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Structured summaryBackgroundPulmonary tuberculosis (PTB) due toMycobacterium tuberculosis(Mtb) can be challenging to diagnose because of difficulty obtaining samples, and suboptimal sensitivity of existing tests. We investigated the performance characteristics and diagnostic accuracy of upper respiratory tract tests for diagnosing PTB and hypothesised they would have sufficient accuracy and utility to improve PTB diagnosis.MethodsA systematic review and meta-analysis was conducted by searching MEDLINE, Cinahl, Web of Science, Global Health, and Global Health Archive databases up to 31/01/2021, a second search was conducted for the period 1/1/2021 - 27/5/2022 (subsequently extended to 6/12/2022) to identify studies that reported on the accuracy of upper respiratory tract sampling for TB diagnosis compared to microbiological reference standards. We used a random-effects meta-analysis with a bivariate hierarchical model to estimate pooled sensitivity and specificity, stratified by sampling method. Bias was assessed using QUADAS- 2 criteria. Study registered with PROSPERO (CRD42021262392).Findings10,159 titles were screened for inclusion, 274 studies were assessed for full text review, and 71, comprising 119 test comparisons published between 1933 and 2022 were included in the systematic review (53 in meta-analysis). For laryngeal swabs, pooled sensitivity was 57.8% (95% CI 50.5-65.0%), specificity was 93.8% (95% CI 88.4-96.8%) and diagnostic odds ratio (DOR) was 20.7 (95% CI 11.1-38.8). Nasopharyngeal aspirate sensitivity was 65.2% (95% CI 52.0-76.4%), specificity was 97.9% (95% CI 96.0-99.0%) and DOR was 91.0 (95% CI 37.8-218.8). Oral swabs sensitivity was 56.7% (95% CI 44.3-68.2%), specificity was 91.3% (95% CI 81.0-96.3%), and DOR was 13.8 (95% CI 5.6-34.0).InterpretationUpper respiratory tract sampling holds promise to expand access to TB diagnosis, including for people who can’t produce sputum. Exploring historical methods using modern microbiological techniques may further increase the options for alternative sample types.Prospective studies are needed to optimise accuracy and utility of sampling methods in clinical practice.FundingHRS is funded by the MRC through the MRC DTP programme at LSTM [Grant number MR/N013514/1].Research in contextEvidence before this studyGlobally in 2021, an estimated 4.2 million of 10.6 million people with incident tuberculosis (TB) disease went undiagnosed, emphasising the urgent need for new diagnostic methodologies. Most TB diagnostics are performed on sputum samples, but people who need TB tests are often unable to produce sputum. Upper respiratory tract sampling for TB diagnosis was widely used historically and holds promise to expand non-sputum-based diagnosis.Added value of this studyWe systematically reviewed and synthesised through meta-analysis diagnostic accuracy evaluations of upper respiratory tract sampling for TB. Historically, upper respiratory tract sampling for TB diagnosis was commonly used, with 39/71 studies conducted before 1970, although in recent years there has been a resurgence of interest in oral sampling. We show that upper respiratory tract samples have acceptable sensitivity and specificity compared to sputum culture, and, if testing is optimised using newer molecular and culture-based methods, may be capable of meeting WHO target produce profiles.Implications of all the available evidenceUpper respiratory tract sampling methodologies for TB (oral sampling, and sampling from the larynx and nasopharynx) may hold promise to expand access to TB diagnosis, including for people who can’t produce sputum. These sampling strategies can be optimised using modern microbiological techniques to increase access to diagnostics for TB.

Background Rapid diagnostic tests (RDTs) developed for point of care detection of SARS-CoV-2 antigen are recommended by WHO to use trained health care workers to collect samples. We hypothesised that self-taken samples are non-inferior for use with RDTs to diagnose COVID-19. We designed a prospective diagnostic evaluation comparing self-taken and healthcare worker (HCW)-taken throat/nasal swabs to perform RDTs for SARS-CoV-2, and how these compare to RT-PCR. Methods Eligible participants 18 years or older with symptoms of COVID-19. 250 participants recruited at the NHS Test and Trace drive-through community PCR testing site (Liverpool, UK); one withdrew before analysis. Self-administered throat/nasal swab for the Covios® RDT, a trained HCW taken throat/nasal sample for PCR and HCW comparison throat/nasal swab for RDT were collected. RDT results were compared to RT-PCR, as the reference standard, to calculate sensitivity and specificity. Findings Seventy-five participants (75/249, 30.1%) were positive by RT-PCR. RDTs with self-taken swabs had a sensitivity of 90.5% (67/74, 95% CI: 83.9–97.2), compared to 78.4% (58/74, 95% CI: 69.0–87.8) for HCW-taken swabs (absolute difference 12.2%, 95% CI: 4.7–19.6, p = 0.003). Specificity for self-taken swabs was 99.4% (173/174, 95% CI: 98.3–100.0), versus 98.9% (172/174, 95% CI: 97.3–100.0) for HCW-taken swabs (absolute difference 0.6%, 95% CI: 0.5–1.7, p = 0.317). The PPV of self-taken RDTs (98.5%, 67/68, 95% CI: 95.7–100.0) and HCW-taken RDTs (96.7%, 58/60, 95% CI 92.1–100.0) were not significantly different (p = 0.262). However, the NPV of self-taken swab RDTs was significantly higher (96.1%, 173/180, 95% CI: 93.2–98.9) than HCW-taken RDTs (91.5%, 172/188, 95% CI 87.5–95.5, p = 0.003). Interpretation In conclusion, self-taken swabs for COVID-19 testing offer an accurate alternative to healthcare worker taken swabs for use with RDTs. Our results demonstrate that, with no training, self-taken throat/nasal samples can be used by lay individuals as part of rapid testing programmes for symptomatic adults. This is especially important where the lack of trained healthcare workers restricts access to testing.

Background Individuals infected with SARS-CoV-2 develop neutralising antibodies. We investigated the proportion of individuals with SARS-CoV-2 neutralising antibodies after infection and how this proportion varies with selected covariates. Methodology/Principal findings This systematic review and meta-analysis examined the proportion of individuals with SARS-CoV-2 neutralising antibodies after infection and how these proportions vary with selected covariates. Three models using the maximum likelihood method assessed these proportions by study group, covariates and individually extracted data (protocol CRD42020208913). A total of 983 reports were identified and 27 were included. The pooled (95%CI) proportion of individuals with neutralising antibodies was 85.3% (83.5–86.9) using the titre cut off >1:20 and 83.9% (82.2–85.6), 70.2% (68.1–72.5) and 54.2% (52.0–56.5) with titres >1:40, >1:80 and >1:160, respectively. These proportions were higher among patients with severe COVID-19 (e.g., titres >1:80, 84.8% [80.0–89.2], >1:160, 74.4% [67.5–79.7]) than those with mild presentation (56.7% [49.9–62.9] and 44.1% [37.3–50.6], respectively) and lowest among asymptomatic infections (28.6% [17.9–39.2] and 10.0% [3.7–20.1], respectively). IgG and neutralising antibody levels correlated poorly. Conclusions/Significance 85% of individuals with proven SARS-CoV-2 infection had detectable neutralising antibodies. This proportion varied with disease severity, study setting, time since infection and the method used to measure antibodies., Author summary Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) elicits adaptive immunological responses, including immunoglobulins A, M, and G and neutralising antibodies. Neutralising antibodies are considered markers of functional immunity and protection. However, not all individuals with proven infections have detectable neutralising antibodies. In this systematic review, we investigated the proportion of individuals with former SARS-CoV-2 infections who develop neutralising antibodies, whether their titres vary with disease severity, and their correlation with Immunoglobulin G. We found that approximately 85% of individuals with SARS-CoV-2 infection have detectable neutralising antibodies. This proportion was higher among patients with severe Coronavirus Disease 19 and lower in asymptomatic infections. The variation across studies reflected the wide range of methods used to measure both immunoglobulins and neutralising antibodies, and highlight the need for an international reference standard to measure SARS-CoV-2 antibodies.