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SCOPE: In 2009, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) published the first treatment guidance document for Clostridioides difficile infection (CDI). This document was updated in 2014. The growing literature on CDI antimicrobial treatment and novel treatment approaches, such as fecal microbiota transplantation (FMT) and toxin-binding monoclonal antibodies, prompted the ESCMID study group on C. difficile (ESGCD) to update the 2014 treatment guidance document for CDI in adults.METHODS AND QUESTIONS: Key questions on CDI treatment were formulated by the guideline committee and included: what is the best treatment for initial, severe, severe-complicated, refractory, recurrent and multiple recurrent CDI; what is the best treatment when no oral therapy is possible; can prognostic factors identify patients at risk for severe and recurrent CDI; and is there a place for CDI prophylaxis? Outcome measures for treatment strategy were: clinical cure, recurrence, and sustained cure. For studies on surgical interventions and severe-complicated CDI the outcome was mortality. Appraisal of available literature and drafting of recommendations was performed by the guideline drafting group. The total body of evidence for the recommendations on CDI treatment consists of the literature described in the previous guidelines, supplemented with a systematic literature search on randomized clinical trials and observational studies from 2012 and onwards. The Grades of Recommendation Assessment, Development and Evaluation (GRADE) system was used to grade the strength of our recommendations and the quality of the evidence. The guideline committee was invited to comment on the recommendations. The guideline draft was sent to external experts and a patients' representative for review. Full ESCMID endorsement was obtained after a public consultation procedure.RECOMMENDATIONS: Important changes compared with previous guideline include but are not limited to: (1) metronidazole is no longer recommended for treatment of CDI when fidaxomicin or vancomycin are available, (2) fidaxomicin is the preferred agent for treatment of initial CDI and the first recurrence of CDI when available and feasible, (3) FMT or bezlotoxumab in addition to Standard of Care antibiotics (SoC) are preferred for treatment of a second or further recurrence of CDI, (4) bezlotoxumab in addition to SoC is recommended for the first recurrence of CDI when fidaxomicin was used to manage the initial CDI episode, and (5) bezlotoxumab is considered as an ancillary treatment to vancomycin for a CDI episode with high risk of recurrence when fidaxomicin is not available. Contrary to the previous guideline, in the current guideline emphasis is placed on risk for recurrence as a factor that determines treatment strategy for the individual patient, rather than the disease severity.

Background On June 13, 2019, the US Food and Drug Administration issued a warning after transfer of faeces containing an extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli by faecal microbiota transplantation led to bacteraemia in two immunocompromised patients. Consequently, we evaluated the effectiveness of the faeces donor-screening protocol of the Netherlands Donor Faeces Bank, which consists of screening of donors for multidrug-resistant organisms every 3 months, combined with additional screening on indication (eg, after travelling abroad) and application of a quarantine period for all faecal suspensions delivered within those 3 months.Methods We did a retrospective cohort study of data collected between Jan 1, 2015, and Oct 14, 2019, on the multidrug-resistant organism testing results of donor faeces. Additionally, we tested previously quarantined faecal suspensions approved for faecal microbiota transplantation between Dec 12, 2016, and May 1, 2019, for the presence of multidrug-resistant organisms using both aselective and selective broth enrichment media. Whole-genome sequencing with core-genome multilocus sequence typing (cgMLST) was done on all multidrug-resistant isolates.Findings Among initial screenings, six (9%) of 66 tested individuals were positive for multidrug-resistant organisms and 11 (17%) of 66 tested individuals were positive for multidrug-resistant organisms at any timepoint. Multidrug-resistant organisms were detected in four (25%) of 16 active donors, who had a median donation duration of 268 days (IQR 92 to 366). Among all screening results, 14 (74%) of 19 detected multidrug-resistant organisms were ESBL-producing E coli. 170 (49%) of 344 approved faecal suspensions had corresponding research faeces aliquots available and were tested (from 11 active donors with a median of eight [IQR five to 26] suspensions per donor). No multidrug-resistant organisms were detected in the 170 approved faecal suspensions (one-sided 95% CI 0 to 1.7). cgMLST revealed that all multidrug-resistant organisms were genetically different.Interpretation Healthy faeces donors can become colonised with multidrug-resistant organisms during donation activities. Our screening protocol did not result in approval of multidrug-resistant organism-positive faecal suspensions for microbiota transplantation. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

Background Published data regarding long-lasting immunological rabies memory after pre-exposure prophylaxis (PrEP) are scarce. We tested the hypothesis that rabies booster immunization elicits rapid anamnestic responses. Methods For this observational study, we included participants who had received PrEP 10–24 years before inclusion. We measured rabies antibody titers before, and on days 3, 7, and 14 after a single intramuscular booster. Results All 28 participants responded adequately regardless of route of administration or 2-dose vs 3-dose PrEP regimen. Conclusion Rabies immunological memory is reactivated within 7 days after a single intramuscular booster immunization, even when administered 10–24 years after PrEP.

BackgroundIn face of the developing COVID-19 pandemic with a need for rapid and practical vaccination strategies, Ad26.COV2.S was approved as single shot immunization regimen. While effective against severe COVID-19, Ad26.COV2.S vaccination induces lower SARS-CoV-2-specific antibody levels compared to its mRNA-based counterparts. To support decision making on the need for booster vaccinations in Ad26.COV2.S-primed individuals, we assessed the immunogenicity and reactogenicity of homologous and heterologous booster vaccinations in Ad26.COV2.S-primed health care workers (HCWs).MethodsThe SWITCH trial is a single-(participant)-blinded, multi-center, randomized controlled trial among 434 HCWs who received a single Ad26.COV2.S vaccination. HCWs were randomized to no boost, Ad26.COV2.S boost, mRNA-1273 boost, or BNT162b2 boost. We assessed the level of SARS-CoV-2-specific binding antibodies, neutralizing antibodies against infectious virus, SARS-CoV-2-specific T-cell responses, and reactogenicity.ResultsHomologous and heterologous booster vaccinations resulted in an increase in SARS-CoV-2-specific binding antibodies, neutralizing antibodies and T-cell responses when compared to single Ad26.COV.2.S vaccination. In comparison with the homologous boost, the increase was significantly larger in heterologous regimens with the mRNA-based vaccines. mRNA-1273 boosting was most immunogenic, associated with higher reactogenicity. Only mild to moderate local and systemic reactions were observed on the first two days following booster.ConclusionsBoosting of Ad26.COV2.S-primed HCWs was well-tolerated and immunogenic. Strongest responses were detected after boosting with mRNA-based vaccines. Based on our data, efficacy on infection and transmission of boosters is expected. In addition to efficacy, decision making on boost vaccinations should include timing, target population, level of SARS CoV-2 circulation, and the global inequity in vaccine access.Trial registrationFunded by ZonMW (10430072110001);ClinicalTrials.govnumber,NCT04927936.

The present protocol study was used to summarize the findings of other major COVID-19 vaccination trials and provide an outline of our multicenter, single-blind, randomized controlled trial: the SWITCH trial. In the SWITCH, we compare the immunogenicity and reactogenicity of heterologous versus homologous vaccination strategies of COVID-19 vaccines. We recruit Health Care Workers (HCWs) who received ad.26.Cov2.S as their prime (first vaccination). We randomize HCWs in four groups: no boost (second vaccination), ad.26.Cov2.S, mRNA1273, and BNT162b2). The full protocol of the SWITCH trial can be found in the supplementary material.

Fecal microbiota transplantation (FMT) has become a well-established treatment for recurrent Clostridioides difficile infection (rCDI). While short-term outcomes and adverse events relating to FMT have been well documented, there still is a paucity of data with regard to long-term safety. In this report, we describe the long-term follow-up of the prospective cohort of the first randomized controlled trial of FMT for rCDI, and review the existing literature. A total of 34 patients were treated with FMT for rCDI. Seven patients were still alive after a follow-up of more than 10 years and three patients were lost to follow-up. None of the 34 patients had experienced a new-onset autoimmune, gastrointestinal, or malignant disorder during follow-up. We did not find any deterioration or amelioration of pre-existing medical conditions. Furthermore, no deaths directly attributable to FMT could be identified. These findings are in accordance with the data in available literature. In conclusion, no long-term adverse events or complications directly attributable to FMT were found in our prospective cohort. Review of the available literature does not point to long-term risks associated with FMT in this elderly population, provided that carefully screened fecal suspensions are being used. No firm conclusion on the long-term safety of FMT in younger patients could be drawn.

Background For certain vaccines, dosing can be reduced by intradermal (ID) immunization without loss of immunogenicity, as an alternative to standard routes of administration. However, a certain level of dose-sparing might also be achieved by reducing doses of intramuscular (IM) or subcutaneous (SC) vaccines. Method We conducted a systematic review comparing identical reduced amounts of antigen delivered by either ID, or IM/SC routes (PROSPERO registration no. CRD42020151725). Results Of 6015 articles identified, we included 26 articles, covering eight different vaccines. Equivalent immune responses were demonstrated in 19/26 studies, and 7/26 studies suggested inferior immune responses after IM/SC immunization. Conclusions We conclude that fractional dosed IM/SC vaccination is at best as immunogenic, but potentially inferior to ID vaccination. The safety profiles were at large comparable, although minor local adverse events were more common after ID delivery. Future vaccine trials, depending on the platform used, should add a fractional dose IM/SC arm, besides a fractional dose ID arm.

Background Disease epidemiology of (re-)emerging infectious diseases is changing rapidly, rendering surveillance of travel-associated illness important. Methods We evaluated travel-related illness encountered at EuroTravNet clinics, the European surveillance sub-network of GeoSentinel, between March 1, 1998 and March 31, 2018. Findings 103,739 ill travellers were evaluated, including 11,239 (10.8%) migrants, 89,620 (86.4%) patients seen post-travel, and 2,880 (2.8%) during and after travel. Despite increasing numbers of patient encounters over 20 years, the regions of exposure by year of clinic visits have remained stable. In 5-year increments, greater proportions of patients were migrants or visiting friends and relatives (VFR); business travel-associated illness remained stable; tourism-related illness decreased. Falciparum malaria was amongst the most-frequently diagnosed illnesses with 5,254 cases (5.1% of all patients) and the most-frequent cause of death (risk ratio versus all other illnesses 2.5:1). Animal exposures requiring rabies post-exposure prophylaxis increased from 0.7% (1998-2002) to 3.6% (2013-2018). The proportion of patients with seasonal influenza increased from zero in 1998-2002 to 0.9% in 2013-2018. There were 44 cases of viral haemorrhagic fever, most during the past five years. Arboviral infection numbers increased significantly as did the range of presenting arboviral diseases, Dengue and chikungunya diagnoses increased by 2.6% and 1%, respectively. Interpretation Travel medicine must adapt to serve the changing profile of travellers, with an increase in migrants and persons visiting relatives and friends and the strong emergence of vector-borne diseases, with potential for further local transmission in Europe. Funding This project was supported by a cooperative agreement (U50CK00189) between the Centers for Disease Control and Prevention to the International Society of Travel Medicine (ISTM) and funding from the ISTM and the Public Health Agency of Canada.

Purpose To introduce the COVID-19 Reporting and Data System (CO-RADS) for standardized assessment of pulmonary involvement of COVID-19 on non-enhanced chest CT and report its initial interobserver agreement and performance. Methods The Dutch Radiological Society (NVvR) developed CO-RADS based on other efforts for standardization, such as Lung-RADS or BI-RADS. CO-RADS assesses the suspicion for pulmonary involvement of COVID-19 on a scale from 1 (very low) to 5 (very high). The system is meant to be used in patients presenting with moderate to severe symptoms of COVID-19. The system was evaluated using 105 chest CTs of patients admitted to the hospital with clinical suspicion of COVID-19 in whom RT-PCR was performed (62 +/- 16 years, 61 men, 53 with positive RT-PCR). Eight observers assessed the scans using CO-RADS. Fleiss’ kappa was calculated, and scores of individual observers were compared to the median of the remaining seven observers. The resulting area under the receiver operating characteristics curve (AUC) was compared to results from RT-PCR and clinical diagnosis of COVID-19. Results There was absolute agreement among observers in 573 (68.2%) of 840 observations. Fleiss’ kappa was 0.47 (95% confidence interval (CI) 0.45-0.47), with the highest kappa for CO-RADS categories 1 (0.58, 95% CI 0.54-0.62) and 5 (0.68, 95% CI 0.65-0.72). The average AUC was 0.91 (95% CI 0.85-0.97) for predicting RT-PCR outcome and 0.95 (95% CI 0.91-0.99) for clinical diagnosis. The false negative rate for CO-RADS 1 was 9/161 (5.6%, 95% CI 1.0-10%), and the false positive rate for CO-RADS 5 was 1/286 (0.3%, 95% CI 0-1.0%). Conclusions CO-RADS is a categorical assessment scheme for pulmonary involvement of COVID-19 on non-enhanced chest CT providing very good performance for predicting COVID-19 in patients with moderate to severe symptoms and has a substantial interobserver agreement, especially for categories 1 and 5.

Background The objective of this systematic review and meta-analysis was to summarise the literature regarding the immunogenicity of pneumococcal conjugate vaccines (PCV) and pneumococcal polysaccharide vaccines (PPSV) in adult people living with HIV (PLWH) in the era of advanced combination antiretroviral therapy (cART). Methods The systematic review protocol was published online (PROSPERO ID: CRD 42020153137). We searched Medline (Ovid), EMBASE (Ovid), and the Global Health Library for publications from 2000 to June 11, 2020. We included all studies in adult PLWH that reported vaccine immunogenicity outcomes. The primary outcome was seroconversion rate (SCR) after PCV, PPSV and PCV/PPSV combined. For random-effects meta-analysis, we included studies defining SCR as a ≥ 2-fold increase in IgG from baseline, and reporting SCR for serotypes 6B, 14, or overall SCR, 1–3 months after vaccination. Findings Our search identified 1597 unique studies, of which 115 were eligible for full-text assessment. Of these, 39 met the inclusion criteria (11 RCTs; 28 cohort studies). A high degree of heterogeneity was observed. Nineteen studies were included in the meta-analysis. Pooled overall SCRs were 42% (95% CI 30–56%), 44% (95% CI 33–55%) and 57% (95% CI 50–63%) for PLWH who received PPSV, PCV or a combination of PCV/PPSV, respectively. Compared to PPSV alone, a combination of PCV/PPSV yielded higher SCRs (OR 2.24 95% CI 1.41- 3.58), whereas we did not observe a significant difference in SCR between PCV and PPSV23 alone. There were no statistically significant differences in geometric mean post-vaccination antibody concentrations between vaccination schedules. Vaccination at higher CD4 cell counts improved immunogenicity in 8/21 studies, especially when PCV was administered. No studies assessed the long-term immunogenicity of PCV followed by PPSV23. Quality of evidence ranged from poor (n = 19) to good quality (n = 7). A limited number of pneumococcal serotypes was assessed in the majority of studies. Interpretation We show that the recommended immunisation schedule consisting of a combination of PCV13/PPSV23, is immunogenic in PLWH in the era of advanced cART. However, the durability of this vaccination schedule remains unknown and must be addressed in future research. Vaccination with PCV should be delayed until immunological recovery (CD4>200) in recently diagnosed PLWH for optimal immunogenicity. The evidence gathered here supports wide implementation of the combination of PCV/PPSV23 for all PLWH. We recommend reassessment of this strategy once higher-valent PCVs become available. Funding HMGG is funded by a public research grant of ZonMw (project number 522004005).

Background: The Netherlands Donor Feces Bank provides standardized ready-to-use donor faecal suspensions for faecal microbiota transplantation treatment of patients with recurrent Clostridioides difficile infection. Objective: The purpose of this study was evaluation of safety, feasibility and outcome of faecal microbiota transplantation facilitated by a national stool bank. Methods: The methods used included: observational cohort study of donors and recipients of faecal suspensions; assessment of donor screening and patient selection performed by an expert panel of medical microbiologists, gastroenterologists and infectious disease specialists; and patient outcome evaluated at different timepoints after faecal microbiota transplantation. Results: Of 871 volunteers who registered as a potential faeces donor, 16 (2%) became active donors. Nine donors stopped or were excluded after a mean donation period of 5.7 months. In 2016–2019, 47 (27%) of 176 requests for faecal microbiota transplantations were deemed not indicated by the expert panel. In total, 129 patients with recurrent C. difficile infection were treated with 143 faecal suspensions in 40 different hospitals. The cure rate at two months after a single infusion was 89% (107/120). Of 84 patients, long-term follow-up (median 42 weeks) was available and sustained cure was achieved in 61 (73%). Early C. difficile infection relapses (within two months after faecal microbiota transplantation) and late recurrences (after more than two months) occurred more frequently in patients who received non-C. difficile antibiotics within three weeks after faecal microbiota transplantation and in moderately to severely immunocompromised patients. Of 21 patients with C. difficile infection after faecal microbiota transplantation, 14 were cured with anti-C. difficile antibiotics and seven with a second transplantation. No faecal microbiota transplantation-related serious adverse events were observed, but gastro-intestinal complaints (nausea, abdominal pain or diarrhoea) persisted in 32% of the treated patients at long-term follow-up. Conclusion: Faecal suspensions provided by a centralized stool bank, supported by a multidisciplinary expert team, resulted in effective, appropriate and safe application of faecal microbiota transplantation for recurrent C. difficile infection. Level of evidence: Level II, prospective cohort study.

ObjectiveTo compare survival of subjects with COVID-19 treated in hospitals that either did or did not routinely treat patients with hydroxychloroquine or chloroquine.MethodsWe analysed data of COVID-19 patients treated in 9 hospitals in the Netherlands. Inclusion dates ranged from February 27th 2020, to May 15th, when the Dutch national guidelines no longer supported the use of (hydroxy)chloroquine. Seven hospitals routinely treated subjects with (hydroxy)chloroquine, two hospitals did not. Primary outcome was 21-day all-cause mortality. We performed a survival analysis using log-rank test and Cox-regression with adjustment for age, sex and covariates based on premorbid health, disease severity, and the use of steroids for adult respiratory distress syndrome, including dexamethasone.ResultsAmong 1893 included subjects, 21-day mortality was 23.4% in 1552 subjects treated in hospitals that routinely prescribed (hydroxy)chloroquine, and 17.0% in 341 subjects that were treated in hospitals that did not. In the adjusted Cox-regression models this difference disappeared, with an adjusted hazard ratio of 1.17 (95%CI 0.88-1.55). When stratified by actually received treatment in individual subjects, the use of (hydroxy)chloroquine was associated with an increased 21-day mortality (HR 1.58; 95%CI 1.25-2.01) in the full model.ConclusionsAfter adjustment for confounders, mortality was not significantly different in hospitals that routinely treated patients with (hydroxy)chloroquine, compared with hospitals that did not. We compared outcomes of hospital strategies rather than outcomes of individual patients to reduce the chance of indication bias. This study adds evidence against the use of (hydroxy)chloroquine in patients with COVID-19.

Since the outbreak of the COVID-19 (coronavirus disease 2019) pandemic, clinicians have been struggling with the optimal diagnostic approach of suspected patients. RT-PCR (real-time reverse transcriptase-polymerase chain reaction) testing of respiratory samples is generally being considered as the reference standard for establishing SARS-CoV-2 infection [1]. However, RT-PCR results take hours to become available and, although highly specific, sensitivity is moderate [2–4]. This could result in delayed and suboptimal clinical decision making., “In a high-prevalence emergency department setting, chest CT showed a high probability of COVID-19 in 30% of patients with a negative or indeterminate initial RT-PCR result”

Introduction Patients with a weakened immune system due to immunosuppressive treatment are at increased risk of infection with Streptococcus pneumoniae. Although pneumococcal vaccination is highly recommended for those patients, the effectiveness of pneumococcal vaccination in this population remains largely unknown. Therefore, the objective of this PROSPERO-registered systematic review and meta-analysis was to evaluate the effect of the most commonly prescribed immunosuppressive agents such as azathioprine, methotrexate, anti-Tumor Necrosis Factor α (TNFα), or rituximab, on the initial serologic response to pneumococcal vaccination in patients with auto-immune disease. Methods We included 22 articles comprising 2077 patients, of whom 1623 were treated with immunosuppressive agents, and 454 were controls. Results and discussion The findings of our systematic review indicate that, in patients treated with immunosuppressive medication and compared to controls, the initial serologic response to pneumococcal conjugate vaccine (PCV) and pneumococcal polysaccharide vaccine (PPSV) are impaired. Moreover, this impaired response was more profound after PCV than after PPSV. We hypothesize that the immunosuppressive medication mainly compromises the cellular immunity, explaining the more severely reduced response rate to PCV (which induces a T-cell dependent immune response), compared to PPSV. Treatment with TNFα blocking agents was associated with a more favorable response, compared to patients treated with other immunosuppressive medication. Targeted research applying uniform correlates of protection is needed to bridge the knowledge gap in vaccination immunology in this patient group. PROSPERO registration: CRD42017058364.

Background Invasive pneumococcal disease (IPD) is associated with high morbidity and mortality, with immunocompromised patients (ICPs) at particular risk. Therefore, guidelines recommend pneumococcal vaccination for these patients. However, guidelines are scarcely underpinned with references to incidence studies of IPD in this population. This, potentially results in unawareness of the importance of vaccination and low vaccination rates. The objective of this systematic review and meta-analysis was to assess the incidence of IPD in ICPs. Methods We systematically searched PubMed and Embase to identify studies in English published before December 6th, 2017 that included terms related to ‘incidence’, ‘rate’, ‘pneumococcal’, ‘pneumoniae’, ‘meningitis’, ‘septicemia’, or ‘bacteremia’. We focused on patients with HIV, transplantation and chronic inflammatory diseases. Results We included 45 studies in the systematic review reporting an incidence or rate of IPD, defined as isolation of Streptococcus pneumoniae from a normally sterile site. Random effects meta-analysis of 38 studies showed a pooled IPD incidence of 331/100,000 person years in patients with HIV in the late-antiretroviral treatment era in non-African countries, and 318/100,000 in African countries; 696 and 812/100,000 in patients who underwent an autologous or allogeneic stem cell transplantation, respectively; 465/100,000 in patients with a solid organ transplantation; and 65/100,000 in patients with chronic inflammatory diseases. In healthy control cohorts, the pooled incidence was 10/100,000. Discussion ICPs are at increased risk of contracting IPD, especially those with HIV, and those who underwent transplantation. Based on our findings, we recommend pneumococcal vaccination in immunocompromised patients. Prospero registration ID: CRD42016048438.

Background Rickettsial diseases present as acute febrile illnesses, sometimes with inoculation eschars. Methods We performed a systematic review of studies published between 1997 and 2017 to assess the underestimation of non-eschar rickettsial disease (NERD) relative to eschar rickettsial disease (ERD), as a cause of acute fever in patients with rickettsial diseases that commonly present with eschar(s): scrub typhus (ST), Mediterranean spotted fever (MSF), and African tick-bite fever. We compared ERD/NERD ratios according to study design: ‘complete approach’ studies, with testing performed in all patients with ‘unspecified febrile illness’; versus ‘clinical judgement’ studies, with testing performed if patients presented with specific symptoms. Results In ‘complete approach’ studies, ERD/NERD ratios were significantly lower, suggesting a considerable under-diagnosis of NERD in ‘clinical judgement’ studies. Based on these results, we estimate that the diagnosis of rickettsial disease was missed in 66.5% of patients with ST, and in 57.9% of patients with MSF. Conclusions Study design influences the reported eschar rates in ST and MSF significantly. NERD is likely to be a vastly underdiagnosed entity, and clinicians should consider and test for the disease more often. PROSPERO registration number CRD 42016053348

Leptospirosis is a potentially fatal emerging zoonosis with worldwide distribution and a broad range of clinical presentations and exposure risks. It typically affects vulnerable populations in (sub)tropical countries but is increasingly reported in travelers as well. Diagnostic methods are cumbersome and require further improvement. Here, we describe leptospirosis among travelers presenting to the GeoSentinel Global Surveillance Network. We performed a descriptive analysis of leptospirosis cases reported in GeoSentinel from January 1997 through December 2016. We included 180 travelers with leptospirosis (mostly male; 74%; mostly tourists; 81%). The most frequent region of infection was Southeast Asia (52%); the most common source countries were Thailand (N = 52), Costa Rica (N = 13), Indonesia, and Laos (N = 11 each). Fifty-nine percent were hospitalized; one fatality was reported. We also distributed a supplemental survey to GeoSentinel sites to assess clinical and diagnostic practices. Of 56 GeoSentinel sites, three-quarters responded to the survey. Leptospirosis was reported to have been most frequently considered in febrile travelers with hepatic and renal abnormalities and a history of freshwater exposure. Serology was the most commonly used diagnostic method, although convalescent samples were reported to have been collected infrequently. Within GeoSentinel, leptospirosis was diagnosed mostly among international tourists and caused serious illness. Clinical suspicion and diagnostic workup among surveyed GeoSentinel clinicians were mainly triggered by a classical presentation and exposure history, possibly resulting in underdiagnosis. Suboptimal usage of available diagnostic methods may have resulted in additional missed, or misdiagnosed, cases. Published version

Background The recent West African Ebola virus disease (EVD) outbreak had catastrophic impact on populations, health care systems and economies of the affected countries. Somatic symptoms have been reported to persist long beyond the acute infection. This review was conducted to provide an overview on neuro- and socio-psychological long-term sequelae of EVD survivors. Methods Utilizing Pubmed and PsycInfo databases, a systematic review prepared according to PRISMA guidelines. Only studies reporting quantitative data on neuropsychological sequelae three weeks or later after discharge from the Ebola-treating unit were included. Pooled proportions of common outcomes were calculated. Results In total, 224 papers were identified, of which 10 were included. Depression, insomnia, fatigue, anxiety and post-traumatic stress were common sequelae in EVD survivors. However, data from high-quality studies were scarce. Conclusions EVD survivors have been thought to commonly face neuropsychological long-term sequelae. Methodological drawbacks and heterogeneity of current studies limit conclusions of the impact and magnitude of such sequelae. We advocate the preparation of a prospective, controlled cohort study protocol in preparation for a future outbreak.

Human immunodeficiency virus (HIV)-infected individuals are at increased risk of chronic kidney disease (CKD). Human immunodeficiency virus infection, traditional CKD risk factors, and combination antiretroviral therapy (cART) may all contribute. We compared prevalence of renal impairment (estimated glomerular filtration rate [eGFR] 2.93μg/mmol and/or fractional phosphate excretion >20% with plasma phosphate

Background: Immunocompromised and chronically ill travellers (ICCITs) are susceptible to travel related diseases. In ICCITs, pre-travel care regarding vaccinations and prophylactics is complex. We evaluated the protection level by preventive measures in ICCITs by analysing rates of vaccination protection, antibody titres, and the prescription of standby antibiotics. Methods: We analysed, and reported according to STROBE guidelines, pre-travel care data for ICCITs visiting the medical pre-travel clinic at the Academic Medical Centre, The Netherlands from 2011 to 2016. Results: We analysed 2104 visits of 1826 ICCITs. Mean age was 46.6 years and mean travel duration 34.5 days. ICCITs on immunosuppressive treatment (29.7%), HIV (17.2%) or diabetes mellitus (10.2%) comprised the largest groups. Most frequently visited countries were Suriname, Indonesia, and Ghana. Most vaccination rates were >90%. Of travellers in high need of hepatitis A and B protection, 56.6 and 75.7%, underwent titre assessments, respectively. Of ICCITs with a respective indication, 50.6% received a prescription for standby antibiotics. Conclusion: Vaccination rates in our study population were overall comparable to those of healthy travellers studied previously in our centre. However, regarding antibody titre assessments and prescription of standby antibiotics, this study demonstrates that uniform pre-travel guidelines for ICCITs are highly needed. (C) 2017 Elsevier Ltd. All rights reserved

Background: The acute phase of chikungunya is well documented; less so are its long-term effects. This systematic literature review provides an overview of the currently available data. Methods: We performed an electronic search in PubMed/Medline and checked reference lists. We included studies in English on long-term sequelae of chikungunya in adults and on long-term sequelae of congenital infection from 2000 to 2016. Case reports, reviews and studies with a follow-up shorter than 6 weeks were excluded. Results: In total, 37 studies were included; with follow-up periods ranging from 1.5 to 72 months. Most studies were questionnaire-based studies only, in which clinical diagnoses such as arthritis, alopecia and depression were mostly recorded without professional verification. Persisting arthralgia/arthritis (arthralgia/joint stiffness plus joint swelling) was the most frequent problem encountered. Further frequently mentioned sequelae were alopecia and depression. Quality of life was reduced in many for months to years after the acute phase of chikungunya. Female gender, older age, some co-morbidities and the severity of the acute phase were associated with persistent arthralgia. Congenital infection was associated with neurocognitive dysfunctioning in early childhood. Conclusion: Chikungunya leads to (self-perceived) long-term sequelae in a considerable proportion of patients, impacting significantly on quality of life. Long-term chikungunya sequelae must be taken into account when dealing with this disease because of its important effect on public and individual health. Prospective large-scale, long-term studies with objective assessment of signs and symptoms attributed to the disease are needed to optimally quantify and qualify these problems. (C) 2017 Elsevier Ltd. All rights reserved

Background Although people living with human immunodeficiency virus (PLWH) are at increased risk of invasive pneumococcal disease (IPD) and community-acquired pneumonia (CAP), it is unclear whether this remains the case in the setting of early initiation of combination antiretroviral therapy (cART), at high CD4 cell counts. This is important, as pneumococcal vaccination coverage in PLWH is low in Europe and the United States, despite longstanding international recommendations. Methods We identified all CAP and IPD cases between 2008 and 2017 in a cohort of PLWH in a Dutch HIV referral center. We calculated incidence rates stratified by CD4 count and cART status and conducted a case-control study to identify risk factors for CAP in PLWH receiving cART. Results Incidence rates of IPD and CAP in PLWH were 111 and 1529 per 100 000 patient-years of follow-up (PYFU). Although IPD and CAP occurred more frequently in patients with CD4 counts 500 cells/μL remained higher compared with the general population (946 vs 188 per 100 000 PYFU). All IPD isolates were vaccine serotypes. Risk factors for CAP were older age, CD4 counts Conclusions The incidence of IPD and CAP among PLWH remains higher compared with the general population, even in those who are virally suppressed and have high CD4 counts. With all serotyped IPD isolates covered by pneumococcal vaccines, our study provides additional argumentation against the poor current adherence to international recommendations to vaccinate PLWH.

Purpose: We report 18 cases of confirmed Zika virus (ZIKV) infection in travellers returning to the Netherlands from Surinam (South America, bordering northern Brazil) and the Dominican Republic. Methods: In a multi-centre study, we collected epidemiological, virological and clinical characteristics, as well as data on travel history, underlying illness and laboratory results of the 18 imported ZIKV infection cases using a standardised form. Results: Most cases had a self-limiting course of disease, two patients developed complications, one had Guillain–Barre and another had severe thrombocytopenia. Four patients had underlying illness. One of the reported cases was pregnant. Three of 13 patients tested had a weak-positive result for dengue IgM. The majority of patients were born in Suriname and/or visiting friends and relatives (VFR). Conclusions: Providing pre-travel advice among travellers, especially VFR travellers, is needed to enhance the use of preventive measures against ZIKV infection. Further evidence on health risks associated with ZIKV infection is urgently needed.

Background Vaccine supply shortages are of global concern. We hypothesise that intradermal (ID) immunisation as an alternative to standard routes might augment vaccine supply utilisation without loss of vaccine immunogenicity and efficacy. Methods We conducted a systematic review and meta-analysis searching Medline, Embase and Web of Science databases. Studies were included if: licensed, currently available vaccines were used; fractional dose of ID was compared to IM or SC immunisation; primary immunisation schedules were evaluated; immunogenicity, safety data and/or cost were reported. We calculated risk differences (RD). Studies were included in meta-analysis if: a pre-defined immune correlate of protection was assessed; WHO-recommend schedules and antigen doses were used in the control group; the same schedule was applied to both ID and control groups (PROSPERO registration no. CRD42020151725). Results The primary search yielded 5,873 articles, of which 156 articles were included; covering 12 vaccines. Non-inferiority of immunogenicity with 20–60% of antigen used with ID vaccines was demonstrated for influenza (H1N1: RD -0·01; 95% CI -0·02, 0·01; I2 = 55%, H2N3: RD 0·00; 95% CI -0·01, 0·01; I2 = 0%, B: RD -0·00; 95% CI -0·02, 0·01; I2 = 72%), rabies (RD 0·00; 95% CI -0·02, 0·02; I2 = 0%), and hepatitis B vaccines (RD -0·01; 95% CI -0·04, 0·02; I2 = 20%). Clinical trials on the remaining vaccines yielded promising results, but are scarce. Conclusions There is potential for inoculum/antigen dose-reduction by using ID immunisation as compared to standard routes of administration for some vaccines (e.g. influenza, rabies). When suitable, vaccine trials should include an ID arm.

Background Patients with inflammatory bowel disease (IBD) are at increased risk of invasive pneumococcal infections. Therefore, vaccination with the 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) 2 months later is recommended. However, the level of immunogenicity induced by this vaccination schedule in IBD patients with and without immunosuppressive medication remains unclear. Methods We prospectively assessed the immunogenicity of PCV13 followed by PPSV23 in IBD patients by measuring serotype-specific pneumococcal immunoglobulin G antibody concentrations at baseline and 4–8 weeks postvaccination. Response to vaccination was defined as a postvaccination antibody concentration ≥1.3 μg/mL for 70% of the measured serotypes. We analyzed the immunogenic effect of 4 different medication regimens: (1) conventional immunomodulators (ie, oral prednisolone >10 mg/day, thiopurines, methotrexate); (2) anti–tumor necrosis factor agents; (3) combination therapy; and (4) no treatment with immunosuppressive agents (control group). Results One hundred forty-one IBD patients were included, of whom 37 were controls. Adequate response to vaccination was 59% (61/104) in patients using immunosuppressive agents (groups 1–3) vs 81% (30/37) in controls (odds ratio, 0.33 [95% confidence interval, .13–.82]). A combination of different immunosuppressive drugs most severely impaired the immune response to pneumococcal vaccination (response, 52% [15/29]). Conclusions Although the sequential vaccination schedule of PCV13 followed by PPSV23 is safe, immunogenic, and thus beneficial in the majority of IBD patients, those receiving immunosuppressive agents, and especially those receiving combination therapy, have an impaired immune response compared to controls. Therefore, preferably, vaccinations should be administered before the initiation of immunosuppressive therapy.

During the late phase of the large West-African Ebola virus disease (EVD) outbreak, the majority of patients were cared for in designated treatment centers. However, the preexisting healthcare infrastructure was already overwhelmed by the outbreak. This had a huge impact on other, non-EVD-related diseases, causing an unprecedented increase in morbidity and mortality, which most likely exceeded the toll due to EVD directly. Consequently, a crucial question is how to provide appropriate healthcare and safeguard functionality of a healthcare system that also serves patients not suspected or diagnosed to have EVD. Here, we report on the Lion Heart Medical Center's experience in Sierra Leone and note that a case definition of Ebola that is broader than those commonly applied may be better suited when it is necessary to identify atypically presenting, pauci-symptomatic cases.

BACKGROUND: Clostridium difficile is the leading cause of antibiotic-associated diarrhoea, both in healthcare facilities and in the community. The recurrence rate of C. difficile infection (CDI) remains high, up to 20%. Since the publication of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidance document on CDI treatment in 2014, new therapeutic approaches have been developed and tested to achieve higher sustained clinical cure in CDI.AIM: To review novel treatments and approaches for CDI, except probiotics and vaccines. We focused on new antibiotics, antibiotic inactivators, monoclonal antibodies and gut microbiota modulating therapies.SOURCES: A literature review was performed for clinical trials published in PubMed, Embase or Cochrane Library between January 2013 and November 2017.CONTENT: We analysed 28 clinical trials and identified 14 novel agents. Completed phase 2 studies were found for cadazolid, LFF571, ridinilazole and nontoxigenic C. difficile strains. Four phase 3 active comparator studies comparing vancomycin with bezlotoxumab, surotomycin (n = 2) and rifaximin have been published. Seven clinical trials for treatment of multiple recurrent CDI with faecal microbiota transplantation were analysed, describing faecal microbiota transplantation by upper or lower gastrointestinal route (n = 5) or by capsules (n = 2).IMPLICATIONS: Metronidazole is mentioned in the ESCMID guideline as first-line therapy, but we propose that oral vancomycin will become the first choice when antibiotic treatment for CDI is necessary. Fidaxomicin is a good alternative, especially in patients at risk of relapse. Vancomycin combined with faecal microbiota transplantation remains the primary therapy for multiple recurrent CDI. We anticipate that new medication that protects the gut microbiota will be further developed and tested to prevent CDI during antibiotic therapy.

Background Immunocompromised travellers (ICTs) are at increased risk of travel-related health problems. Therefore, they are advised to attend specialised pre-travel clinics for advice on vaccination, malaria chemoprophylaxis and on-demand antibiotics. However, studies yield conflicting data regarding travel-related health problems encountered by ICTs; questioning the rationale for certain advices, and particularly the advice of on-demand antibiotics. Objective To evaluate self-reported travel-related health problems, antibiotic use, medical visits and risk behaviours in ICTs and controls. Methods We conducted a questionnaire-based observational study with pilot character. We recruited participants from a (medical) pre-travel clinic. Telephone interviews were conducted 2–4 weeks post-travelling, applying a structured questionnaire. Results We included 30 ICTs and 30 controls. More ICTs than controls reported travel-related health problems, antibiotic use and medical visits, although not statistically significant. Travellers' diarrhoea appeared to be more severe in ICTs. Furthermore one ICT was hospitalized post-travel due to pneumonia. Of ICTs, 2/30 (7%) used on demand antibiotics while not indicated (according to the protocol of the Dutch national coordinating centre for travel advice or prescribed by a physician). Reversely, 6/30 (20%) did not use on demand antibiotics while actually indicated according to this protocol. Discussion Our findings substantiate the recommendation of on demand antibiotics. However, ICTs did often not use on demand antibiotics correctly; they therefore need very careful instructions.

Background Rabies is a lethal, but vaccine preventable disease. Vaccination uptake is however hampered by the time-consuming three-dose, 21/28-day schedule. The aim of this study was to examine whether adequate rabies antibody titers are reached after two intradermal (ID) doses of rabies vaccine, with a seven-day window. Method We conducted an observational cohort study with military personnel. A titer was assessed by RFFIT, on the day of the third vaccination, to ensure an adequate rabies antibody response after ID immunization. Results After this abbreviated two-dose, seven-day ID schedule, seroconversion was reached in 99.3% (427/430) with a geometric mean titer of 7.59 IU/mL (95% CI 7.04–8.17). Conclusions Implementation of this two-dose schedule will protect more people against Rabies. Travelers and military personnel under time constraints, who otherwise would remain unvaccinated, can be considered adequately protected after this two-dose schedule. For populations in endemic areas, local application of a two-dose schedule could provide an opportunity to vaccinate more people with less vaccine. Given the paucity of published data, this study adds relevant evidence in support of the new policy (2017) of WHO, concerning a two-dose, seven-day schedule is approved for all healthy individuals.

International audience

Since late 2015, an unprecedented outbreak of Zika virus is spreading quickly across Southern America. The large size of the current outbreak in The Americas will also result in an increase in Zika virus infections among travelers returning from endemic areas. We report five cases of imported Zika virus infection to The Netherlands. Although the clinical course is usually mild, establishing the diagnosis is important, mainly because of the association with congenital microcephaly and the possibility of sexual transmission.

Background Leptospirosis is a potentially fatal zoonotic disease that is prevalent in travellers. Here, we describe epidemiological and diagnostic characteristics of all returning travellers diagnosed with leptospirosis in the Netherlands between 2009 and 2016. Furthermore, we present a detailed clinical case series of all travellers with leptospirosis who presented at the Academic Medical Center (AMC) in the same period. Method We extracted data from the records of the Dutch Leptospirosis Reference Center (NRL) of all cases of leptospirosis in travellers in the Netherlands from 2009 to 2016. Patients who presented at the AMC were identified and clinical data were extracted from the hospital records. Results 224 cases of travel-related leptospirosis were included. An increase of cases was observed from 2014 onwards. The majority of cases were male (78.1%), and had travelled to South-East Asia (62.1%). Of 41 AMC cases, 53.7% were hospitalised, but most patients had a relatively mild disease course, with no fatalities. A longer delay in diagnosis and treatment initiation existed in hospitalised compared to non-hospitalised patients, suggesting a benefit of early recognition and treatment. Conclusions Leptospirosis was increasingly observed in returning travellers in the Netherlands, and is a diagnosis that should be considered in any returning febrile traveller.

BACKGROUND: Fecal microbiota transfer (FMT) is an effective treatment for recurrent Clostridium difficile infection (CDI), but data on procedure-related complications and long-term outcome are scarce.METHODS: All patients treated with FMT for recurrent CDI at the Academic Medical Center between July 2010 and January 2016 were included. FMT was performed according to the FECAL trial protocol: administration of fresh donor feces (related or unrelated donor) through a duodenal tube after pre-treatment with vancomycin and bowel lavage. We collected information on FMT-related complications, recurrent CDI, and short- and long-term adverse events by telephone interviews using a structured questionnaire at three months after FMT, and at the time of data collection of this study.RESULTS: In total, 39 patients were treated with FMT. The primary cure rate (no recurrence ≤8 weeks after one infusion with donor feces) was 82% (32 of 39 patients). Of the seven patients with recurrent CDI after FMT, four were cured by antibiotic therapy alone (fidaxomicin in three patients, metronidazole in one patient) and three by repeat FMT. Peri-procedural complications occurred in five patients, comprising fecal regurgitation or vomiting. One patient died one week post-FMT due to pneumonia; a causal relation with FMT could not be excluded. The follow-up period ranged between 3 and 68 months. No long-term side effects were reported.CONCLUSIONS: Our data underline the efficacy of FMT as treatment for recurrent CDI. Importantly, it is possible to cure post-FMT recurrences with antibiotic therapy alone. Peri-procedural complications do occur and should be closely monitored to help identify high-risk patients. To minimize the risk of complications, all FMT candidates should be evaluated to assess the most ideal delivery method.

Fecal microbiota transplantation (FMT) is a very effective treatment for recurrent Clostridium difficile infection (CDI). Less is known about the application of FMT as a curative treatment of severe or complicated CDI. In this review, we present and discuss evidence supporting the curative use of FMT in severe or complicated CDI. We performed a literature search in PubMed and Embase for studies on the curative use of FMT in severe or complicated CDI. In addition, we describe a patient with severe CDI not responding to initial antibiotic treatment, who was successfully treated with curative FMT. We found 23 reports (12 case reports; 11 case series) about FMT as treatment for severe or complicated CDI. The patients described all had severe or complicated CDI, did not respond to conventional CDI antibiotic treatment and received FMT as last resort treatment. Patients were treated with (sequential) FMT, whether or not followed by additional antibiotic treatment for CDI. FMT, with or without additional antibiotic CDI treatment, appears to be a promising curative treatment option in patients with severe and complicated CDI, or only complicated CDI, who do not respond sufficiently to conventional antibiotic treatment. Treatment with FMT should be considered in these patients before proceeding to emergency bowel surgery.

Background There is increasing recognition of the contribution of community-acquired cases to the global burden of Clostridium difficile infection (CDI). The epidemiology of CDI among international travellers is poorly understood, and factors associated with international travel, such as antibiotic use and changes in gut microbiota, could potentially put travellers at higher risk. Methods We summarized demographic, travel-associated and geographic characteristics of travellers with CDI in the GeoSentinel database from 1997 to 2015. We also surveyed GeoSentinel sites to compare various testing indications, approaches, and diagnostic modalities. Results We identified 260 GeoSentinel records, including 187 that satisfied criteria for analysis (confirmed cases in non-immigrant travellers aged >2 years, seen

Clostridium difficile infections (CDIs) are a common cause of antibiotic-associated diarrhoea and associated with CDI-related mortality in c . 10%. To date, there is no prediction model in use that guides clinicians to identify patients at high risk for complicated CDI. From 2006 to 2009, nine Dutch hospitals included hospitalized CDI patients in a prospective cohort. Potential predictors of a complicated course (ICU admission, colectomy or death due to CDI) were evaluated in uni- and multivariate logistic regression. A score was constructed that was internally validated by bootstrapping. Furthermore, a pilot external validation was performed. Twelve per cent of 395 CDI patients had a complicated course within 30 days after diagnosis. Age (≥85 years, OR 4.96; 50–84 years, 1.83), admission due to diarrhoea (OR 3.27), diagnosis at the ICU department (OR 7.03), recent abdominal surgery (OR 0.23) and hypotension (OR 3.25) were independent predictors of a complicated course. These variables were used to construct a prediction model. A score subsequently classified patients into high risk (39% with a complicated course), intermediate (16%), low (5%) or virtually no risk of experiencing a complicated course. The score performed well after internal validation (AUC 0.78) and a pilot external validation among 139 patients showed similar good performance (AUC 0.73). We present an easy-to-use, clinically useful risk score that is capable of categorizing CDI patients according to their outcome. Because classification is available at diagnosis, it could have major implications for treatment choice.

Rabies is a deadly disease, and current preexposure vaccination schedules are lengthy and expensive. We identified nine studies investigating abbreviated schedules. Although initial responses were lower, accelerated adequate immune responses were elicited after booster vaccinations. Lower-dose (and therefore cheaper) vaccination schedules may constitute a valid alternative to current vaccination schedules.

International audience; Background: Zika virus has spread rapidly in the Americas and has been imported into many nonendemic countries by travelers. Objective: To describe clinical manifestations and epidemiology of Zika virus disease in travelers exposed in the Americas. Design: Descriptive, using GeoSentinel records. Setting: 63 travel and tropical medicine clinics in 30 countries. Patients: Ill returned travelers with a confirmed, probable, or clinically suspected diagnosis of Zika virus disease seen between January 2013 and 29 February 2016. Measurements: Frequencies of demographic, trip, and clinical characteristics and complications. Results: Starting in May 2015, 93 cases of Zika virus disease were reported. Common symptoms included exanthema (88%), fever (76%), and arthralgia (72%). Fifty-nine percent of patients were exposed in South America; 71% were diagnosed in Europe. Case status was established most commonly by polymerase chain reaction (PCR) testing of blood and less often by PCR testing of other body fluids or serology and plaque-reduction neutralization testing. Two patients developed Guillain-Barre syndrome, and 3 of 4 pregnancies had adverse outcomes (microcephaly, major fetal neurologic abnormalities, and intrauterine fetal death). Limitation: Surveillance data collected by specialized clinics may not be representative of all ill returned travelers, and denominator data are unavailable. Conclusion: These surveillance data help characterize the clinical manifestations and adverse outcomes of Zika virus disease among travelers infected in the Americas and show a need for global standardization of diagnostic testing. The serious fetal complications observed in this study highlight the importance of travel advisories and prevention measures for pregnant women and their partners. Travelers are sentinels for global Zika virus circulation and may facilitate further transmission.

To date, the management of patients with suspected or confirmed Ebolavirus disease (EVD) depends on quarantine, symptomatic management and supportive care, as there are no approved vaccines or treatments available for human use. However, accelerated by the recent large outbreak in West Africa, significant progress has been made towards vaccine development but also towards specific treatment with convalescent plasma and monoclonal antibodies. Areas covered: We describe recent developments in monoclonal antibody treatment for EVD, encompassing mAb114 and the MB-003, ZMAb, ZMapp™ and MIL-77E cocktails. Expert opinion: Preventive measures, are, and will remain essential to curb EVD outbreaks; even more so with vaccine development progressing. However, research for treatment options must not be neglected. Small-scale animal and individual human case studies show that monoclonal antibodies (mAbs) can be effective for EVD treatment; thus justifying exploration in clinical trials. Potential limitations are that high doses may be needed to yield clinical efficacy; epitope mutations might reduce efficacy; and constant evolution of (outbreak-specific) mAb mixtures might be required. Interim advice based on the clinical experience to date is that treatment of patients with mAbs is sensible, provided those could be made available in the necessary amounts in time.

Introduction Prompted by recent amendments of Yellow Fever (YF) vaccination guidelines from boost to single vaccination strategy and the paucity of clinical data to support this adjustment, we used the profile of the YF-specific CD8+ T-cell subset profiles after primary vaccination and neutralizing antibodies as a proxy for potentially longer lasting immunity. Methods and Findings PBMCs and serum were collected in six individuals on days 0, 3, 5, 12, 28 and 180, and in 99 individuals >10 years after YF-vaccination. Phenotypic characteristics of YF- tetramer+ CD8+ T-cells were determined using class I tetramers. Antibody responses were measured using a standardized plaque reduction neutralization test (PRNT). Also, characteristics of YF-tetramer positive CD8+ T-cells were compared between individuals who had received a primary- and a booster vaccination. YF-tetramer+ CD8+ T-cells were detectable on day 12 (median tetramer+ cells as percentage of CD8+ T-cells 0.2%, range 0.07–3.1%). On day 180, these cells were still present (median 0.06%, range 0.02–0.78%). The phenotype of YF-tetramer positive CD8+ T-cells shifted from acute phase effector cells on day 12, to late differentiated or effector memory phenotype (CD45RA-/+CD27-) on day 28. Two subsets of YF-tetramer positive T-cells (CD45RA+CD27- and CD45RA+CD27+) persisted until day 180. Within all phenotypic subsets, the T-bet: Eomes ratio tended to be high on day 28 after vaccination and shifted towards predominant Eomes expression on day 180 (median 6.0 (day 28) vs. 2.2 (day 180) p = 0.0625), suggestive of imprinting compatible with long-lived memory properties. YF-tetramer positive CD8+ T-cells were detectable up to 18 years post vaccination, YF-specific antibodies were detectable up to 40 years after single vaccination. Booster vaccination did not increase titers of YF-specific antibodies (mean 12.5 vs. 13.1, p = 0.583), nor induce frequencies or alter phenotypes of YF-tetramer+ CD8+ T-cells. Conclusion The presence of a functionally competent YF-specific memory T-cell pool 18 years and sufficient titers of neutralizing antibodies 35–40 years after first vaccination suggest that single vaccination may be sufficient to provide long-term immunity.

Background The 17D-yellow fever (YF) vaccination is considered contraindicated in immune-compromised patients; however, accidental vaccination occurs. In this population, measuring the immune response is useful in clinical practice. Methods In this study we compare two antibody tests (the Immune Fluorescence Assay and the Plaque Reduction Neutralization Test) in a group of Dutch immune-compromised travellers with a median of 33 days (IQR [28–49]) after primary YF vaccination. Results We collected samples of 15 immune-compromised vaccinees vaccinated with the 17D yellow fever vaccine between 2004 and 2012. All samples measured in the plaque reduction neutralization test yielded positive results (>80% virus neutralization with a 1:10 serum dilution). Immune Fluorescence Assay sensitivity was 28% (95% CI [0.12–0.49]). No adverse events were reported. Conclusions All immune-compromised patients mounted an adequate response with protective levels of virus neutralizing antibodies to the 17-D YF vaccine. No adverse effects were reported. Compared to the plaque reduction neutralization test, the sensitivity of the Immune Fluorescence Assay test was low. Further research is needed to ascertain that 17D vaccination in immune-compromised patients is safe.