BackgroundInterpretation of serological assays in Lyme borreliosis requires an understanding of the clinical indications and the limitations of the currently available tests. We therefore systematically reviewed the accuracy of serological tests for the diagnosis of Lyme borreliosis in Europe.MethodsWe searched EMBASE en MEDLINE and contacted experts. Studies evaluating the diagnostic accuracy of serological assays for Lyme borreliosis in Europe were eligible. Study selection and data-extraction were done by two authors independently. We assessed study quality using the QUADAS-2 checklist. We used a hierarchical summary ROC meta-regression method for the meta-analyses. Potential sources of heterogeneity were test-type, commercial or in-house, Ig-type, antigen type and study quality. These were added as covariates to the model, to assess their effect on test accuracy.ResultsSeventy-eight studies evaluating an Enzyme-Linked ImmunoSorbent assay (ELISA) or an immunoblot assay against a reference standard of clinical criteria were included. None of the studies had low risk of bias for all QUADAS-2 domains. Sensitivity was highly heterogeneous, with summary estimates: erythema migrans 50 % (95 % CI 40 % to 61 %); neuroborreliosis 77 % (95 % CI 67 % to 85 %); acrodermatitis chronica atrophicans 97 % (95 % CI 94 % to 99 %); unspecified Lyme borreliosis 73 % (95 % CI 53 % to 87 %). Specificity was around 95 % in studies with healthy controls, but around 80 % in cross-sectional studies. Two-tiered algorithms or antibody indices did not outperform single test approaches.ConclusionsThe observed heterogeneity and risk of bias complicate the extrapolation of our results to clinical practice. The usefulness of the serological tests for Lyme disease depends on the pre-test probability and subsequent predictive values in the setting where the tests are being used. Future diagnostic accuracy studies should be prospectively planned cross-sectional studies, done in settings where the test will be used in practice.

CXCL13 in cerebrospinal fluid (CSF) could be an important component for diagnosing Lyme neuroborreliosis (LNB). Levels of intrathecal CXCL13 were determined for 58 LNB patients and 210 controls; sensitivity was 88% and specificity was 89% (cutoff, 250 pg of CXCL13/ml of CSF). Elevated levels of CXCL13 can aid in the diagnosis of LNB, but levels should be interpreted with care.Diagnosing Lyme neuroborreliosis (LNB) is difficult because one of the most specific markers, the antibody index (AI), is negative in 21 to 45% of patients (1). Intrathecal levels of CXCL13 have been suggested to be a potential biomarker for LNB. CXCL13 is produced by antigen-presenting cells and is a selective chemoattractant for B cells and B-helper T cells. It has been shown that CXCL13 is expressed at high levels in cerebrospinal fluid (CSF) from LNB patients, while levels were barely detectable in CSF from subjects with noninflammatory neurological disease. Overall sensitivity for LNB ranged from 96 to 100%, and specificity ranged from 63 to 98% (3,6,11,12). Case reports describing early diagnosis of LNB using CXCL13 levels in CSF have already been published (5, 9).Our aim was to determine the diagnostic potential of levels of intrathecal CXCL13 to distinguish acute and late LNB from other central nervous system diseases in the pediatric and adult population.Patients were identified retrospectively using the OLVG Hospital laboratory information management system. CSF and serum samples from 58 LNB patients before treatment were included. Criteria for diagnosing LNB patients were that their meningitis had no other cause and that they had three of the following four characteristics: positive serology at presentation, pleocytosis, positive AI with an Ideia Lyme neuroborreliosis kit (Oxoid, Cambridge, United Kingdom), and objective neurological complaints with clinical improvement after treatment. From this group, definite LNB patients (n ϭ 45) were those who had a pleocytosis and a positive AI, and probable LNB patients (n ϭ 13) were those who had either pleocytosis (n ϭ 12) or a positive AI (n ϭ 1) (4). Ninety-one percent of the LNB patients presented within 6 months of the start of complaints; the range was 7 days to 48 months. Forty-one percent of LNB patients were children. Most LNB patients presented with a facial nerve paralysis (60%) or meningoradiculitis (26%). Seventeen percent of LNB patients reported experiencing erythema migrans (EM) before or at presentation.As controls, we included 36 patients with Lyme borreliosis that did not meet the criteria for LNB, 93 patients with an infectious cause of meningitis/encephalitis, 62 patients with neurological inflammatory diseases, and 12 patients with noninflammatory neurological complaints. Furthermore, seven HIV patients with no neurological complaints or evidence of an intrathecal infection were tested. For patient characteristics, see Table S1 in the supplemental material.CSF samples were tested with a Quantikine human CXCL13/BLC/BCA-1 immunoassay (R&D Systems, Minneapolis, MN).Resu...

Measles occurred in 6 twice-vaccinated HCWs, despite 2 having adequate pre-exposure neutralizing antibodies. None of the twice-vaccinated cases had severe measles, and none had onward transmission, consistent with laboratory findings suggesting a secondary immune response. Improving 2-dose MMR coverage among HCWs would have likely reduced the size of this outbreak.

Borrelia burgdorferi, the agent of Lyme disease, is transmitted by ticks. During transmission from the tick to the host, spirochetes are delivered with tick saliva, which contains the salivary protein Salp15. Salp15 has been shown to protect spirochetes against B. burgdorferi-specific antibodies. We now show that Salp15 from both Ixodes ricinus and Ixodes scapularis protects serum-sensitive isolates of Borrelia burgdorferi sensu lato against complement-mediated killing. I. ricinus Salp15 showed strong protective effects compared to those of I. scapularis Salp15. Deposition of terminal C5b to C9 (one molecule each of C5b, C6, C7, and C8 and one or more molecules of C9) complement complexes, part of the membrane attack complex, on the surface of B. burgdorferi was inhibited in the presence of Salp15. In the presence of normal human serum, serum-sensitive Borrelia burgdorferi requires protection against complement-mediated killing, which is provided, at least in part, by the binding to the tick salivary protein Salp15.The Lyme disease agent Borrelia burgdorferi survives in a tick-mouse cycle. In the United States, B. burgdorferi sensu stricto is maintained primarily in Ixodes scapularis ticks, while the European vector of B. burgdorferi sensu stricto, B. garinii, and B. afzelii strains are generally Ixodes ricinus ticks. Feeding of ixodid ticks normally takes several days (2), which gives the host immune system time to react to the arthropod. The ticks have developed several mechanisms to evade both the innate and adaptive host responses, which enable them to take an effective blood meal. Tick saliva possesses proteins with immunosuppressive (14, 18), anticomplement (5,19,27), and antihemostatic (21, 22) activity. Salp15, a feeding-induced tick salivary protein, is known to inhibit CD4 ϩ T-cell activation and proliferation by specifically binding to the CD4 coreceptor of the T cells (1, 6, 13). Also, Salp15 appeared to enhance the survival of B. burgdorferi in the host after transmission by the tick by specifically interacting with B. burgdorferi outer surface protein C (OspC) and providing protection against borreliacidal antibodies (25). Recently we found three Salp15 homologues in I. ricinus ticks (12), and one of these homologues, Salp15 Iric-1, showed 80% similarity to I. scapularis Salp15 (Iscap Salp15) at the DNA level.The innate response, the complement system in particular, plays a crucial role in the eradication of invading pathogens. The complement system is important in the initiation of attack against B. burgdorferi. The spirochetes are opsonized and also directly killed by the formation of the lytic pore-forming membrane attack complex (MAC) (3, 23). B. burgdorferi sensu stricto, B. garinii, and B. afzelii isolates are able to activate complement both by the classical pathway and by the alternative pathway in nonimmune human serum (NHS) in the absence of specific antibodies, but they differ in susceptibility to complement-mediated killing (28). Serum-resistant Borrelia strains are able to evade comple...

We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine individuals with this variant had a 0.54 to 0.74 log 10 increase (i.e., a ~3.5-fold to 5.5-fold increase) in viral load compared with, and exhibited CD4 cell decline twice as fast as, 6604 individuals with other subtype-B strains. Without treatment, advanced HIV—CD4 cell counts below 350 cells per cubic millimeter, with long-term clinical consequences—is expected to be reached, on average, 9 months after diagnosis for individuals in their thirties with this variant. Age, sex, suspected mode of transmission, and place of birth for the aforementioned 109 individuals were typical for HIV-positive people in the Netherlands, which suggests that the increased virulence is attributable to the viral strain. Genetic sequence analysis suggests that this variant arose in the 1990s from de novo mutation, not recombination, with increased transmissibility and an unfamiliar molecular mechanism of virulence.