The Utility of Risk Factors to Define Complicated Staphylococcus aureus Bacteremia in a Setting With Low Methicillin-Resistant S. aureus Prevalence.

INTRODUCTION: Recommended duration of antibiotic treatment of Staphylococcus aureus bacteremia (SAB) is frequently based on distinguishing uncomplicated and complicated SAB, and several risk factors at the onset of infection have been proposed to define complicated SAB. Predictive values of risk factors for complicated SAB have not been validated, and consequences of their use on antibiotic prescriptions are unknown. METHODS: In a prospective cohort, patients with SAB were categorized as complicated or uncomplicated through adjudication (reference definition). Associations and predictive values of 9 risk factors were determined, compared with the reference definition, as was accuracy of Infectious Diseases Society of America (IDSA) criteria that include 4 risk factors, and the projected consequences of applying IDSA criteria on antibiotic use. RESULTS: Among 490 patients, 296 (60%) had complicated SAB. In multivariable analysis, persistent bacteremia (odds ratio [OR], 6.8; 95% confidence interval [CI], 3.9-12.0), community acquisition of SAB (OR, 2.9; 95% CI, 1.9-4.7) and presence of prosthetic material (OR, 2.3; 95% CI, 1.5-3.6) were associated with complicated SAB. Presence of any of the 4 risk factors in the IDSA definition of complicated SAB had a positive predictive value of 70.9% (95% CI, 65.5-75.9) and a negative predictive value of 57.5% (95% CI, 49.1-64.8). Compared with the reference, IDSA criteria yielded 24 (5%) false-negative and 90 (18%) false-positive classifications of complicated SAB. Median duration of antibiotic treatment of these 90 patients was 16 days (interquartile range, 14-19), all with favorable clinical outcome. CONCLUSIONS: Risk factors have low to moderate predictive value to identify complicated SAB and their use may lead to unnecessary prolonged antibiotic use.

Epidemiology of Pathogens Listed as Potential Bioterrorism Agents, the Netherlands, 2009‒2019.

We provide incidences (cases/10 million persons) in the Netherlands during 2009-2019 for pathogens listed as potential bioterrorism agents. We included pathogens from the highest categories of the European Medicines Agency or the US Centers for Disease Control and Prevention. Notifiable diseases and recently published data were used to calculate the average annual incidence. Coxiella burnetii had the highest incidence because of a Q fever epidemic during 2007-2010. Incidence then decreased to 10.8 cases/. Pathogens with an incidence >1 were Brucella spp. (2.5 cases), Francisella tularensis (1.3 cases), and Burkholderia pseudomallei (1.1 cases). Pathogens with an incidence <1 were hemorrhagic fever viruses (0.3 cases), Clostridium botulinum (0.2 cases), and Bacillus anthracis (0.1 cases). Variola major and Yersinia pestis were absent. The generally low incidences make it unlikely that ill-meaning persons can isolate these pathogens from natural sources in the Netherlands. However, the pathogens are stored in laboratories, underscoring the need for biosecurity measures.

Immunogenicity and 1-year boostability of a three-dose intramuscular rabies pre-exposure prophylaxis schedule in adults receiving immunosuppressive monotherapy: a prospective single-centre clinical trial.

BACKGROUND: For immunocompromised patients (ICPs), administration of rabies immunoglobulins (RIG) after exposure is still recommended regardless of prior vaccination, due to a lack of data. We aimed to assess the 1-year boostability of a three-dose rabies pre-exposure prophylaxis (PrEP) schedule in individuals using immunosuppressive monotherapy. METHODS: In this prospective study, individuals on immunosuppressive monotherapy with a conventional immunomodulator (cIM) or a TNF-alpha inhibitor (TNFi) for a chronic inflammatory disease received a three-dose intramuscular PrEP schedule (days 0,7,21-28) with 1 mL Rabipur®, followed by a two-dose simulated post-exposure prophylaxis (PEP) schedule (days 0,3) after 12 months. Rabies neutralizing antibodies were assessed at baseline, on day 21-28 (before the third PrEP dose), day 60, month 12 and month 12 + 7 days. The primary outcome was 1-year boostability, defined as the proportion of patients with a neutralizing antibody titre of ≥ 0.5 IU/mL at month 12 + 7 days. Secondary outcomes were geometric mean titres (GMTs) and factors associated with the primary endpoint. RESULTS: We included 56 individuals, of whom 52 completed the study. The 1-year boostability was 90% (47/52) with a GMT of 6.16 (95% CI 3.83-9.91). All participants seroconverted at some point in the study. Early response to PrEP (at day 21-28) was significantly associated with 100% boostability (Odds Ratio 51; 95% confidence interval [5.0-6956], P < 0.01). The vaccination schedule was safe and well tolerated. No vaccine-related serious adverse events occurred. CONCLUSION: In patients using immunosuppressive monotherapy, a three-dose rabies PrEP schedule followed by a two-dose PEP schedule is immunogenic, with all patients seroconverting at some point in the study. Although boostability 7 days after PEP was not 100%, nobody would wrongly be denied RIG when only administered to those who responded early to PrEP while reducing the administration of RIG by 73%.

Long-term Memory Response After a Single Intramuscular Rabies Booster Vaccination 10-24 Years After Primary Immunization.

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.

A review of severe thrombocytopenia in Zika patients - Pathophysiology, treatment and outcome.

BACKGROUND: During the 2015 Zika virus infection (ZVI) epidemic swiping through the Americas, few cases of ZVI with severe, potentially life-threatening thrombocytopenia were reported. Platelet transfusion, corticosteroids and intravenous immunoglobulins (IVIG) were in most cases applied as therapeutic options, predominantly with success. We present a comprehensive overview concerning the pathophysiology, treatment strategies and outcomes of patients with ZVI and severe thrombocytopenia (platelet count <50 × 109/L). METHOD: A literature search was performed. RESULTS: Eleven case reports and case series with a total of 28 patients met the inclusion criteria; including five cases with lethal outcome. Therapeutic strategies, including platelet transfusion, administration of steroids and/or IVIG were described in 24 cases. CONCLUSIONS: Severe thrombocytopenia is a rare, but potentially life-threatening complication of ZVI. The principal pathophysiological mechanism appears to immune-induced thrombocytopenia. Due to a paucity of cases, the optimal treatment strategy remains to be elucidated.

Comparison of equivalent fractional vaccine doses delivered by intradermal and intramuscular or subcutaneous routes: A systematic review.

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.

Fractional dose of intradermal compared to intramuscular and subcutaneous vaccination - A systematic review and meta-analysis.

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.

Can dengue virus be sexually transmitted?

It has been well documented that Zika virus (ZIKV) can be sexually transmitted. Dengue virus (DENV) shows many similarities with ZIKV; both belong to the genus Flavivirus and share the same main vector route of transmission. Moreover, they share overall architectural features on a molecular level, with a highly similar structure and distinctive insertions, deletions and mutations of their respective E proteins, and it has been suggested that they use a common pathophysiological pathway. In view of similarities with other sexually transmissible viruses, the question arises as to whether DENV could also be sexually transmissible. Limited animal model data do not suggest otherwise. The presence of dengue virus in - and human-to-human, non-vector transmission from - various bodily fluids other than semen or vaginal secretions has been documented anecdotally. Several anecdotal reports described prolonged presence of DENV in semen, urine and vaginal secretions. In 2019, two cases of likely sexual transmission were reported from Spain and South Korea, respectively. We discuss the evidence for and against a relevant DENV sexual transmission potential, highlight controversies and propose a future research agenda on this issue.

[Revision of the rabies policy in the Netherlands]. / Gewijzigde Nederlandse rabiësrichtlijnen.

Revision of the rabies policy in the Netherlands The WHO aims to eliminate dog-transmitted rabies deaths in humans by 2030 ('zero by 30'). The Dutch rabies policy advisory board has revised its national rabies guidelines on the basis of the WHO guidelines revised in 2018. In the revised Dutch guidelines, there is increased focus on the importance of instant wound care after potential exposure to the rabies virus. Pre-exposure prophylaxis (PrEP) is limited to two vaccines given on days 0 and 7, rather than the previous regime of three vaccines. Post-exposure prophylaxis (PEP) no longer consists of five vaccines for unvaccinated individuals; instead it is four vaccines on days 0, 3, 7, and 14-28. For type III wounds, when indicated, rabies immunoglobulin (RIG) is only injected into and around the wound bed; residual volumes are no longer administered intramuscularly. RIG no longer needs to be administered in cases of potential mucosal contact exposure to the rabies virus where there is no injury. The vaccination scheme for PrEP (3) and PEP (5) does not change for immunocompromised patients, and RIG is administered regardless of the vaccination status of the affected individual.

Rabies Antibody Response After Booster Immunization: A Systematic Review and Meta-analysis.

Although fatal once symptomatic, rabies is preventable by administration of pre- and post-exposure vaccines. International guidelines suggest lifelong protection by a pre-exposure vaccination scheme followed by timely post-exposure vaccines. Rapidity and magnitude of the antibody recall response after booster inoculation are essential, as many people have been previously immunized a long time ago. The objective of this study was therefore to systematically review the evidence on the boostability of rabies immunization to date. We included 36 studies, of which 19 studies were suitable for meta-analysis. Reduced antibody levels were found after intradermal primary schedules as compared to intramuscular schedules. However, responses after booster immunization were adequate for both routes. Although studies showed that antibody levels decline over time, adequate booster responses were still retained over long time intervals indicating that post-exposure treatment is effective without extra measures after long periods of time.

Travel-related leptospirosis in the Netherlands 2009-2016: An epidemiological report and case series.

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.

Rabies antibody response after two intradermal pre-exposure prophylaxis immunizations: An observational cohort study.

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.

Pre-travel care for immunocompromised and chronically ill travellers: A retrospective study.

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.

Long-term sequelae of chikungunya virus disease: A systematic review.

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.