination strategies in a convenience cohort of 331 healthy individuals. All regimens induce immunity to the vaccine antigen. Immunity after vaccination with ChAdOx1-nCoV-19 followed by either BNT162b2 (n = 66) or mRNA-1273 (n = 101) is equivalent to or more pronounced than homologous mRNA-regimens (n = 43 BNT162b2, n = 59 mRNA-1273) or homologous ChAdOx1-nCoV-19 vaccination (n = 62). We note highest levels of spike-specific CD8 T-cells following both heterologous regimens. Among mRNA-containing combinations, spike-specific CD4 T-cell levels in regimens including mRNA-1273 are higher than respective combinations with BNT162b2. Polyfunctional T-cell levels are highest in regimens based on ChAdOx1-nCoV-19-priming. All five regimens are well tolerated with most pronounced reactogenicity upon ChAdOx1-nCoV-19-priming, and ChAdOx1-nCoV-19/mRNA-1273-boosting. In conclusion, we present comparative analyses of immunogenicity and reactogenicity for heterologous vector/mRNA-boosting and homologous mRNA-regimens.

Awareness and perceptions of medical students and doctors regarding Tropical Medicine education and training in Europe: An international, online-based survey.

BACKGROUND: Multifactorial health determinants and shifts in global patterns of disease increase the need for Tropical Medicine training across Europe. A survey of university and postgraduate opportunities in Europe was conducted to identify and analyse gaps. METHOD: An online survey was circulated to medical students and doctors in Europe between April and June 2021. Significance tests and a thematic analysis of the data were conducted. RESULTS: 500 respondents (285 students and 215 doctors) from 27 countries were included. 17.2% of doctors were unsure whether postgraduate training in Tropical Medicine was available in their country. 20% of students and 10.7% of doctors said they were unsure whether they had been taught Tropical Medicine during university. 67.7% of students and 79.1% of doctors stated that the amount of Tropical Medicine training they encountered was or had been "not enough". CONCLUSIONS: Respondents demonstrated great interest in Tropical Medicine. Their self-reported knowledge, awareness, and perceived competence were partly dependent on whether there is specific teaching accessible at the university. Postgraduate training options were available in some countries but not all respondents were aware of these. There is a pressing need for harmonized curricula and expanded postgraduate training to improve Tropical Medicine competencies across Europe.

Diagnostic Specificity of Two Dengue Virus IgG ELISAs after Yellow Fever and Japanese Encephalitis Virus Vaccination.

Dengue virus (DENV) antibody assays frequently cross-react with sera from individuals who have been infected with or vaccinated against related flaviviruses. The goal of this study was to determine the specificity of two DENV ELISAs with sera from individuals vaccinated against yellow fever virus (YFV) and Japanese encephalitis virus (JEV). The Panbio and the Novatec Dengue IgG ELISAs were tested with sera obtained 3-4 weeks or 0.5-6 years after YFV or JEV vaccination and the diagnostic specificity of the assays was determined. As controls, the sera were tested using DENV, YFV, JEV, Zika and West Nile virus neutralization assays. The diagnostic specificity of the Panbio and the Novatec ELISA with sera from YFV-vaccinated subjects was 98.2% and 88.2%, respectively. Cross-reactions were rare in the first 4 weeks despite high YFV-neutralizing antibody titers and were mostly found later. The specificity of the Panbio and Novatec assays with sera from JEV-vaccinated individuals was 100% and 92.9%. Cross-reactions occurred in the early time period after vaccination. The measurement values of the two ELISAs correlated strongly. Thus, the Panbio ELISA showed higher diagnostic specificity and may be suitable for seroprevalence studies in areas with high disease prevalence.

The Role of Physicians in Digitalizing Health Care Provision: Web-Based Survey Study.

BACKGROUND: Digitalization affects all areas of society, including the health care sector. However, the digitalization of health care provision is progressing slowly compared to other sectors. In the professional and political literature, physicians are partially portrayed as digitalization sceptics. Thus, the role of physicians in this process requires further investigation. The theory of "digital natives" suggests a lower hurdle for younger generations to engage with digital technologies. OBJECTIVE: The objective of this study was to investigate the role of physicians in the process of digitalizing health care provision in Germany and to assess the age factor. METHODS: We conducted a large-scale study to assess the role of this professional group in the progress of the digital transformation of the German health care sector. Therefore, in an anonymous online survey, we inquired about the current digital penetration of the personal working environment, expectations, attitude toward, and concerns regarding digitalization. Based on these data, we studied associations with the nominal variable age and variations across 2 age groups. RESULTS: The 1274 participants included in the study generally showed a high affinity towards digitalization with a mean of 3.88 on a 5-point Likert scale; 723 respondents (56.75%) stated they personally use mobile apps in their everyday working life, with a weak tendency to be associated with the respondents' age (η=0.26). Participants saw the most noticeable existing benefits through digitalization in data quality and readability (882/1274, 69.23%) and the least in patient engagement (213/1274, 16.72%). Medical practitioners preponderantly expect further improvements through increased digitalization across almost all queried areas but the most in access to medical knowledge (1136/1274, 89.17%), treatment of orphan diseases (1016/1274, 79.75%), and medical research (1023/1274, 80.30%). CONCLUSIONS: Respondents defined their role in the digitalization of health care provision as ambivalent: "scrutinizing" on the one hand but "active" and "open" on the other. A gap between willingness to participate and digital sovereignty was indicated. Thus, education on digitalization as a means to support health care provision should not only be included in the course of study but also in the continuing process of further and advanced training.

Cellular immunity predominates over humoral immunity after homologous and heterologous mRNA and vector-based COVID-19 vaccine regimens in solid organ transplant recipients.

Knowledge on the immunogenicity of vector-based and mRNA-vaccines in solid organ transplant recipients is limited. Therefore, SARS-CoV-2-specific T cells and antibodies were analyzed in 40 transplant recipients and 70 controls after homologous or heterologous vaccine-regimens. Plasmablasts and SARS-CoV-2-specific CD4 and CD8 T cells were quantified using flow cytometry. Specific antibodies were analyzed by ELISA and neutralization assay. The two vaccine types differed after the first vaccination, as IgG and neutralizing activity were more pronounced after mRNA priming (p = .0001 each), whereas CD4 and CD8 T cell levels were higher after vector priming (p = .009; p = .0001). All regimens were well tolerated, and SARS-CoV-2-specific antibodies and/or T cells after second vaccination were induced in 100% of controls and 70.6% of transplant recipients. Although antibody and T cell levels were lower in patients, heterologous vaccination led to the most pronounced induction of antibodies and CD4 T cells. Plasmablast numbers were significantly higher in controls and correlated with SARS-CoV-2-specific IgG- and T cell levels. While antibodies were only detected in 35.3% of patients, cellular immunity was more frequently found (64.7%) indicating that assessment of antibodies is insufficient to identify COVID-19-vaccine responders. In conclusion, heterologous vaccination seems promising in transplant recipients, and combined analysis of humoral and cellular immunity improves the identification of responders among immunocompromised individuals.

Immunogenicity and reactogenicity of heterologous ChAdOx1 nCoV-19/mRNA vaccination.

Heterologous priming with the ChAdOx1 nCoV-19 vector vaccine followed by boosting with a messenger RNA vaccine (BNT162b2 or mRNA-1273) is currently recommended in Germany, although data on immunogenicity and reactogenicity are not available. In this observational study we show that, in healthy adult individuals (n = 96), the heterologous vaccine regimen induced spike-specific IgG, neutralizing antibodies and spike-specific CD4 T cells, the levels of which which were significantly higher than after homologous vector vaccine boost (n = 55) and higher or comparable in magnitude to homologous mRNA vaccine regimens (n = 62). Moreover, spike-specific CD8 T cell levels after heterologous vaccination were significantly higher than after both homologous regimens. Spike-specific T cells were predominantly polyfunctional with largely overlapping cytokine-producing phenotypes in all three regimens. Recipients of both the homologous vector regimen and the heterologous vector/mRNA combination reported greater reactogenicity following the priming vector vaccination, whereas heterologous boosting was well tolerated and comparable to homologous mRNA boosting. Taken together, heterologous vector/mRNA boosting induces strong humoral and cellular immune responses with acceptable reactogenicity profiles.

Simple Questionnaires to Improve Pooling Strategies for SARS-CoV-2 Laboratory Testing.

Background: Liberal PCR testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is key to contain the coronavirus disease 2019 (COVID-19) pandemic. Combined multi-sample testing in pools instead of single tests might enhance laboratory capacity and reduce costs, especially in low- and middle-income countries. Objective: The purpose of our study was to assess the value of a simple questionnaire to guide and further improve pooling strategies for SARS-CoV-2 laboratory testing. Methods: Pharyngeal swabs for SARS-CoV-2 testing were obtained from healthcare and police staff, hospital inpatients, and nursing home residents in the southwestern part of Germany. We designed a simple questionnaire, which included questions pertaining to a suggestive clinical symptomatology, recent travel history, and contact with confirmed cases to stratify an individual's pre-test probability of having contracted COVID-19. The questionnaire was adapted repeatedly in face of the unfolding pandemic in response to the evolving epidemiology and observed clinical symptomatology. Based on the response patterns, samples were either tested individually or in multi-sample pools. We compared the pool positivity rate and the number of total PCR tests required to obtain individual results between this questionnaire-based pooling strategy and randomly assembled pools. Findings: Between March 11 and July 5, 2020, we processed 25,978 samples using random pooling (n = 6,012; 23.1%) or questionnaire-based pooling (n = 19,966; 76.9%). The overall prevalence of SARS-CoV-2 was 0.9% (n = 238). Pool positivity (14.6% vs. 1.2%) and individual SARS-CoV-2 prevalence (3.4% vs. 0.1%) were higher in the random pooling group than in the questionnaire group. The average number of PCR tests needed to obtain the individual result for one participant was 0.27 tests in the random pooling group, as compared to 0.09 in the questionnaire-based pooling group, leading to a laboratory capacity increase of 73% and 91%, respectively, as compared to single PCR testing. Conclusions: Strategies that combine pool testing with a questionnaire-based risk stratification can increase laboratory testing capacities for COVID-19 and might be important tools, particularly in resource-constrained settings.