SARS-CoV-2 human challenge reveals biomarkers that discriminate early and late phases of respiratory viral infections.

Blood transcriptional biomarkers of acute viral infections typically reflect type 1 interferon (IFN) signalling, but it is not known whether there are biological differences in their regulation that can be leveraged for distinct translational applications. We use high frequency sampling in the SARS-CoV-2 human challenge model to show induction of IFN-stimulated gene (ISG) expression with different temporal and cellular profiles. MX1 gene expression correlates with a rapid and transient wave of ISG expression across all cell types, which may precede PCR detection of replicative infection.

Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children (MIS-C).

Multisystem inflammatory syndrome in children (MIS-C) is a rare condition following SARS-CoV-2 infection associated with intestinal manifestations. Genetic predisposition, including inborn errors of the OAS-RNAseL pathway, has been reported. We sequenced 154 MIS-C patients and utilized a novel statistical framework of gene burden analysis, "burdenMC," which identified an enrichment for rare predicted-deleterious variants in BTNL8 (OR = 4.

Detection of DNA in peripheral blood mononuclear cells of tuberculosis contacts does not associate with blood RNA signatures for incipient tuberculosis.

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Resolution of tuberculosis blood RNA signatures fails to discriminate persistent sputum culture positivity after 8 weeks of anti-tuberculous treatment.

Background: Concerted efforts aim to reduce the burden of 6 months of anti-tuberculous treatment for tuberculosis (TB). Treatment cessation at 8 weeks is effective for most but incurs increased risk of disease relapse. We tested the hypothesis that blood RNA signatures or C-reactive protein (CRP) measurements discriminate 8-week sputum culture status, as a prerequisite for a biomarker to stratify risk of relapse following treatment cessation at this time-point.

Blood RNA signatures outperform CRP triage of tuberculosis lymphadenitis and pericarditis.

Background: Limited data are available on the diagnostic accuracy of blood RNA biomarker signatures for extrapulmonary TB (EPTB). We addressed this question among people investigated for TB lymphadenitis and TB pericarditis, in Cape Town, South Africa.

Methods: We enrolled 440 consecutive adults referred to a hospital for invasive sampling for presumptive TB lymphadenitis (n=300) or presumptive TB pericarditis (n=140).

Single-cell analysis of bronchoalveolar cells in inflammatory and fibrotic post-COVID lung disease.

Background: Persistent radiological lung abnormalities are evident in many survivors of acute coronavirus disease 2019 (COVID-19). Consolidation and ground glass opacities are interpreted to indicate subacute inflammation whereas reticulation is thought to reflect fibrosis. We sought to identify differences at molecular and cellular level, in the local immunopathology of post-COVID inflammation and fibrosis.

Blood RNA biomarkers for tuberculosis screening in people living with HIV before antiretroviral therapy initiation: a diagnostic accuracy study.

Background: Undiagnosed tuberculosis remains a major threat for people living with HIV. Multiple blood transcriptomic biomarkers have shown promise for tuberculosis diagnosis. We sought to evaluate their diagnostic accuracy and clinical utility for systematic pre-antiretroviral therapy (ART) tuberculosis screening.

Point-of-care C-reactive protein and Xpert MTB/RIF Ultra for tuberculosis screening and diagnosis in unselected antiretroviral therapy initiators: a prospective, cross-sectional, diagnostic accuracy study.

Background: Tuberculosis, a major cause of death in people living with HIV, remains challenging to diagnose. Diagnostic accuracy data are scarce for promising triage and confirmatory tests such as C-reactive protein (CRP), sputum and urine Xpert MTB/RIF Ultra (Xpert Ultra), and urine Determine TB LAM Ag (a lateral flow lipoarabinomannan [LF-LAM] test), without symptom selection. We evaluated novel triage and confirmatory tests in ambulatory people with HIV initiating antiretroviral therapy (ART).

Blood RNA biomarkers for tuberculosis screening in people living with HIV prior to anti-retroviral therapy initiation: A diagnostic accuracy study.

Background: Undiagnosed tuberculosis (TB) remains a major threat for people living with HIV (PLHIV). Multiple blood transcriptomic biomarkers have shown promise for TB diagnosis. We sought to evaluate their diagnostic accuracy and clinical utility for systematic pre-antiretroviral therapy (ART) TB screening.

Point-of-care C-reactive protein and Xpert MTB/RIF Ultra for tuberculosis screening and diagnosis in unselected antiretroviral therapy initiators: a prospective diagnostic accuracy study.

Background: Tuberculosis (TB), a major cause of death in people living with HIV (PLHIV), remains challenging to diagnose. Diagnostic accuracy data are lacking for promising triage tests, such as C-reactive protein (CRP), and confirmatory tests, such as sputum and urine Xpert MTB/RIF Ultra (Ultra), and urine LAM, without prior symptom selection.

Methods: 897 PLHIV initiating antiretroviral therapy were consecutively recruited in settings with high TB incidence, irrespective of symptoms.

Clinical utility of WHO-recommended screening tools and development and validation of novel clinical prediction models for pulmonary tuberculosis screening among outpatients living with HIV: an individual participant data meta-analysis.

Background: The World Health Organization (WHO) recommends that outpatient people living with HIV (PLHIV) undergo tuberculosis screening with the WHO four-symptom screen (W4SS) or C-reactive protein (CRP) (5 mg·L cut-off) followed by confirmatory testing if screen positive. We conducted an individual participant data meta-analysis to determine the performance of WHO-recommended screening tools and two newly developed clinical prediction models (CPMs).

Methods: Following a systematic review, we identified studies that recruited adult outpatient PLHIV irrespective of tuberculosis signs and symptoms or with a positive W4SS, evaluated CRP and collected sputum for culture.

Large clones of pre-existing T cells drive early immunity against SARS-COV-2 and LCMV infection.

T cell responses precede antibody and may provide early control of infection. We analyzed the clonal basis of this rapid response following SARS-COV-2 infection. We applied T cell receptor (TCR) sequencing to define the trajectories of individual T cell clones immediately.

meningitis and the CNS barriers.

(SPN) is a globally significant cause of meningitis, the pathophysiology of which involves damage to the brain by both bacterial virulence factors and the host inflammatory response. In most cases of SPN meningitis bacteria translocate from the blood into the central nervous system (CNS). The principal site of SPN translocation into the CNS is not known, with possible portals of entry proposed to be the cerebral or meningeal blood vessels or the choroid plexus.

Toward a more generalizable blood RNA signature for bacterial and viral infections.

Host-response profiles can discriminate different infections. A new 8-gene blood RNA signature to discriminate bacterial and viral infections extends our focus hitherto on the case mix from the US and Europe to include that of low- and middle-income countries. Challenges remain.

Clinical utility of C-reactive protein-based triage for presumptive pulmonary tuberculosis in South African adults.

Background: Identification of an accurate, low-cost triage test for pulmonary TB among people presenting to healthcare facilities is an urgent global research priority. We assessed the diagnostic accuracy and clinical utility of C-reactive protein (CRP) for TB triage among symptomatic adult outpatients, irrespective of HIV status.

Methods: We prospectively enrolled adults reporting at least one (for people with HIV) or two (for people without HIV) symptoms of cough, fever, night sweats, or weight loss at two TB clinics in Cape Town, South Africa.