Influenza Season and Outcome After Elective Cardiac Surgery: An Observational Cohort Study.

BACKGROUND: An asymptomatic respiratory viral infection during cardiac surgery could lead to pulmonary complications and increased mortality. For elective surgery, testing for respiratory viral infection before surgery or vaccination could reduce the number of these pulmonary complications. The aim of this study was to investigate the association between influenzalike illness (ILI) seasons and prolonged mechanical ventilation and inhospital mortality in a Dutch cohort of adult elective cardiac surgery patients. METHODS: Cardiac surgery patients who were admitted to the intensive care unit between January 1, 2014, and February 1, 2020, were included. The primary endpoint was the duration of invasive mechanical ventilation in the ILI season compared with baseline season. Secondary endpoints were the median Pao2 to fraction of inspired oxygen ratio on days 1, 3, and 7 and postoperative inhospital mortality. RESULTS: A total of 42,277 patients underwent cardiac surgery, 12,994 (30.7%) in the ILI season, 15,843 (37.5%) in the intermediate season, and 13,440 (31.8%) in the baseline season. No hazard rates indicative of a longer duration of invasive mechanical ventilation during the ILI season were found. No differences were found for the median Pao2 to fraction of inspired oxygen ratio between seasons. However, inhospital mortality was higher in the ILI season compared with baseline season (odds ratio 1.67; 95% CI, 1.14-2.46). CONCLUSIONS: Patients undergoing cardiac surgery during the ILI season were at increased risk of inhospital mortality compared with patients in the baseline season. No evidence was found that this difference is caused by direct postoperative pulmonary complications.

Immune Determinants of Viral Clearance in Hospitalised COVID-19 Patients: Reduced Circulating Naïve CD4+ T Cell Counts Correspond with Delayed Viral Clearance.

Virus-specific cellular and humoral responses are major determinants for protection from critical illness after SARS-CoV-2 infection. However, the magnitude of the contribution of each of the components to viral clearance remains unclear. Here, we studied the timing of viral clearance in relation to 122 immune parameters in 102 hospitalised patients with moderate and severe COVID-19 in a longitudinal design. Delayed viral clearance was associated with more severe disease and was associated with higher levels of SARS-CoV-2-specific (neutralising) antibodies over time, increased numbers of neutrophils, monocytes, basophils, and a range of pro-inflammatory cyto-/chemokines illustrating ongoing, partially Th2 dominating, immune activation. In contrast, early viral clearance and less critical illness correlated with the peak of neutralising antibodies, higher levels of CD4 T cells, and in particular naïve CD4+ T cells, suggesting their role in early control of SARS-CoV-2 possibly by proving appropriate B cell help. Higher counts of naïve CD4+ T cells also correlated with lower levels of MIF, IL-9, and TNF-beta, suggesting an indirect role in averting prolonged virus-induced tissue damage. Collectively, our data show that naïve CD4+ T cell play a critical role in rapid viral T cell control, obviating aberrant antibody and cytokine profiles and disease deterioration. These data may help in guiding risk stratification for severe COVID-19.

B-Cell Immunophenotyping to Predict Vaccination Outcome in the Immunocompromised - A Systematic Review.

Vaccination is the most effective measure to prevent infections in the general population. Its efficiency strongly depends on the function and composition of the immune system. If the immune system lacks critical components, patients will not be fully protected despite a completed vaccination schedule. Antigen-specific serum immunoglobulin levels are broadly used correlates of protection. These are the products of terminally differentiated B cells - plasma cells. Here we reviewed the literature on how aberrancies in B-cell composition and function influence immune responses to vaccinations. In a search through five major literature databases, 6,537 unique articles published from 2000 and onwards were identified. 75 articles were included along three major research lines: extremities of life, immunodeficiency and immunosuppression. Details of the protocol can be found in the International Prospective Register of Systematic Reviews [PROSPERO (registration number CRD42021226683)]. The majority of articles investigated immune responses in adults, in which vaccinations against pneumococci and influenza were strongly represented. Lack of baseline information was the most common reason of exclusion. Irrespective of study group, three parameters measured at baseline seemed to have a predictive value in assessing vaccine efficacy: (1) distribution of B-cell subsets (mostly a reduction in memory B cells), (2) presence of exhausted/activated B cells, or B cells with an aberrant phenotype, and (3) pre-existing immunological memory. In this review we showed how pre-immunization (baseline) knowledge of circulating B cells can be used to predict vaccination efficacy. We hope that this overview will contribute to optimizing vaccination strategies, especially in immunocompromised patients.

Assessment of Risks Associated With Severe Acute Respiratory Syndrome Coronavirus 2 Experimental Human Infection Studies.

Controlled human infection (CHI) models for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been proposed as a tool to accelerate the development of vaccines and drugs. Such models carry inherent risks. Participants may develop severe disease or complications after deliberate infection. Prolonged isolation may negatively impact their well-being. Through secondary infection of study personnel or participant household contacts, the experimental virus strain may cause a community outbreak. We identified risks associated with such a SARS-CoV-2 CHI model and assessed their likelihood and impact and propose strategies that mitigate these risks. In this report, we show that risks can be minimized with proper risk mitigation strategies; the residual risk, however, should be weighed carefully against the scientific and social values of such a CHI model.

Predicting morbidity in older travellers during a short-term stay in the tropics: the ELDEST study.

BACKGROUND: Older persons may suffer more from travel-related health problems because of ageing and underlying chronic disorders. Knowledge on who is more likely to have these health problems helps to tailor travel health advice more specifically. This study aimed to determine predictors of travel-related morbidity in older travellers by assessing their pre-travel characteristics and performance using physical and cognitive functioning tests. METHODS: Multicentre prospective cohort study among older travellers (≥60 years) who consulted one of the participating Dutch travel clinics. Handgrip strength and cognitive performance were measured pre-travel. Participants completed questionnaires before departure and 1 and 4 weeks after return. A diary recorded health complaints during travel until 2-week post-travel. RESULTS: In total, 477 travellers completed the study (follow-up rate of 97%). Participants' median age was 66 years. The most visited regions were South-East Asia (34%) and South Asia (14%). Median travel duration was 19 days. Polypharmacy (≥5 medications per day) was not uncommon (16%). The median Charlson Comorbidity Index (CCI) score was 0. Self-reported travel-related infectious diseases concerned primarily respiratory tract infections (21%) and gastroenteritis (10%) whereas non-infectious complaints were injuries (13%), peripheral edema (12%) and dehydration (3%). Medical assistance was sought by 18%, mostly post-travel from their general practitioner (87%). Self-reported physical and mental health-related quality of life significantly improved during and after travel. Predictors for an increased risk of travel-related morbidity were higher CCI score, more travel experience, longer travel duration, higher number of daily medications, visiting northern Africa or South-East and East Asia, and phone and social media use. CONCLUSION: Older Dutch travellers are generally fit, well-prepared and suffer not only from common infectious health problems, but also from injuries. Travel improved their self-perceived health. The predictors could be used to identify the more at-risk older traveller and to decrease travel-related morbidity by optimizing pre-travel advice.

Safety and immunogenicity of a primary yellow fever vaccination under low-dose methotrexate therapy-a prospective multi-centre pilot study1.

BACKGROUND: More people on immunosuppression live in or wish to travel to yellow fever virus (YFV)-endemic areas. Data on the safety and immunogenicity of yellow fever vaccination (YFVV) during immunosuppression are scarce. The aim of this study was to compare the safety and immunogenicity of a primary YFVV between travellers on methotrexate and controls. METHODS: We conducted a prospective multi-centre controlled observational study from 2015 to 2017 in six Swiss travel clinics. 15 adults (nine with rheumatic diseases, five with dermatologic conditions and one with a gastroenterological disease) on low-dose methotrexate (≤20 mg/week) requiring a primary YFVV and 15 age and sex-matched controls received a YFVV. Solicited/unsolicited adverse reactions were recorded, YFV-RNA was measured in serum samples on Days 3, 7, 10, 14, 28 and neutralizing antibodies on Days 0, 7, 10, 14, 28. RESULTS: Patients´ and controls' median ages were 53 and 52 years; 9 patients and 10 controls were female. 43% of patients and 33% of controls showed local side effects (P = 0.71); 86% of patients and 66% of controls reported systemic reactions (P = 0.39). YFV-RNA was detected in patients and controls on Day 3-10 post-vaccination and was never of clinical significance. Slightly more patients developed YFV-RNAaemia (Day 3: n = 5 vs n = 2, Day 7: n = 9 vs n = 7, Day 10: n = 3 vs n = 2, all P > 0.39). No serious reactions occurred. On Day 10, a minority of vaccinees was seroprotected (patients: n = 2, controls: n = 6). On Day 28, all vaccinees were seroprotected. CONCLUSIONS: First-time YFVV was safe and immunogenic in travellers on low-dose methotrexate. Larger studies are needed to confirm these promising results.

Travel preparation and health risks in Dutch and Belgian medical students during an elective in low- or middle-income countries: A prospective self-reporting cohort study.

BACKGROUND: Medical schools offer students the opportunity to perform international electives. This study aimed to assess health risks among medical students, to tailor institutional guidelines. METHODS: Multicenter study at Dutch and Belgian universities, among medical students who visited low- or middle-income countries. Students completed four questionnaires: once before the elective and two weeks, three- and six months after return. RESULTS: Data was complete for 479 students (follow-up rate 84%). Most traveled to Surinam (29%) and South-Africa (14%). Half of the students encountered difficulties in adapting to local culture. Almost 40% visited malaria endemic countries. Nearly all (87%) used chemoprophylaxis as prescribed. Definite needle-stick or splash injuries were reported by 7%. All were dealt with adequately in accordance with national guidelines. However, less than half of 24 possible incidents were handled adequately. Two-and-a-half percent had unprotected sex with a new partner. The incidence of travelers' diarrhea (TD) was 46%. In those with TD, the incidence of post-travel new-onset abdominal complaints was 3%. Three percent were involved in a minor traffic accident, 18% were injured during leisure activities, 5% were threatened or experienced physical violence. Only half of the students visiting a highly endemic country were screened for tuberculosis post-travel. For schistosomiasis this was 6%. CONCLUSIONS: Students abroad are exposed to medical and non-medical challenges, which should be addressed during pre-travel counseling. Contact details of a professional back home should be provided, so students can confer in case of problems while abroad. Lastly, we recommend a centrally organized post-travel health check.

The Cellular Immune Response to Rabies Vaccination: A Systematic Review.

The effectiveness of rabies vaccines is conventionally determined by serological testing. In addition to this assessment of humoral immunity, cellular immunity could help assess effectiveness and protection through a broad range of parameters. Therefore, this study aimed to systematically review all literature on the kinetics and composition of the cellular immune response to rabies vaccination in humans. A total of 1360 studies were identified in an extensive literature search. Twenty studies were selected for inclusion. In a primary response, plasma cells are detectable from day 7 to day 14, peaking at day 10. Memory B-cells appear from day 10 up to at least day 28. After revaccination, natural killer (NK) cells are the first detectable cellular parameters. Further research is required to assess cellular parameters in relation to long-term (serological) immunity. This review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42019134416.

Fractional-dose yellow fever vaccination: how much more can we do with less?

PURPOSE OF REVIEW: Climate change, deforestation, urbanization, and increased population mobility have made the risk of large outbreaks of yellow fever more likely than ever. Yellow fever vaccine production barely meets demands. In this review, we address the causes of the recent yellow fever outbreaks, why fractional dose yellow fever vaccination works, the role of virus neutralizing antibodies in the protection against yellow fever, and the need for revaccination. RECENT FINDINGS: Human activities have profoundly changed the epidemiology of yellow fever. The excess of infectious viral particles in routine yellow fever vaccine batches allows for off-label use of fractional dose yellow fever vaccination in response to emergency situations. Two studies have confirmed long-term protection after fractional dose yellow fever vaccination. The need for the presence of virus neutralizing antibodies (VNA) to protect an individual against yellow fever depends on the epidemiological setting. In case of sylvatic transmission, population immunity is irrelevant for individual protection, as mosquitoes are transmitting the virus from infected nonhuman primates to human. SUMMARY: With the growing connectivity through air travel, countries with high densities of nonimmune populations and of the urban mosquito vector, Aedes aegypti, should ensure that their citizens are properly vaccinated against yellow fever before traveling to a yellow fever endemic country. In the situation of sylvatic transmission, the presence of protective levels of VNA will determine the outcome and may require revaccination at some point in time.

Comparison of the immunogenicity of Dukoral® oral cholera vaccine between renal transplant recipients on either a calcineurin inhibitor or mycophenolate - A controlled trial.

BACKGROUND: The evidence for recommendations regarding vaccination in solid organ transplant recipients is sparse. There is little data comparing vaccine responses between groups on different immunosuppressive drugs. This study was conducted to evaluate the antibody response to Dukoral® oral cholera vaccine in renal transplant recipients (RTR). METHODS: In a single-center non-randomized controlled clinical trial, healthy volunteers (n = 21) and renal transplant recipients (n = 30) were vaccinated with the oral whole cell/recombinant B subunit cholera vaccine Dukoral® (Valneva Inc., Vienna, Austria). The RTR were stratified according to their maintenance immunosuppressive therapy: either prednisone and a calcineurin inhibitor (cyclosporine A or tacrolimus; P/CNI group; n = 15) or prednisone and mycophenolate (P/MMF group; n = 15). All volunteers ingested Dukoral® at baseline and at day 14. Serum samples were drawn at day 0 and day 21. The primary outcome was seroconversion, defined as either a 3-fold IgA serum titer increase in anti-cholera toxin B antibodies and/or a 4-fold rise in the serum vibriocidal titer. RESULTS: Follow-up was complete. Seroconversion after vaccination was 57% (standard error, SE 9%) in RTR and 81% (SE 9%) in healthy controls (Relative Risk, RR 0.70; 95% CI 0.48-1.02). When stratified according to maintenance immunosuppression, the seroconversion rate was 67% (SE 12%) in the P/CNI group (RR compared with controls 0.82; 95% CI 0.55-1.25) and 47% (SE 13%) in the P/MMF group (RR compared with controls 0.58; 95% CI 0.32-1.03). CONCLUSION: Adverse events were mild to moderate and transient. The response to Dukoral was weaker and the seroconversion rate was lower in renal transplant recipients than in healthy controls. In particular, those using mycophenolate had a poor response. Nevertheless, more than half of the transplant recipients seroconverted. Therefore oral vaccines should not be discarded as a potential tool for protection of solid organ transplant recipients. This trial is registered in clinicaltrials.gov under NCT01109914.

Single visit rabies pre-exposure priming induces a robust anamnestic antibody response after simulated post-exposure vaccination: results of a dose-finding study.

BACKGROUND: The current standard 3-dose intramuscular rabies PrEP schedule suffers from a number of disadvantages that severely limit accessibility and availability. The cost of is often prohibitive, it requires 3 visits to the clinic, and there are regular vaccine shortages. METHODS: Volunteers ( N = 30) were randomly assigned to 4 study arms: 1 standard dose intramuscular (IM) dose of PVRV (purified Vero cell rabies vaccine, Verorab), and 1/5th, 2/5th or 3/5th- fractional intradermal (ID) dose of PVRV in a single visit. All subjects received a simulated rabies post-exposure prophylaxis (D0, D3) 1 year later. Rabies virus neutralizing antibodies (RVNA) were determined by virus neutralization microtest (FAVN) on D0, D7, D28, Y1 and Y1 + D7. RESULTS: 28 out of 30 subjects (93%) seroconverted 1 month after primary vaccination; 1 subject in the 1-dose IM arm and 1 in the 1/5th-fractional dose ID arm did not. After 1 year, 22 out of 30 subjects (73%) no longer had RVNA above 0.5 IU/ml, with no discernible difference between study groups. After 1 year, all 30 subjects mounted a booster response within 7 days after simulated PEP, with the highest titers found in the single dose IM group ( P < 0.03). CONCLUSIONS: This dose finding study demonstrates that priming with a single dose of rabies vaccine was sufficient to induce an adequate anamnestic antibody response to rabies PEP in all subjects 1 year later, even in those in whom the RVNA threshold of 0.5 IU/ml was not reached after priming.

Advances and controversies in yellow fever vaccination.

Ever since its development in 1937, the live-attenuated 17D yellow fever (YF) vaccine has been one of the most effective vaccines available to man. In this review we highlight the major steps in the development of 17D YF vaccine. We discuss the use of neutralizing antibodies as a surrogate marker for protection, and explore the strengths and weaknesses of the current plaque reduction neutralization test (PRNT), a technique developed in the 1960s that continues to be superior to every modern test in both sensitivity and specificity. The neutralizing antibodies demonstrated by the PRNT can be detected for several decades after vaccination, possibly even for the remainder of the recipient's natural life. We review the available evidence on the duration of protection after primary vaccination, a topic that has been the subject of controversy over the last few months. For persons who are immunocompromised due to disease, medication or advancing age, the duration of protection may be shorter: they should always have their vaccine response checked by PRNT. Due to the higher risk of severe adverse events after vaccination with 17D YF in this group, the development of a new, inactivated vaccine will have substantial benefits in this population.