Genome-wide analyses in Lyme borreliosis: identification of a genetic variant associated with disease susceptibility and its immunological implications.

BACKGROUND: Genetic variation underly inter-individual variation in host immune responses to infectious diseases, and may affect susceptibility or the course of signs and symptoms. METHODS: We performed genome-wide association studies in a prospective cohort of 1138 patients with physician-confirmed Lyme borreliosis (LB), the most common tick-borne disease in the Northern hemisphere caused by the bacterium Borrelia burgdorferi sensu lato. Genome-wide variants in LB patients-divided into a discovery and validation cohort-were compared to two healthy cohorts. Additionally, ex vivo monocyte-derived cytokine responses of peripheral blood mononuclear cells to several stimuli including Borrelia burgdorferi were performed in both LB patient and healthy control samples, as were stimulation experiments using mechanistic/mammalian target of rapamycin (mTOR) inhibitors. In addition, for LB patients, anti-Borrelia antibody responses were measured. Finally, in a subset of LB patients, gene expression was analysed using RNA-sequencing data from the ex vivo stimulation experiments. RESULTS: We identified a previously unknown genetic variant, rs1061632, that was associated with enhanced LB susceptibility. This polymorphism was an eQTL for KCTD20 and ETV7 genes, and its major risk allele was associated with upregulation of the mTOR pathway and cytokine responses, and lower anti-Borrelia antibody production. In addition, we replicated the recently reported SCGB1D2 locus that was suggested to have a protective effect on B. burgdorferi infection, and associated this locus with higher Borrelia burgdorferi antibody indexes and lower IL-10 responses. CONCLUSIONS: Susceptibility for LB was associated with higher anti-inflammatory responses and reduced anti-Borrelia antibody production, which in turn may negatively impact bacterial clearance. These findings provide important insights into the immunogenetic susceptibility for LB and may guide future studies on development of preventive or therapeutic measures. TRIAL REGISTRATION: The LymeProspect study was registered with the International Clinical Trials Registry Platform (NTR4998, registration date 2015-02-13).

Efficacy and safety of rezafungin and caspofungin in candidaemia and invasive candidiasis: pooled data from two prospective randomised controlled trials.

BACKGROUND: Rezafungin, a new US Food and Drug Administration-approved, long-acting echinocandin to treat candidaemia and invasive candidiasis, was efficacious with a similar safety profile to caspofungin in clinical trials. We conducted pooled analyses of the phase 2 STRIVE and phase 3 ReSTORE rezafungin trials. METHODS: ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial conducted at 66 tertiary care centres in 15 countries. STRIVE was a multicentre, double-blind, double-dummy, randomised phase 2 trial conducted at 44 centres in 10 countries. Adults (≥18 years) with candidaemia or invasive candidiasis were treated with once-a-week intravenous rezafungin (400 mg and 200 mg) or once-a-day intravenous caspofungin (70 mg and 50 mg). Efficacy was evaluated in a pooled modified intent-to-treat (mITT) population. Primary efficacy endpoint was day 30 all-cause mortality (tested for non-inferiority with a pre-specified margin of 20%). Secondary efficacy endpoint was mycological response. Safety was also evaluated. The STRIVE and ReSTORE trials are registered with ClinicalTrials.gov, NCT02734862 and NCT03667690, and both studies are complete. FINDINGS: ReSTORE was conducted from Oct 12, 2018, to Oct 11, 2021, and STRIVE from July 26, 2016, to April 18, 2019. The mITT population, pooling the data from the two trials, comprised 139 patients for rezafungin and 155 patients for caspofungin. Day 30 all-cause mortality rates were comparable between groups (19% [26 of 139] for the rezafungin group and 19% [30 of 155] for the caspofungin group) and the upper bound of the 95% CI for the weighted treatment difference was below 10% (-1·5% [95% CI -10·7 to 7·7]). Mycological eradication occurred by day 5 in 102 (73%) of 139 rezafungin patients and 100 (65%) of 155 caspofungin patients (weighted treatment difference 10·0% [95% CI -0·3 to 20·4]). Safety profiles were similar across groups. INTERPRETATION: Rezafungin was non-inferior to caspofungin for all-cause mortality, with a potential early treatment benefit, possibly reflecting rezafungin's front-loaded dosing regimen. These findings are of clinical importance in fighting active and aggressive infections and reducing the morbidity and mortality caused by candidaemia and invasive candidiasis. FUNDING: Melinta Therapeutics and Cidara Therapeutics.

Determinants of persistent symptoms after treatment for Lyme borreliosis: a prospective observational cohort study.

BACKGROUND: Patients treated for Lyme borreliosis (LB) frequently report persistent symptoms. Little is known about risk factors and etiology. METHODS: In a prospective observational cohort study with a follow-up of one year, we assessed a range of microbiological, immunological, genetic, clinical, functional, epidemiological, psychosocial and cognitive-behavioral variables as determinants of persistent symptoms after treatment for LB. Between 2015 and 2018 we included 1135 physician-confirmed LB patients at initiation of antibiotic therapy, through clinical LB centers and online self-registration. Two reference cohorts of individuals without LB (n = 4000 and n = 2405) served as a control. Prediction analyses and association studies were used to identify determinants, as collected from online questionnaires (three-monthly) and laboratory tests (twice). FINDINGS: Main predictors of persistent symptoms were baseline poorer physical and social functioning, higher depression and anxiety scores, more negative illness perceptions, comorbidity, as well as fatigue, cognitive impairment, and pain in 295 patients with persistent symptoms. The primary prediction model correctly indicated persistent symptoms in 71.0% of predictions (AUC 0.79). In patients with symptoms at baseline, cognitive-behavioral responses to symptoms predicted symptom persistence. Of various microbiological, immunological and genetic factors, only lower IL-10 concentrations in ex vivo stimulation experiments were associated with persistent symptoms. Clinical LB characteristics did not contribute to the prediction of persistent symptoms. INTERPRETATION: Determinants of persistent symptoms after LB were mainly generic, including baseline functioning, symptoms and cognitive-behavioral responses. A potential role of host immune responses remains to be investigated. FUNDING: Netherlands Organisation for Health Research and Development (ZonMw); the Dutch Ministry of Health, Welfare and Sport (VWS).

Classical Borrelia Serology Does Not Aid in the Diagnosis of Persistent Symptoms Attributed to Lyme Borreliosis: A Retrospective Cohort Study.

OBJECTIVE: The diagnosis of Lyme borreliosis is based on two-tier testing using an ELISA and Western blot. About 5-10% of patients report persistent symptoms of unknown etiology after treatment, resulting in substantial difficulties in further diagnostic workup. This paper presents a study aimed at determining whether serology can differentiate between patients with persistent symptoms attributed to Lyme and other patients with Lyme borreliosis. METHODS: A retrospective cohort study included 162 samples from four subgroups: patients with persistent symptoms of Lyme (PSL), early Lyme borreliosis with erythema migrans (EM), patients tested in a general practitioner setting (GP), and healthy controls (HC). ELISA, Western blots, and multiplex assays from different manufacturers were used to determine inter-test variations in PSL and to compare reactivity against Borrelia-specific antigens among the groups. RESULTS: In comparing the IgG and IgM reactivity by Western blot, IgG was more often positive in the PSL group than in the GP group. The individual antigen reactivity was similar between the PSL and EM or GP groups. Inter-test agreement among the manufacturers was variable, and agreement was higher for IgG testing compared to IgM. CONCLUSIONS: Serological testing is unable to define the subgroup of patients with persistent symptoms attributed to Lyme borreliosis. Additionally, the current two-tier testing protocol shows a large variance among different manufacturers in these patients.

Corrections to "Prevalence of persistent symptoms after treatment for lyme borreliosis: a prospective observational cohort study" [The Lancet Regional Health - Europe 6 (2021) 100142].

[This corrects the article DOI: 10.1016/j.lanepe.2021.100142.].

Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial.

BACKGROUND: Rezafungin is a next-generation, once-a-week echinocandin in development for the treatment of candidaemia and invasive candidiasis and for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp after blood and marrow transplantation. We aimed to compare the efficacy and safety of intravenous rezafungin versus intravenous caspofungin in patients with candidaemia and invasive candidiasis. METHODS: ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial done at 66 tertiary care centres in 15 countries. Adults (≥18 years) with systemic signs and mycological confirmation of candidaemia or invasive candidiasis were eligible for inclusion and randomly assigned (1:1) to receive intravenous rezafungin once a week (400 mg in week 1, followed by 200 mg weekly, for a total of two to four doses) or intravenous caspofungin (70 mg loading dose on day 1, followed by 50 mg daily) for no more than 4 weeks. The primary endpoints were global cure (consisting of clinical cure, radiological cure, and mycological eradication) at day 14 for the European Medical Agency (EMA) and 30-day all-cause mortality for the US Food and Drug Administration (FDA), both with a target non-inferiority margin of 20%, assessed in the modified intention-to-treat population (all patients who received one or more doses of study drug and had documented Candida infection based on a culture from blood or another normally sterile site obtained within 96 h before randomisation). Safety was evaluated by the incidence and type of adverse events and deaths in the safety population, defined as all patients who received any amount of study drug. The trial is registered with ClinicalTrials.gov, NCT03667690, and is complete. FINDINGS: Between Oct 12, 2018, and Aug 29, 2021, 222 patients were screened for inclusion, and 199 patients (118 [59%] men; 81 [41%] women; mean age 61 years [SD 15·2]) were randomly assigned (100 [50%] patients to the rezafungin group and 99 [50%] patients to the caspofungin group). 55 (59%) of 93 patients in the rezafungin group and 57 (61%) of 94 patients in the caspofungin group had a global cure at day 14 (weighted treatment difference -1·1% [95% CI -14·9 to 12·7]; EMA primary endpoint). 22 (24%) of 93 patients in the rezafungin group and 20 (21%) of 94 patients in the caspofungin group died or had an unknown survival status at day 30 (treatment difference 2·4% [95% CI -9·7 to 14·4]; FDA primary endpoint). In the safety analysis, 89 (91%) of 98 patients in the rezafungin group and 83 (85%) of 98 patients in the caspofungin group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events that occurred in at least 5% of patients in either group were pyrexia, hypokalaemia, pneumonia, septic shock, and anaemia. 55 (56%) patients in the rezafungin group and 52 (53%) patients in the caspofungin group had serious adverse events. INTERPRETATION: Our data show that rezafungin was non-inferior to caspofungin for the primary endpoints of day-14 global cure (EMA) and 30-day all-cause mortality (FDA). Efficacy in the initial days of treatment warrants evaluation. There were no concerning trends in treatment-emergent or serious adverse events. These phase 3 results show the efficacy and safety of rezafungin and support its ongoing development. FUNDING: Cidara Therapeutics and Mundipharma.

[Conflicts of interest in scientific advisory panels]. / Belangenverstrengeling bij wetenschappelijke advisering.

Independence is crucial for the quality and credibility of scientific recommendations and guidelines. The composition of advisory committees requires a full understanding of the relationships and interests of prospective committee members. In addition to financial relationships, intellectual interests, professional interests, and reputation may also play a role. In addition to preventing conflicts of interest among committee members, precautions are also required during the review and authorisation stages of draft recommendations. We describe which potential or perceived conflicts of interests may occur, and how quality and independence of the advisory process can be safeguarded.

Identifying platelet-derived factors as amplifiers of B. burgdorferi-induced cytokine production.

Previous studies have shown that monocytes can be 'trained' or tolerized by certain stimuli to respond stronger or weaker to a secondary stimulation. Rewiring of glucose metabolism was found to be important in inducing this phenotype. As we previously found that Borrelia burgdorferi (B. burgdorferi), the causative agent of Lyme borreliosis (LB), alters glucose metabolism in monocytes, we hypothesized that this may also induce long-term changes in innate immune responses. We found that exposure to B. burgdorferi decreased cytokine production in response to the TLR4-ligand lipopolysaccharide (LPS). In addition, B. burgdorferi exposure decreased baseline levels of glycolysis, as assessed by lactate production. Using GWAS analysis, we identified a gene, microfibril-associated protein 3-like (MFAP3L) as a factor influencing lactate production after B. burgdorferi exposure. Validation experiments proved that MFAP3L affects lactate- and cytokine production following B. burgdorferi stimulation. This is mediated by functions of MFAP3L, which includes activating ERK2 and through activation of platelet degranulation. Moreover, we showed that platelets and platelet-derived factors play important roles in B. burgdorferi-induced cytokine production. Certain platelet-derived factors, such chemokine C-X-C motif ligand 7 (CXCL7) and (C-C motif) ligand 5 (CCL5), were elevated in the circulation of LB patients in comparison to healthy individuals.

Immunological Effects of Anti‒IL-17/12/23 Therapy in Patients with Psoriasis Complicated by Candida Infections.

Biologics that block the T helper (Th) 17 pathway are very effective in the treatment of psoriasis and other inflammatory diseases. However, IL-17 is also crucial for antifungal host defense, and clinical trial data suggest an increase in the incidence of Candida infections during IL-17 inhibitor (IL-17i) therapy. We investigated the innate and adaptive immune responses of patients with psoriasis with a history of skin and/or mucosal candidiasis during IL-17i or IL-12/23 inhibitor therapy, comparing those responses with those of healthy controls. Patients with psoriasis with IL-17i showed significantly lower CD4+Th1-like (CCR6‒CXCR3+CCR4‒) and Th1 Th17-like (CD4+CCR6+CXCR3+CCR4‒) cell percentages. Patient cells stimulated with Candida albicans produced significantly lower IL-6 in the IL-12/23 inhibitor group and IL-1ß in the IL-17i group, whereas the release of TNF-α and ROS was similar between patients and controls. IFN-γ and IL-10 production in response to several stimuli after 7 days was particularly decreased in patients receiving IL-17i therapy. Finally, after stimulation with the polarizing cytokines IL-1ß and IL-23, the Th17 cytokine response was significantly lower in the IL-17i patient group. These innate and adaptive immune response defects can diminish antifungal host immune response and thereby increase susceptibility to candidiasis in patients treated with IL-17i or IL-12/23 inhibitor.

Diagnostic parameters of cellular tests for Lyme borreliosis in Europe (VICTORY study): a case-control study.

BACKGROUND: Cellular tests for Lyme borreliosis might be able to overcome major shortcomings of serological testing, such as its low sensitivity in early stages of infection. Therefore, we aimed to assess the sensitivity and specificity of three cellular tests. METHODS: This was a nationwide, prospective, multiple-gate case-control study done in the Netherlands. Patients with physician-confirmed Lyme borreliosis, either early localised or disseminated, were consecutively included as cases at the start of antibiotic treatment. Controls were those without Lyme borreliosis from the general population (healthy controls) and those with potentially cross-reactive conditions (eg, autoimmune disease). We used three cellular tests for Lyme borreliosis (Spirofind Revised, iSpot Lyme, and LTT-MELISA) as index tests, and standard two-tier serological testing (STTT) as a comparator. Clinical data from Lyme borreliosis patients were collected at baseline and at 12 weeks after inclusion, and blood samples were obtained at baseline, 6 weeks, and 12 weeks. Control participants underwent clinical and laboratory assessments at baseline only. FINDINGS: Cases comprised 271 patients with Lyme borreliosis (of whom 245 had early-localised Lyme borreliosis and 26 had disseminated disease) and controls comprised 228 participants without Lyme borreliosis from the general population and 41 participants with potentially cross-reactive conditions. Recruitment occurred between May 14, 2018, and March 16, 2020. The specificity of STTT in healthy controls (216 of 228 samples [94·7%, 95% CI 91·5-97·7]) was higher than that of the cellular tests: Spirofind (140 of 171 [81·9%, 76·1-87·2]), iSpot Lyme (32 of 103 [31·1%, 21·5-40·3]) and LTT-MELISA (100 of 190 [52·6%, 44·9-60·3]). Cellular tests had varying sensitivities: Spirofind (88 of 204 [43·1%, 36·4-50·4]), iSpot Lyme (51 of 94 [54·3%, 44·5-63·7]), and LTT-MELISA (66 of 218 [30·3%, 23·8-36·7]). The Spirofind and iSpot Lyme outperformed STTT for sensitivity, but were similar to the C6-ELISA (C6-ELISA: 135 of 270 [50·0%, 44·5-55·5]; STTT: 76 of 270 [28·1%, 23·0-33·6]). INTERPRETATION: The cellular tests for Lyme borreliosis used in this study have a low specificity compared with serological tests, which leads to a high number of false-positive test results. We conclude that these cellular tests are unfit for clinical use at this stage. FUNDING: Netherlands Organization for Health Research and Development, AMC Foundation (Amsterdam UMC), and Ministry of Health of the Netherlands.

Borrelia burgdorferi Is a Poor Inducer of Gamma Interferon: Amplification Induced by Interleukin-12.

Laboratory diagnosis of Lyme borreliosis (LB) is mainly based on serology, which has limitations, particularly in the early stages of the disease. In recent years there have been conflicting reports concerning a new diagnostic tool using the cytokine interferon-gamma (IFN-γ). Previous studies have generally found low concentrations of IFN-γ in early LB infection. The goal of this study is to investigate IFN-γ regulation during early LB and provide insights into the host response to B. burgdorferi. We performed in vitro experiments with whole blood assays and peripheral blood mononuclear cells (PBMCs) of LB patients and healthy volunteers exposed to B. burgdorferi and evaluated the IFN-γ response using ELISA and related interindividual variation in IFN-γ production to the presence of single nucleotide polymorphisms. IFN-γ production of B. burgdorferi-exposed PBMCs and whole blood was amplified by the addition of interleukin-12 (IL-12) to the stimulation system. This effect was observed after 24 h of B. burgdorferi stimulation in both healthy individuals and LB patients. The effect was highly variable between individuals, but was significantly higher in LB patients 6 weeks since the start of antibiotic treatment compared to healthy individuals. IL-12 p40 and IL-18 mRNA were upregulated upon exposure to B. burgdorferi, whereas IL-12 p35 and IFN-γ mRNA expression remained relatively unchanged. SNP Rs280520 in the downstream IL-12 pathway, Tyrosine Kinase 2, was associated with increased IFN-γ production. This study shows that IL-12 evokes an IFN-γ response in B. burgdorferi exposed cells, and that LB patients and healthy controls respond differently to this stimulation.

Risk Factors for Intra-Abdominal Candidiasis in Intensive Care Units: Results from EUCANDICU Study.

INTRODUCTION: Intra-abdominal infections represent the second most frequently acquired infection in the intensive care unit (ICU), with mortality rates ranging from 20% to 50%. Candida spp. may be responsible for up to 10-30% of cases. This study assesses risk factors for development of intra-abdominal candidiasis (IAC) among patients admitted to ICU. METHODS: We performed a case-control study in 26 European ICUs during the period January 2015-December 2016. Patients at least 18 years old who developed an episode of microbiologically documented IAC during their stay in the ICU (at least 48 h after admission) served as the case cohort. The control group consisted of adult patients who did not develop episodes of IAC during ICU admission. Matching was performed at a ratio of 1:1 according to time at risk (i.e. controls had to have at least the same length of ICU stay as their matched cases prior to IAC onset), ICU ward and period of study. RESULTS: During the study period, 101 case patients with a diagnosis of IAC were included in the study. On univariate analysis, severe hepatic failure, prior receipt of antibiotics, prior receipt of parenteral nutrition, abdominal drain, prior bacterial infection, anastomotic leakage, recurrent gastrointestinal perforation, prior receipt of antifungal drugs and higher median number of abdominal surgical interventions were associated with IAC development. On multivariate analysis, recurrent gastrointestinal perforation (OR 13.90; 95% CI 2.65-72.82, p = 0.002), anastomotic leakage (OR 6.61; 95% CI 1.98-21.99, p = 0.002), abdominal drain (OR 6.58; 95% CI 1.73-25.06, p = 0.006), prior receipt of antifungal drugs (OR 4.26; 95% CI 1.04-17.46, p = 0.04) or antibiotics (OR 3.78; 95% CI 1.32-10.52, p = 0.01) were independently associated with IAC. CONCLUSIONS: Gastrointestinal perforation, anastomotic leakage, abdominal drain and prior receipt of antifungals or antibiotics may help to identify critically ill patients with higher probability of developing IAC. Prospective studies are needed to identify which patients will benefit from early antifungal treatment.

Global Risk of Bacterial Skin Infections and Herpesviridae Infections with Ustekinumab, Secukinumab, and Tumour Necrosis Factor-alpha Inhibitors: Spontaneous Reports of Adverse Drug Reactions from the World Health Organization Pharmacovigilance Center.

Genetic defects in interleukin-12/23/17 immunity are associated with an increased risk of Staphylococcus aureus and herpesvirus skin infections. This study analysed spontaneous safety reports from the WHO Pharmacovigilance Center of bacterial skin or herpesvirus infections associated with secukinumab, ustekinumab and tumour necrosis factor-α inhibitors. Associations found in disproportionality analyses were expressed as reporting odds ratios (ROR). For bacterial skin infections, ustekinumab showed the strongest association (ROR 6.09; 95% confidence interval (95% CI) 5.44-6.81), and, among the tumour necrosis factor-α inhibitors, infliximab showed the strongest association (ROR 4.18; 95% CI 3.97-4.40). Risk was comparable between infliximab and secukinumab (ROR 3.51; 95% CI 3.00-4.09). Secukinumab showed the strongest association with herpes simplex infection (ROR 4.80; 95% CI 3.78-6.10). All biologics were equally associated with herpes zoster. Infliximab was the only biologic associated with cytomegalovirus infection (ROR 5.66; 95% CI 5.08-6.31) and had the strongest association with Epstein-Barr virus infection (ROR 6.90; 95% CI 6.03-7.90). All biologics evaluated were positively associated with bacterial skin infections, herpes simplex, and herpes zoster, compared with all other drugs in the WHO database for which individual case safety reports were collected. The possibility of under-reporting, reporting bias and difference in causality assessment between countries and reporters must be taken into account when interpreting the results of disproportionality analyses.

Risk of candidiasis associated with interleukin-17 inhibitors: A real-world observational study of multiple independent sources.

BACKGROUND: Biologics directed against the T-helper (Th)-17 pathway have been approved for several inflammatory diseases. Interleukin (IL)-17 is involved in anti- Candida host defense, and clinical trials suggested increased candidiasis incidence during IL-17 inhibitor therapy. We describe the worldwide epidemiology of candidiasis during Th17 inhibitor therapy, and immunological mechanisms involved in candidiasis susceptibility. METHODS: A comprehensive analysis of multiple independent sources reporting Candida adverse events during biologics inhibiting the Th17 pathway was performed. Association between Th17 inhibitors and candidiasis was assessed using safety reports of (1) WHO and (2) EMA, (3) a population-based prescriptions registry, and (4) a psoriasis cohort. In a cohort of psoriasis patients experiencing candidiasis during Th17 inhibitors, Candida killing by immune cells and serum inflammatory proteome were analyzed. FINDINGS: A strong association between IL-17 inhibitors and candidiasis (ROR 10·20) was found in the WHO database, particularly for cutaneous (ROR 12·28), oropharyngeal (ROR 19·18), and esophageal candidiasis (ROR 21·20). Risk was higher relative to TNF-α inhibitors (4-10-fold, depending on candidiasis type), confirmed by EMA reports (16-33-fold), prescriptions registry (2-42-fold), and a psoriasis cohort (3-25-fold). After start of IL-17 inhibitors, patients' risk of candidiasis requiring antifungals increased 2-16 fold. In the psoriasis cohort, 58% of IL-17 treatment episodes were associated with candidiasis. In Th17 inhibitor recipients, proteins involved in anti- Candida immunity and Candida killing by mononuclear leukocytes were impaired. INTERPRETATION: IL-17 inhibitors are associated with an increased risk of oropharyngeal, esophageal, and cutaneous candidiasis, posing a significant disease burden for IL-17 inhibitor recipients. FUNDING: RadboudUMC.

An Exaggerated Monocyte-Derived Cytokine Response to Candida Hyphae in Patients With Recurrent Vulvovaginal Candidiasis.

BACKGROUND: Recurrent vulvovaginal candidiasis (RVVC) affects up to 8% of women. The immunopathogenesis is poorly understood but it has been suggested that RVVC might be due to dysregulated innate immune response. The aim of this study was to compare cytokine profiles in stimulated primary mononuclear cells (PBMCs) from RVVC and healthy individuals. METHODS: PBMCs isolated from RVVC patients (n = 24) and healthy volunteers (n = 30) were stimulated with unspecific and pathogen-specific antigens. Cytokine production was assessed after 24 hours, 48 hours, and 7 days using ELISA. RESULTS: No significant differences in cytokine production were found in T helper 1 (Th1), Th2, and Th17 immunity in response to both unspecific and pathogen-specific stimulations. Tumor necrosis factor-α (TNF-α) production in response to C. albicans hyphae was significantly higher in patients than controls and within the patient group, a significant positive correlation was found between interleukin-1ß (IL-1ß) and both TNF-α and IL-6. Both IL-1ß/IL-1Ra and TNF-α/IL-10 ratios in Candida hyphae-stimulated PBMCs were significantly higher in patients than controls. CONCLUSIONS: Women affected by RVVC showed increased monocytes-derived cytokine production, which might contribute to an exaggerated vaginal immune response to Candida hyphae. RVVC patients show no defective Th-dependent adaptive immune response upon Candida stimulation.

Prevalence of persistent symptoms after treatment for lyme borreliosis: A prospective observational cohort study.

BACKGROUND: Concerns about long-lasting symptoms attributed to Lyme borreliosis (LB) are widespread in the Western world, while such symptoms are highly prevalent in the general population. METHODS: In the largest prospective study to date, adults with physician-confirmed LB were included at the start of antibiotic treatment. Primary outcomes, prevalence of persistent symptoms and symptom severity, were assessed using three-monthly standardised questionnaires during one year. Persistent symptoms were defined as impaired scores for fatigue (CIS, subscale fatigue), cognitive impairment (CFQ) or pain (SF-36, subscale bodily pain) ≥6 months, with onset <6 months. Outcomes were compared with a longitudinal general population and a tick-bite cohort without LB as a reference. FINDINGS: Of 1135 LB patients (94•8% erythema migrans, 5•2% disseminated LB), 1084 fulfilled primary analysis criteria, as well as 1942 population and 1887 tick-bite controls. Overall prevalence of persistent symptoms in LB patients was 27•2% (95%CI, 24•7%-29•7%); 6•0% and 3•9% higher than in population (21•2%, 95%CI, 19•3%-23•1%; p < 0•0001) and tick-bite (23•3%, 95%CI 21•3%-25•3%; p = 0•016) cohorts, respectively. At 12 months, fatigue, cognitive impairment, and pain were significantly more severe in erythema migrans patients than in reference cohorts, while in disseminated LB patients, only pain was more severe. INTERPRETATION: In treated LB patients, persistent symptoms were significantly more prevalent and symptoms were more severe than in individuals without LB, although the background prevalence was substantial. This suggests an association, either direct or indirect, between persistent symptoms and LB in a relatively small subset of patients. FUNDING: ZonMw; Dutch Ministry of Health, Welfare and Sport.

Expectancies as predictors of symptom improvement after antimicrobial therapy for persistent symptoms attributed to Lyme disease.

INTRODUCTION/OBJECTIVE: Expectancies about symptom improvement or deterioration are reliable predictors of symptom progression and treatment outcomes (symptom resolution or symptomatic improvement) in many (non-)pharmacological studies and treatments. This study examined predictors of symptom improvement after antimicrobial therapy for persistent symptoms attributed to Lyme disease, hypothesizing particularly pre-treatment expectancies regarding symptom improvement to be predictive. METHODS: A predictive study was performed on pre-treatment and post-treatment individual characteristics, including expectancies, and physical and mental health-related quality of life (HRQoL) from the PLEASE-trial comparing randomized 12-weeks of doxycycline, clarithromycin-hydroxychloroquine, or placebo following 2 weeks of intravenous ceftriaxone. At end-of-treatment (14 weeks after trial start) and follow-up (52 weeks), complete data of 231 and 170 (of initial 280) patients with persistent symptoms temporally related to a history of erythema migrans or otherwise confirmed symptomatic Lyme disease, or accompanied by B. burgdorferi IgG or IgM antibodies, were examined through hierarchical regression analyses. RESULTS: In addition to pre-treatment HRQoL, pre-treatment expectancies regarding symptom improvement were consistently associated with stronger physical and mental HRQoL improvements at both end-of-treatment and follow-up (95% CI range: .09;.54, p < .01 to .27;.92, p < .001). Post-treatment expectancies regarding having received antibiotics vs. placebo was associated with more HRQoL improvement at end-of-treatment, but not at follow-up (95% CI-range 1.00;4.75, p = .003 to -7.34; -2.22, p < .001). CONCLUSIONS: The present study shows that, next to pre-treatment functioning, patients' pre-treatment and post-treatment expectancies regarding improvement of persistent symptoms attributed to Lyme disease relate to a more beneficial symptom course. Expectancies of patients may be relevant to explain and potentially improve patient outcomes (e.g., by optimized communication about treatment success). TRIAL REGISTRATION: ClinicalTrials.gov, NCT01207739 (Registration date: 23-09-2010) Key Points • As there is currently no sufficient symptom resolution or symptomatic improvement for many patients with persistent symptoms attributed to Lyme disease, it is relevant to know which factors determine symptom progression and predict heterogeneity in treatment response. • Next to pre-treatment functioning, expectancies regarding symptom improvement and having received antimicrobial study medication are associated with a more beneficial symptom course after both shorter-term and longer-term antimicrobial treatment. • Expectancies are relevant to consider in treatment studies and may be useful in clinical settings to improve symptom course and treatment outcome (e.g., by optimized communication about treatment success).

EORTC/MSGERC Definitions of Invasive Fungal Diseases: Summary of Activities of the Intensive Care Unit Working Group.

The EORTC/MSGERC recently revised and updated the consensus definitions of invasive fungal disease (IFD). These definitions primarily focus on patients with cancer and stem cell or solid-organ transplant patients. They may therefore not be suitable for intensive care unit (ICU) patients. More in detail, while the definition of proven IFD applies to a broad range of hosts, the categories of probable and possible IFD were primarily designed for classical immunocompromised hosts and may therefore not be ideal for other populations. Moreover, the scope of the possible category of IFD has been diminished in the recently revised definitions for classically immunocompromised hosts. Diagnosis of IFD in the ICU presents many challenges, which are different for invasive candidiasis and for invasive aspergillosis. The aim of this article is to review progresses made in recent years and difficulties remaining in the development of definitions applicable in the ICU setting.