By using commercial insurance claims data, we estimated that Lyme disease was diagnosed and treated in ≈476,000 patients in the United States annually during 2010-2018. Our results underscore the ...need for accurate diagnosis and improved prevention.
National surveillance provides important information about Lyme disease (LD) but is subject to underreporting and variations in practice. Information is limited about the national epidemiology of LD ...from other sources. Retrospective analysis of a nationwide health insurance claims database identified patients from 2005-2010 with clinician-diagnosed LD using International Classification of Diseases, Ninth Revision, Clinical Modification, codes and antimicrobial drug prescriptions. Of 103,647,966 person-years, 985 inpatient admissions and 44,445 outpatient LD diagnoses were identified. Epidemiologic patterns were similar to US surveillance data overall. Outpatient incidence was highest among boys 5-9 years of age and persons of both sexes 60-64 years of age. On the basis of extrapolation to the US population and application of correction factors for coding, we estimate that annual incidence is 106.6 cases/100,000 persons and that ≈329,000 (95% credible interval 296,000-376,000) LD cases occur annually. LD is a major US public health problem that causes substantial use of health care resources.
Countries with ongoing outbreaks of Zika virus have observed a notable rise in reported cases of Guillain-Barré syndrome (GBS), with mounting evidence of a causal link between Zika virus infection ...and the neurological syndrome. However, the risk of GBS following a Zika virus infection is not well characterized. In this work, we used data from 11 locations with publicly available data to estimate the risk of GBS following an infection with Zika virus, as well as the location-specific incidence of infection and the number of suspect GBS cases reported per infection.
We built a mathematical inference framework utilizing data from 11 locations that had reported suspect Zika and GBS cases, two with completed outbreaks prior to 2015 (French Polynesia and Yap) and nine others in the Americas covering partial outbreaks and where transmission was ongoing as of early 2017.
We estimated that 2.0 (95% credible interval 0.5-4.5) reported GBS cases may occur per 10,000 Zika virus infections. The frequency of reported suspect Zika cases varied substantially and was highly uncertain, with a mean of 0.11 (95% credible interval 0.01-0.24) suspect cases reported per infection.
These estimates can help efforts to prepare for the GBS cases that may occur during Zika epidemics and highlight the need to better understand the relationship between infection and the reported incidence of clinical disease.
Dengue virus (DENV) is a serious mosquito-borne pathogen causing significant global disease burden, either as classic dengue fever (DF) or in its most severe manifestation dengue hemorrhagic fever ...(DHF). Nearly half of the world's population is at risk of dengue disease and there are estimated to be millions of infections annually; a situation which will continue to worsen with increasing expansion of the mosquito vectors and epidemic DF/DHF. Currently there are no available licensed vaccines or antivirals for dengue, although significant effort has been directed toward the development of safe and efficacious dengue vaccines for over 30 years. Promising vaccine candidates are in development and testing phases, but a better understanding of immune responses to DENV infection and vaccination is needed. Humoral immune responses to DENV infection are complex and may exacerbate pathogenicity, yet are essential for immune protection. In this report, we develop DENV-2 envelope (E) protein epitope-specific antigens and measure immunoglobulin responses to three distinct epitopes in DENV-2 infected human serum samples. Immunoglobulin responses to DENV-2 infection exhibited significant levels of individual variation. Antibody populations targeting broadly cross-reactive epitopes centered on the fusion peptide in structural domain II were large, highly variable, and greater in primary than in secondary DENV-2 infected sera. E protein domain III cross-reactive immunoglobulin populations were similarly variable and much larger in IgM than in IgG. DENV-2 specific domain III IgG formed a very small proportion of the antibody response yet was significantly correlated with DENV-2 neutralization, suggesting that the highly protective IgG recognizing this epitope in murine studies plays a role in humans as well. This report begins to tease apart complex humoral immune responses to DENV infection and is thus important for improving our understanding of dengue disease and immunological correlates of protection, relevant to DENV vaccine development and testing.
The current recommendation for the laboratory confirmation of Lyme disease is serology-based diagnostics. Specifically, a standardized two-tiered testing (STTT) algorithm is applied that utilizes a ...first-tier immunofluorescence assay or enzyme immunoassay (EIA) that, if the result is positive or equivocal, is followed by second-tier immunoblotting. Despite the standardization and performance achievements, STTT is considered technically complex and subjective, as well as insensitive for early acute infection. These issues have prompted development of novel algorithms and testing platforms. In this study, we evaluated the performance of several commonly used assays for STTT. Several modified two-tiered testing (MTTT) algorithms, including a 2-EIA algorithm and modified criteria for second-tier IgG immunoblots, were also evaluated. All tests were performed on sera from a recently available, well-defined archive of positive- and negative-control patients. Our study demonstrates differences in the results between individual first- and second-tier tests, although the overall agreement of the different STTT algorithms used was strong. In addition, the MTTT algorithm utilizing 2-EIAs was found to be equivalent to all STTT algorithms tested, with agreement ranging from 94 to 97%. The 2-EIA MTTT algorithm slightly enhanced sensitivity in early disease compared to the STTT algorithms evaluated. Furthermore, these data add to the mounting evidence that a 2-EIA-based MTTT algorithm, where immunoblotting is replaced by the C6 EIA, performs as well or better than STTT.
Hemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal disorder characterized by fever, pancytopenia, hepatosplenomegaly, and increased serum ferritin. HLH is being increasingly ...reported as a complication of dengue, a common tropical acute febrile illness.
After a cluster of pediatric dengue-associated HLH patients was identified during the 2012-2013 dengue epidemic in Puerto Rico, active surveillance and a case-control investigation was conducted at four referral hospitals to determine the incidence of HLH in children and identify risk factors for HLH following dengue. Patients with dengue-associated HLH (cases) were matched by month of illness onset and admission hospital to dengue patients that did not develop HLH (controls). During 2008-2013, a total of 33 HLH patients were identified, of which 22 (67%) were associated with dengue and 1 died (dengue-associated HLH case-fatality rate: 4.5%). Two patients with dengue-associated HLH had illness onset in 2009, none had illness onset during the 2010 dengue epidemic, and 20 had illness onset during the 2012-2013 epidemic. Frequency of infection with either dengue virus (DENV)-1 or DENV-4 did not differ between cases and controls. Cases were younger than controls (median age: 1 vs. 13 years, p < 0.01), were hospitalized longer (18 vs. 5 days, p < 0.01), and were admitted more frequently to pediatric intensive care units (100% vs. 16%, p < 0.01). Cases had co-infection (18.2% vs. 4.5%, p = 0.04), recent influenza-like illness (54.5% vs. 25.0%, p = 0.01), and longer duration of fever (7 vs. 5 days; p < 0.01). Cases were more likely to have lymphadenopathy, hepatomegaly, splenomegaly, anemia, and elevated liver transaminases (p ≤ 0.02).
During this cluster of dengue-associated HLH cases that was temporally associated with the 2012-2013 epidemic, most patients with dengue-associated HLH were infants and had higher morbidity than dengue inpatients. Physicians throughout the tropics should be aware of HLH as a potential complication of dengue, particularly in patients with anemia and severe liver injury.
Abstract
Since the 2007 Zika epidemic in the Micronesian state of Yap, it has been apparent that not all people infected with Zika virus (ZIKV) experience symptoms. However, the proportion of ...infections that result in symptoms remains unclear. Existing estimates have varied in their interpretation of symptoms due to other causes and the case definition used, and they have assumed perfect test sensitivity and specificity. Using a Bayesian model and data from ZIKV serosurveys in Yap (2007), French Polynesia (2013–2014), and Puerto Rico (2016), we found that assuming perfect sensitivity and specificity generally led to lower estimates of the symptomatic proportion. Incorporating reasonable assumptions for assay sensitivity and specificity, we estimated that 27% (95% credible interval (CrI): 15, 37) (Yap), 44% (95% CrI: 26, 66) (French Polynesia), and 50% (95% CrI: 34, 92) (Puerto Rico) of infections were symptomatic, with variation due to differences in study populations, study designs, and case definitions. The proportion of ZIKV infections causing symptoms is critical for surveillance system design and impact assessment. Here, we accounted for key uncertainties in existing seroprevalence data and found that estimates for the symptomatic proportion ranged from 27% to 50%, suggesting that while the majority of infections are asymptomatic or mildly symptomatic, symptomatic infections might be more common than previously estimated.
In 2016, four clusters of local mosquitoborne Zika virus transmission were identified in Miami-Dade County, Florida, USA, generating "red zones" (areas into which pregnant women were advised against ...traveling). The Miami-Dade County Mosquito Control Division initiated intensive control activities, including property inspections, community education, and handheld sprayer applications of larvicides and adulticides. For the first time, the Mosquito Control Division used a combination of areawide ultralow-volume adulticide and low-volume larvicide spraying to effectively control Aedes aegypti mosquitoes, the primary Zika virus vector within the county. The number of mosquitoes rapidly decreased, and Zika virus transmission was interrupted within the red zones immediately after the combination of adulticide and larvicide spraying.
Standard two-tiered testing (STTT) is the recommended algorithm for laboratory diagnosis of Lyme disease (LD). Several limitations are associated with STTT that include low sensitivity in the early ...stages of disease, as well as technical complexity and subjectivity associated with second-tier immunoblotting; therefore, modified two-tiered testing (MTTT) algorithms that utilize two sequential first-tier tests and eliminate immunoblotting have been evaluated. Recently, a novel MTTT that uses a VlsE chemiluminescence immunoassay followed by a C6 enzyme immunoassay has been proposed. The purpose of this study was to evaluate the performance of the VlsE/C6 MTTT using well-characterized serum samples. Serum samples from the CDC Lyme Serum Repository were tested using three MTTTs, VlsE/C6, whole-cell sonicate (WCS)/C6, and WCS/VlsE, and three STTTs (immunoblotting preceded by three different first-tier assays: VlsE, C6, and WCS). Significant differences were not observed between the results of the MTTTs assessed; however, the VlsE/C6 MTTT resulted in the highest specificity (100%) when other diseases were tested and the lowest sensitivity (75%) for LD samples. Significant differences were present between the results for various MTTTs and STTTs evaluated. Specifically, all MTTTs resulted in higher sensitivities than the STTTs for all LD groups combined and were significantly more accurate (i.e., higher proportion of correct classifications) for this group, with the exception of the WCS/ViraStripe STTT. Additionally, when other diseases were tested, only the results of the VlsE/C6 MTTT differed significantly from those of the WCS/ViraStripe STTT, with the VlsE/C6 MTTT resulting in a 6.2% higher accuracy. Overall, the VlsE/C6 MTTT offers an additional laboratory testing algorithm for LD with equivalent or enhanced performance compared to that of the other MTTTs and STTTs evaluated in this study.
Post-treatment Lyme disease symptoms/syndrome (PTLDS) occurs in approximately 10% of Lyme disease patients following antibiotic treatment. Biomarkers or specific clinical symptoms to identify PTLDS ...patients do not currently exist and the PTLDS classification is based on the report of persistent, subjective symptoms for ≥ 6 months following antibiotic treatment for Lyme disease.
Untargeted liquid chromatography-mass spectrometry metabolomics was used to determine longitudinal metabolic responses and biosignatures in PTLDS and clinically cured non-PTLDS Lyme patients. Evaluation of biosignatures included: 1) defining altered classes of metabolites; 2) elastic net regularization to define metabolites that most strongly defined PTLDS and non-PTLDS patients at different timepoints; 3) changes in the longitudinal abundance of metabolites; 4) linear discriminant analysis to evaluate robustness in a second patient cohort.
This study determined that observable metabolic differences exist between PTLDS and non-PTLDS patients at multiple timepoints. The metabolites with differential abundance included those from glycerophospholipid, bile acid and acylcarnitine metabolism. Distinct longitudinal patterns of metabolite abundance indicated a greater metabolic variability in PTLDS vs non-PTLDS patients. Small numbers of metabolites (6-40) could be used to define PTLDS vs. non-PTLDS patients at defined time points, and the findings were validated in a second cohort of PTLDS and non-PTLDS patients.
These data provide evidence that an objective metabolite-based measurement can distinguish patients with PTLDS and help understand the underlying biochemistry of PTLDS.
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