Diagnosis of human leptospirosis: systematic review and meta-analysis of the diagnostic accuracy of the Leptospira microscopic agglutination test, PCR targeting Lfb1, and IgM ELISA to Leptospira fainei serovar Hurstbridge.

BACKGROUND: Leptospirosis is an underdiagnosed infectious disease with non-specific clinical presentation that requires laboratory confirmation for diagnosis. The serologic reference standard remains the microscopic agglutination test (MAT) on paired serum samples. However, reported estimates of MAT's sensitivity vary. We evaluated the accuracy of four index tests, MAT on paired samples as well as alternative standards for leptospirosis diagnosis: MAT on single acute-phase samples, polymerase chain reaction (PCR) with the target gene Lfb1, and ELISA IgM with Leptospira fainei serovar Hurstbridge as an antigen. METHODS: We performed a systematic review of studies reporting results of leptospirosis diagnostic tests. We searched eight electronic databases and selected studies that tested human blood samples and compared index tests with blood culture and/or PCR and/or MAT (comparator tests). For MAT selection criteria we defined a threshold for single acute-phase samples according to a national classification of leptospirosis endemicity. We used a Bayesian random-effect meta-analysis to estimate the sensitivity and specificity of MAT in single acute-phase and paired samples separately, and assessed risk of bias using the Quality Assessment of Studies of Diagnostic Accuracy Approach- 2 (QUADAS-2) tool. RESULTS: For the MAT accuracy evaluation, 15 studies were included, 11 with single acute-phase serum, and 12 with paired sera. Two included studies used PCR targeting the Lfb1 gene, and one included study used IgM ELISA with Leptospira fainei serovar Hurstbridge as antigen. For MAT in single acute-phase samples, the pooled sensitivity and specificity were 14% (95% credible interval [CrI] 3-38%) and 86% (95% CrI 59-96%), respectively, and the predicted sensitivity and specificity were 14% (95% CrI 0-90%) and 86% (95% CrI 9-100%). Among paired MAT samples, the pooled sensitivity and specificity were 68% (95% CrI 32-92%) and 75% (95% CrI 45-93%) respectively, and the predicted sensitivity and specificity were 69% (95% CrI 2-100%) and 75% (2-100%). CONCLUSIONS: Based on our analysis, the accuracy of MAT in paired samples was not high, but it remains the reference standard until a more accurate diagnostic test is developed. Future studies that include larger numbers of participants with paired samples will improve the certainty of accuracy estimates.

Estimating sensitivity and specificity of diagnostic tests using latent class models that account for conditional dependence between tests: a simulation study.

BACKGROUND: Latent class models are increasingly used to estimate the sensitivity and specificity of diagnostic tests in the absence of a gold standard, and are commonly fitted using Bayesian methods. These models allow us to account for 'conditional dependence' between two or more diagnostic tests, meaning that the results from tests are correlated even after conditioning on the person's true disease status. The challenge is that it is not always clear to researchers whether conditional dependence exists between tests and whether it exists in all or just some latent classes. Despite the increasingly widespread use of latent class models to estimate diagnostic test accuracy, the impact of the conditional dependence structure chosen on the estimates of sensitivity and specificity remains poorly investigated. METHODS: A simulation study and a reanalysis of a published case study are used to highlight the impact of the conditional dependence structure chosen on estimates of sensitivity and specificity. We describe and implement three latent class random-effect models with differing conditional dependence structures, as well as a conditional independence model and a model that assumes perfect test accuracy. We assess the bias and coverage of each model in estimating sensitivity and specificity across different data generating mechanisms. RESULTS: The findings highlight that assuming conditional independence between tests within a latent class, where conditional dependence exists, results in biased estimates of sensitivity and specificity and poor coverage. The simulations also reiterate the substantial bias in estimates of sensitivity and specificity when incorrectly assuming a reference test is perfect. The motivating example of tests for Melioidosis highlights these biases in practice with important differences found in estimated test accuracy under different model choices. CONCLUSIONS: We have illustrated that misspecification of the conditional dependence structure leads to biased estimates of sensitivity and specificity when there is a correlation between tests. Due to the minimal loss in precision seen by using a more general model, we recommend accounting for conditional dependence even if researchers are unsure of its presence or it is only expected at minimal levels.

Diagnostic performance of the IMMY cryptococcal antigen lateral flow assay on serum and cerebrospinal fluid for diagnosis of cryptococcosis in HIV-negative patients: a systematic review.

BACKGROUND: The incidence of cryptococcosis amongst HIV-negative persons is increasing. Whilst the excellent performance of the CrAg testing in people living with HIV is well described, the diagnostic performance of the CrAg LFA has not been systematically evaluated in HIV-negative cohorts on serum or cerebrospinal fluid. METHODS: We performed a systematic review to characterise the diagnostic performance of IMMY CrAg® LFA in HIV-negative populations on serum and cerebrospinal fluid. A systematic electronic search was performed using Medline, Embase, Global Health, CENTRAL, WoS Science Citation Index, SCOPUS, Africa-Wide Information, LILACS and WHO Global Health Library. Studies were screened and data extracted from eligible studies by two independent reviewers. A fixed effect meta-analysis was used to estimate the diagnostic sensitivity and specificity. RESULTS: Of 447 records assessed for eligibility, nine studies met our inclusion criteria, including 528 participants overall. Amongst eight studies that evaluated the diagnostic performance of the IMMY CrAg® LFA on serum, the pooled median sensitivity was 96% (95% Credible Interval (CrI) 68-100%) with a pooled specificity estimate of 96% (95%CrI 84-100%). Amongst six studies which evaluated the diagnostic performance of IMMY CrAg® LFA on CSF, the pooled median sensitivity was 99% (95%CrI 95-100%) with a pooled specificity median of 99% (95%CrI 95-100%). CONCLUSIONS: This review demonstrates a high pooled sensitivity and specificity for the IMMY CrAg® LFA in HIV-negative populations, in keeping with findings in HIV-positive individuals. The review was limited by the small number of studies. Further studies using IMMY CrAg® LFA in HIV-negative populations would help to better determine the diagnostic value of this test.

A dependent Bayesian Dirichlet process model for source apportionment of particle number size distribution.

The relationship between particle exposure and health risks has been well established in recent years. Particulate matter (PM) is made up of different components coming from several sources, which might have different level of toxicity. Hence, identifying these sources is an important task in order to implement effective policies to improve air quality and population health. The problem of identifying sources of particulate pollution has already been studied in the literature. However, current methods require an a priori specification of the number of sources and do not include information on covariates in the source allocations. Here, we propose a novel Bayesian nonparametric approach to overcome these limitations. In particular, we model source contribution using a Dirichlet process as a prior for source profiles, which allows us to estimate the number of components that contribute to particle concentration rather than fixing this number beforehand. To better characterize them we also include meteorological variables (wind speed and direction) as covariates within the allocation process via a flexible Gaussian kernel. We apply the model to apportion particle number size distribution measured near London Gatwick Airport (UK) in 2019. When analyzing this data, we are able to identify the most common PM sources, as well as new sources that have not been identified with the commonly used methods.

Diagnostic accuracy of multiplex respiratory pathogen panels for influenza or respiratory syncytial virus infections: systematic review and meta-analysis.

Respiratory syncytial virus (RSV) and influenza viruses are important global causes of morbidity and mortality. We evaluated the diagnostic accuracy of the Luminex NxTAG respiratory pathogen panels (RPPs)™ (index) against other RPPs (comparator) for detection of RSV and influenza viruses. Studies comparing human clinical respiratory samples tested with the index and at least one comparator test were included. A random-effect latent class meta-analysis was performed to assess the specificity and sensitivity of the index test for RSV and influenza. Risk of bias was assessed using the QUADAS-2 tool and certainty of evidence using GRADE. Ten studies were included. For RSV, predicted sensitivity was 99% (95% credible interval [CrI] 96-100%) and specificity 100% (95% CrI 98-100%). For influenza A and B, predicted sensitivity was 97% (95% CrI 89-100) and 98% (95% CrI 88-100) respectively; specificity 100% (95% CrI 99-100) and 100% (95% CrI 99-100), respectively. Evidence was low certainty. Although index sensitivity and specificity were excellent, comparators' performance varied. Further research with clear patient recruitment strategies could ascertain performance across different populations.Protocol Registration: Prospero CRD42021272062.

Predicting mortality in febrile adults: comparative performance of the MEWS, qSOFA, and UVA scores using prospectively collected data among patients in four health-care sites in sub-Saharan Africa and South-Eastern Asia.

Background: Clinical severity scores can identify patients at risk of severe disease and death, and improve patient management. The modified early warning score (MEWS), the quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA), and the Universal Vital Assessment (UVA) were developed as risk-stratification tools, but they have not been fully validated in low-resource settings where fever and infectious diseases are frequent reasons for health care seeking. We assessed the performance of MEWS, qSOFA, and UVA in predicting mortality among febrile patients in the Lao PDR, Malawi, Mozambique, and Zimbabwe. Methods: We prospectively enrolled in- and outpatients aged ≥ 15 years who presented with fever (≥37.5 °C) from June 2018-March 2021. We collected clinical data to calculate each severity score. The primary outcome was mortality 28 days after enrolment. The predictive performance of each score was determined using area under the receiver operating curve (AUC). Findings: A total of 2797 participants were included in this analysis. The median (IQR) age was 32 (24-43) years, 38% were inpatients, and 60% (1684/2797) were female. By the time of follow-up, 7% (185/2797) had died. The AUC (95% CI) for MEWS, qSOFA and UVA were 0.67 (0.63-0.71), 0.68 (0.64-0.72), and 0.82 (0.79-0.85), respectively. The AUC comparison found UVA outperformed both MEWS (p < 0.001) and qSOFA (p < 0.001). Interpretation: We showed that the UVA score performed best in predicting mortality among febrile participants by the time follow-up compared with MEWS and qSOFA, across all four study sites. The UVA score could be a valuable tool for early identification, triage, and initial treatment guidance of high-risk patients in resource-limited clinical settings. Funding: FCDO.

Using trained dogs and organic semi-conducting sensors to identify asymptomatic and mild SARS-CoV-2 infections: an observational study.

BACKGROUND: A rapid, accurate, non-invasive diagnostic screen is needed to identify people with SARS-CoV-2 infection. We investigated whether organic semi-conducting (OSC) sensors and trained dogs could distinguish between people infected with asymptomatic or mild symptoms, and uninfected individuals, and the impact of screening at ports-of-entry. METHODS: Odour samples were collected from adults, and SARS-CoV-2 infection status confirmed using RT-PCR. OSC sensors captured the volatile organic compound (VOC) profile of odour samples. Trained dogs were tested in a double-blind trial to determine their ability to detect differences in VOCs between infected and uninfected individuals, with sensitivity and specificity as the primary outcome. Mathematical modelling was used to investigate the impact of bio-detection dogs for screening. RESULTS: About, 3921 adults were enrolled in the study and odour samples collected from 1097 SARS-CoV-2 infected and 2031 uninfected individuals. OSC sensors were able to distinguish between SARS-CoV-2 infected individuals and uninfected, with sensitivity from 98% (95% CI 95-100) to 100% and specificity from 99% (95% CI 97-100) to 100%. Six dogs were able to distinguish between samples with sensitivity ranging from 82% (95% CI 76-87) to 94% (95% CI 89-98) and specificity ranging from 76% (95% CI 70-82) to 92% (95% CI 88-96). Mathematical modelling suggests that dog screening plus a confirmatory PCR test could detect up to 89% of SARS-CoV-2 infections, averting up to 2.2 times as much transmission compared to isolation of symptomatic individuals only. CONCLUSIONS: People infected with SARS-CoV-2, with asymptomatic or mild symptoms, have a distinct odour that can be identified by sensors and trained dogs with a high degree of accuracy. Odour-based diagnostics using sensors and/or dogs may prove a rapid and effective tool for screening large numbers of people.Trial Registration NCT04509713 (clinicaltrials.gov).