Altered IL-6 signalling and risk of tuberculosis disease: a meta-analysis and Mendelian randomisation study

Hamilton, Fergus; Schurz, Haiko; Yates, Tom A; Gilchrist, James W; Möller, Marlo; Naranbhai, Vivek; Ghazal, Peter; Timpson, Nicholas J.; Parks, Tom; Pollara, Gabriele

doi:10.1101/2023.02.07.23285472

Cited by 5 publications

(4 citation statements)

References 63 publications

(111 reference statements)

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“…If so, then despite recent interest in adopting point-of-care CRP as a triage test for TB 12 , 15 , 38 we may expect that blood RNA biomarkers provide a more consistent performance for the range of disease manifestations beyond pulmonary TB. Interestingly, IL-6 signalling has also been associated with risk of TB 39 and its immunopathogenesis 31 consistent with the finding that CRP levels are higher in TB pericarditis that reflects a more severe variant of disease than TB lymphadenitis.…”

Section: Discussionsupporting

confidence: 71%

“…At pre-defined Z2 test thresholds for the blood RNA signatures, Roe3 achieved 78% (72-83) sensitivity and 69% (62-75) specificity. A pre-defined test threshold of 10 mg/L for CRP, which we have assessed previously as a triage test for pulmonary TB 12 , achieved a sensitivity of 88.3% (77-87) and specificity of 35% (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). When fixing the sensitivity of each test to 90% (in line with the WHO TPP), Roe3 achieved 52% (45-60) specificity and CRP achieved 27% (21-34) specificity, both below the WHO specificity target of 70% (Supplementary Table 2).…”

Section: Diagnostic Accuracy Of Blood Rna Signatures and Crp For Pool...mentioning

confidence: 99%

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Blood RNA signatures outperform CRP triage of tuberculosis lymphadenitis and pericarditis

Mann,

Minnies,

Gupta

et al. 2024

Preprint

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BackgroundLimited 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.MethodsWe enrolled 440 consecutive adults referred to a hospital for invasive sampling for presumptive TB lymphadenitis (n=300) or presumptive TB pericarditis (n=140). Samples from the site of disease underwent culture and/or molecular testing forMycobacterium tuberculosiscomplex (Mtb). Discrimination of patients with and without TB defined by microbiology or cytology reference standards was evaluated using seven previously reported blood RNA signatures by area under the receiver-operating characteristic curve (AUROC) and sensitivity/specificity at predefined thresholds, benchmarked against blood C-reactive protein (CRP) and the World Health Organization (WHO) target product profile (TPP) for a TB triage test. Decision curve analysis (DCA) was used to evaluate the clinical utility of the best performing blood RNA signature and CRP.ResultsData from 374 patients for whom results were available from at least one microbiological test from the site of disease, and blood CRP and RNA measurements, were included. Using microbiological results as the reference standard in the primary analysis (N=204 with TB), performance was similar across lymphadenitis and pericarditis patients. In the pooled analysis of both cohorts, all RNA signatures had comparable discrimination with AUROC point estimates ranging 0.77-0.82, superior to that of CRP (0.61, 95% confidence interval 0.56-0.67). The best performing signature (Roe3) achieved an AUROC of 0.82 (0.77-0.86). At a predefined threshold of 2 standard deviations (Z2) above the mean of a healthy reference control group, this signature achieved 78% (72-83%) sensitivity and 69% (62-75%) specificity. In this setting, DCA revealed that Roe3 offered greater net benefit than other approaches for services aiming to reduce the number needed to investigate with confirmatory testing to <4 to identify each case of TB.InterpretationRNA biomarkers show better accuracy and clinical utility than CRP to trigger confirmatory TB testing in patients with TB lymphadenitis and TB pericarditis, but still fall short of the WHO TPP for TB triage tests.FundingSouth African MRC, EDCTP2, NIH/NIAID, Wellcome Trust, NIHR, Royal College of Physicians London.Research in contextEvidence before this studyBlood RNA biomarker signatures and CRP measurements have emerged as potential triage tests for TB, but evidence is mostly limited to their performance in pulmonary TB. Microbiological diagnosis of extrapulmonary TB (EPTB) is made challenging by the need for invasive sampling to obtain tissue from the site of disease. This is compounded by lower sensitivity of confirmatory molecular tests for EPTB compared to their performance in pulmonary disease. We performed a systematic review of diagnostic accuracy studies of blood RNA biomarkers or CRP measurements for EPTB, which could mitigate the need for site-of-disease sampling for the diagnosis of TB. We searched PubMed up to 1stAugust 2023, using the following criteria: “extrapulmonary [title/abstract] AND tuberculosis [title/abstract] AND biomarker [title/abstract]”. Although extrapulmonary TB was included in several studies, none focused specifically on EPTB or included an adequate number of EPTB cases to provide precise estimates of test accuracy.Added value of this studyTo the best of our knowledge, we report the first diagnostic accuracy study of blood RNA biomarkers and CRP for TB among people with EPTB syndromes. We examined the performance of seven previously identified blood RNA biomarkers as triage tests for TB lymphadenitis and TB pericarditis compared to a microbiology reference standard among people referred to hospital for invasive sampling in a high TB and HIV prevalence setting. Multiple blood RNA biomarkers showed comparable diagnostic accuracy to that previously reported for pulmonary TB in both EPTB disease cohorts, irrespective of HIV status. All seven blood RNA biomarkers showed superior diagnostic accuracy to CRP for both lymphadenitis and pericarditis, but failed to meet the combined >90% sensitivity and >70% specificity recommended for a blood-based diagnostic triage test by WHO. Nonetheless, in decision curve analysis, an approach of using the best performing blood RNA biomarker to trigger confirmatory microbiological testing showed superior clinical utility in clinical services seeking to reduce the number needed to test (using invasive confirmatory testing) to less than 4 for each EPTB case detected. If acceptable to undertake invasive testing in more than 4 people for each true case detected, then a test-all approach will provide greater net benefit in this TB/HIV hyperendemic setting.Implications of all the available evidenceBlood RNA biomarkers show some potential as diagnostic triage tests for TB lymphadenitis and TB pericarditis, but do not provide the level of accuracy for blood-based triage tests recommended by WHO for community-based tests. CRP has inferior diagnostic accuracy to blood RNA biomarkers and cannot be recommended for diagnostic triage among people with EPTB syndromes referred for invasive sampling.

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Section: Discussionsupporting

confidence: 71%

Section: Diagnostic Accuracy Of Blood Rna Signatures and Crp For Pool...mentioning

confidence: 99%

Blood RNA signatures outperform CRP triage of tuberculosis lymphadenitis and pericarditis

Mann,

Minnies,

Gupta

et al. 2024

Preprint

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“…Higher levels of IL-6 have been associated with lower levels of HDL [ 48 ] and specifically small HDL [ 49 ]. Further, reducing IL-6 signalling is associated with a moderately increased risk of infection in randomised trials of IL-6 antagonists [ 35 ], although this association is complicated by the apparent benefits of reduced IL-6 activity in (some) severe infection [ 30 , 36 , 50 – 52 ]. IL-6 has two major forms of signalling, “classical” signalling, which is mediated by IL-6 binding to a membrane bound receptor (IL6R), and “ trans ” signalling, where IL-6 binds to the soluble form of the IL-6 receptor.…”

Section: Methodsmentioning

confidence: 99%

Low levels of small HDL particles predict but do not influence risk of sepsis

Hamilton,

Pedersen,

Ghazal

et al. 2023

Crit Care

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Background Low levels of high-density lipoprotein (HDL) cholesterol have been associated with higher rates and severity of infection. Alterations in inflammatory mediators and infection are associated with alterations in HDL cholesterol. It is unknown whether the association between HDL and infection is present for all particle sizes, and whether the observed associations are confounded by IL-6 signalling. Methods In the UK Biobank, ~ 270,000 individuals have data on HDL subclasses derived from nuclear magnetic resonance analysis. We estimated the association of particle count of total HDL and HDL subclasses (small, medium, large, and extra-large HDL) with sepsis, sepsis-related death, and critical care admission in a Cox regression model. We subsequently utilised genetic data from UK Biobank and FinnGen to perform Mendelian randomisation (MR) of each HDL subclass and sepsis to test for a causal relationship. Finally, we explored the role of IL-6 signalling as a potential causal driver of changes in HDL subclasses. Results In observational analyses, higher particle count of small HDL was associated with protection from sepsis (Hazard ratio, HR 0.80; 95% CI 0.74–0.86, p = 4 × 10–9 comparing Quartile 4, highest quartile of HDL to Quartile 1, lowest quartile of HDL), sepsis-related death (HR 0.80; 95% CI 0.74–0.86, p = 2 × 10–4), and critical care admission with sepsis (HR 0.72 95% CI 0.60–0.85, p = 2 × 10–4). Parallel associations with other HDL subclasses were likely driven by changes in the small HDL compartment. MR analyses did not strongly support causality of small HDL particle count on sepsis incidence (Odds ratio, OR 0.98; 95% CI 0.89–1.07, p = 0.6) or death (OR 0.94, 95% CI 0.75–1.17, p = 0.56), although the estimate on critical care admission with sepsis supported protection (OR 0.73, 95% CI 0.57–0.95, p = 0.02). Bidirectional MR analyses suggested that increased IL-6 signalling was associated with reductions in both small (beta on small HDL particle count − 0.16, 95% CI − 0.10 to − 0.21 per natural log change in SD-scaled CRP, p = 9 × 10–8).and total HDL particle count (beta − 0.13, 95% CI − 0.09 to − 0.17, p = 7 × 10–10), but that the reverse effect of HDL on IL-6 signalling was largely null. Conclusions Low number of small HDL particles are associated with increased hazard of sepsis, sepsis-related death, and sepsis-related critical care admission. However, genetic analyses did not strongly support this as causal. Instead, we demonstrate that increased IL-6 signalling, which is known to alter infection risk, could confound associations with reduced HDL particle count, and suggest this may explain part of the observed association between (small) HDL particle count and sepsis.

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“…However, the precise balance of IL-6 expression is crucial, as excessive inflammation can lead to immunopathology. [7,8]In contrast, IL-10, an antiinflammatory cytokine, plays a complex role in TB. [9] While it is generally considered an immunosuppressive factor, limiting inflammation and preventing tissue damage, its overexpression can impede protective immune responses.…”

Section: Introductionmentioning

confidence: 99%

Critical involvement of interleukins in pulmonary tuberculosis pathogenesis

Mishra,

Sharma,

Chauhan

et al. 2024

IJLBPR

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Altered IL-6 signalling and risk of tuberculosis disease: a meta-analysis and Mendelian randomisation study

Cited by 5 publications

References 63 publications

Blood RNA signatures outperform CRP triage of tuberculosis lymphadenitis and pericarditis

Blood RNA signatures outperform CRP triage of tuberculosis lymphadenitis and pericarditis

Low levels of small HDL particles predict but do not influence risk of sepsis

Critical involvement of interleukins in pulmonary tuberculosis pathogenesis

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