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The influence of smoke-derived or air pollution-derived cytoplasmic particulate matter (PM) can be detrimental and can lead to failed lung immunity. We investigated mycobacterial uptake, intracellular replication, and soluble immune-mediator responses of human bronchoalveolar lavage cells (BALCs) loaded with/without PM, to infection with mycobacterial strains. We observed that only BALCs containing PM display an ex vivo phenotypic profile dominated by spontaneous interleukin (IL)-10 production. PM-loaded BALCs retained the ability to phagocytose both Mycobacterium bovis Bacille Calmette Guérin (BCG) and Mycobacterium tuberculosis ( M.tb) ΔleuDΔpanCD at equal efficacy as clear non-PM-loaded BALCs. However, immune responsiveness, such as the production of IL-6 ( P = 0.015) and tumor necrosis factor-α (TNF)-α ( P = 0.0172) immediately post M. bovis BCG infection, were dramatically lower in black BALCs loaded with PM versus clear non-PM-loaded BALCs. By 24 h post infection, differential immune responses to M. bovis BCG between black versus clear BALC waned, and instead, production of IL-6 ( P = 0.03) and IL-1α ( P = 0.04) by black BALCs was lower versus clear BALCs following M.tb ΔleuDΔpanCD infection. Considering that TNF-α and IL-6 are characterized as critical to host protection against mycobacteria, our findings suggest that BALCs loaded with inhaled PM, display lower levels of antimycobacterial mediators and that the response magnitude differs according to infective mycobacterial strain. Even though this did not translate into altered mycobacterial killing at early time points post infection, the long-term impact of such changes remains to be established.

Summary Background A rapid, blood-based triage test that allows targeted investigation for tuberculosis at the point of care could shorten the time to tuberculosis treatment and reduce mortality. We aimed to test the performance of a host blood transcriptomic signature (RISK11) in diagnosing tuberculosis and predicting progression to active pulmonary disease (prognosis) in people with HIV in a community setting. Methods In this prospective diagnostic and prognostic accuracy study, adults (aged 18–59 years) with HIV were recruited from five communities in South Africa. Individuals with a history of tuberculosis or household exposure to multidrug-resistant tuberculosis within the past 3 years, comorbid risk factors for tuberculosis, or any condition that would interfere with the study were excluded. RISK11 status was assessed at baseline by real-time PCR; participants and study staff were masked to the result. Participants underwent active surveillance for microbiologically confirmed tuberculosis by providing spontaneously expectorated sputum samples at baseline, if symptomatic during 15 months of follow-up, and at 15 months (the end of the study). The coprimary outcomes were the prevalence and cumulative incidence of tuberculosis disease confirmed by a positive Xpert MTB/RIF, Xpert Ultra, or Mycobacteria Growth Indicator Tube culture, or a combination of such, on at least two separate sputum samples collected within any 30-day period. Findings Between March 22, 2017, and May 15, 2018, 963 participants were assessed for eligibility and 861 were enrolled. Among 820 participants with valid RISK11 results, eight (1%) had prevalent tuberculosis at baseline: seven (2·5%; 95% CI 1·2–5·0) of 285 RISK11-positive participants and one (0·2%; 0·0–1·1) of 535 RISK11-negative participants. The relative risk (RR) of prevalent tuberculosis was 13·1 times (95% CI 2·1–81·6) greater in RISK11-positive participants than in RISK11-negative participants. RISK11 had a diagnostic area under the receiver operating characteristic curve (AUC) of 88·2% (95% CI 77·6–96·7), and a sensitivity of 87·5% (58·3–100·0) and specificity of 65·8% (62·5–69·0) at a predefined score threshold (60%). Of those with RISK11 results, eight had primary endpoint incident tuberculosis during 15 months of follow-up. Tuberculosis incidence was 2·5 per 100 person-years (95% CI 0·7–4·4) in the RISK11-positive group and 0·2 per 100 person-years (0·0–0·5) in the RISK11-negative group. The probability of primary endpoint incident tuberculosis was greater in the RISK11-positive group than in the RISK11-negative group (cumulative incidence ratio 16·0 [95% CI 2·0–129·5]). RISK11 had a prognostic AUC of 80·0% (95% CI 70·6–86·9), and a sensitivity of 88·6% (43·5–98·7) and a specificity of 68·9% (65·3–72·3) for incident tuberculosis at the 60% threshold. Interpretation RISK11 identified prevalent tuberculosis and predicted risk of progression to incident tuberculosis within 15 months in ambulant people living with HIV. RISK11's performance approached, but did not meet, WHO's target product profile benchmarks for screening and prognostic tests for tuberculosis. Funding Bill & Melinda Gates Foundation and the South African Medical Research Council.

Background Diabetes mellitus (DM) patients are three times more likely to develop tuberculosis (TB) than the general population. Active TB screening in people with DM is part of a bidirectional approach. The aim of this study was to conduct pragmatic active TB screening among DM patients in four countries to inform policy. Methods DM patients were recruited in Indonesia (n=809), Peru (n=600), Romania (n=603) and South Africa (n=51). TB cases were diagnosed using an algorithm including clinical symptoms and chest X-ray. Presumptive TB patients were examined with sputum smear and culture. Results A total of 171 (8.3%) individuals reported ever having had TB (South Africa, 26%; Indonesia, 12%; Peru, 7%; Romania, 4%), 15 of whom were already on TB treatment. Overall, 14 (0.73% [95% confidence interval 0.40 to 1.23]) TB cases were identified from screening. Poor glucose control, smoking, lower body mass index, education and socio-economic status were associated with newly diagnosed/current TB. Thirteen of the 14 TB cases diagnosed from this screening would have been found using a symptom-based approach. Conclusions These data support the World Health Organization recommendation for routine symptom-based screening for TB in known DM patients in high TB-burden countries. DM patients with any symptoms consistent with TB should be investigated and diagnostic tools should be easily accessible.

Background Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) infection and is a major public health problem. Clinical challenges include the lack of a blood-based test for active disease. Current blood-based tests, such as QuantiFERON (QFT) do not distinguish active TB disease from asymptomatic Mtb infection. Methods We hypothesized that TruCulture, an immunomonitoring method for whole-blood stimulation, could discriminate active disease from latent Mtb infection (LTBI). We stimulated whole blood from patients with active TB and compared with LTBI donors. Mtb-specific antigens and live bacillus Calmette-Guérin (BCG) were used as stimuli, with direct comparison to QFT. Protein analyses were performed using conventional and digital enzyme-linked immunosorbent assay (ELISA), as well as Luminex. Results TruCulture showed discrimination of active TB cases from LTBI (P < .0001, AUC = .81) compared with QFT (P = .45, AUC = .56), based on an interferon γ (IFNγ) readout after Mtb antigen (Ag) stimulation. This result was replicated in an independent cohort (AUC = .89). In exploratory analyses, TB stratification could be further improved by the Mtb antigen to BCG IFNγ ratio (P < .0001, AUC = .91). Finally, the combination of digital ELISA and transcriptional analysis showed that LTBI donors with high IFNγ clustered with patients with TB, suggesting the possibility to identify subclinical disease. Conclusions TruCulture offers a next-generation solution for whole-blood stimulation and immunomonitoring with the possibility to discriminate active and latent infection., We tested TruCulture, an immunomonitoring tool, to identify active disease from latent Mtb infection. TruCulture showed improved discrimination of tuberculosis cases from LTBI as compared with QuantiFERON. Tuberculosis stratification could be further improved by the Mtb Ag:BCG IFNγ ratio.

Tuberculosis 133, 102169 (2022). doi:10.1016/j.tube.2022.102169, Published by Churchill Livingstone, Edinburgh

BackgroundPeople with diabetes are more likely to develop tuberculosis (TB) and to have poor TB treatment outcomes than those without. We previously showed that blood transcriptomes in people with TB-diabetes (TB-DM) co-morbidity have excessive inflammatory and reduced interferon responses at TB diagnosis. It is unknown whether this persists through treatment, potentially underlying adverse outcomes.MethodsPulmonary TB patients were recruited in South Africa, Indonesia and Romania, and classified as having TB-DM, TB with prediabetes, TB-related hyperglycaemia or uncomplicated TB, based on glycated haemoglobin (HbA1c) concentration at TB diagnosis and after 6 months of TB treatment. Gene expression in blood samples collected at diagnosis and at regular intervals throughout treatment was measured by unbiased RNA-Seq and targeted Multiplex Ligation-dependent Probe Amplification.ResultsGene expression was modulated by TB treatment in all groups but to different extents, such that differences remained in people with TB-DM relative to TB-only throughout, including genes involved in innate responses, anti-microbial immunity and the inflammasome. People with prediabetes or with TB-related hyperglycaemia had gene expression more similar to people with TB-DM than TB-only throughout treatment. The overall pattern of change was similar across clinical groups irrespective of glycaemic index, permitting models predictive of TB treatment to be developed.ConclusionsThe exacerbated transcriptome changes seen in TB-DM take longer to resolve during TB treatment, indicating that prolonged treatment or host-directed therapy may be needed to improve TB treatment outcomes. Development of transcriptome-based biomarker signatures of TB-treatment response should include people with diabetes to be useful across populations.Key PointsHost blood transcriptomes are altered in tuberculosis, and further altered with diabetes co-morbidity. We have shown that there is similar resolution of transcriptomes through treatment, but with differing magnitude and kinetics in TB patients with or without diabetes.

Objectives We evaluated longitudinal kinetics of an 11-gene blood transcriptomic tuberculosis (TB) signature, RISK11, and effects of TB preventative therapy (TPT) and respiratory organisms on RISK1...

Summary Background There is an urgent need for new tools for the diagnosis of TB. We evaluated the usefulness recently described host biomarkers in supernatants from the newest generation of the QuantiFERON test (QuantiFERON Plus) as tools for the diagnosis of active TB. Methods We recruited individuals presenting at primary health care clinics in Cape Town, South Africa with symptoms requiring investigation for TB disease, prior to the establishment of a clinical diagnosis. Participants were later classified as TB or other respiratory diseases (ORD) based on the results of clinical and laboratory tests. Using a multiplex platform, we evaluated the concentrations of 37 host biomarkers in QuantiFERON Plus supernatants from study participants as tools for the diagnosis of TB. Results Out of 120 study participants, 35(29.2%) were diagnosed with active TB, 69(57.5%) with ORD whereas 16(13.3%) were excluded. 14(11.6%) of the study participants were HIV infected. Although individual host markers showed potential as diagnostic candidates, the main finding of the study was the identification of a six-marker biosignature in unstimulated supernatants (Apo-ACIII, CXCL1, CXCL9, CCL8, CCL-1, CD56) which diagnosed TB with sensitivity and specificity of 73.9%(95% CI; 51.6–87.8) and 87.6%(95% CI; 77.2–94.5), respectively, after leave-one-out cross validation. Combinations between TB-antigen specific biomarkers also showed potential (sensitivity of 77.3% and specificity of 69.2%, respectively), with multiple biomarkers being significantly different between TB patients, Quantiferon Plus Positive and Quantiferon Plus negative individuals with ORD, regardless of HIV status. Conclusions Biomarkers detected in QuantiFERON Plus supernatants may contribute to adjunctive diagnosis of TB.

Background Tuberculosis (TB) remains a debilitating, deadly disease that warrants innovative research tools to fully understand the pathogenesis and host immune responses, particularly at the site of infection and disease. In this regard, bronchoscopies with bronchoalveolar lavage (BAL) serve as a valuable technique for site of disease sample retrieval for further clinical- and basic research. Here we investigate the feasibility of research bronchoscopies in a low/middle-income area, where TB remains rife, and assess the value of retrieved BAL cells (BALC) for downstream fluorescent-based cellular evaluations. Methods Using quantitative and qualitative methods, we evaluate the outcomes, safety, tolerability, participant -perception and -experience, while also providing insight into participant recruitment and screening processes of our study. Using light microscopy differential counting for BALC analysis, we evaluate the cellular composition of BAL fluid (BALF) from TB patients, healthy community controls and patients with other lung diseases. We also use flow cytometry to describe the challenges associated with fluorescence-based phenotypic analysis of autofluorescent BALC. Results Our findings suggest that research bronchoscopies are safe, acceptable procedures for research participants and are indeed a feasible technique for future study design. We also suggest that the majority of participants are receptive to the proposition of a second research bronchoscopy. This poses an important avenue for research entailing follow-up investigations of the same study participant. Furthermore, our results show that smoking is characterized by retrieval of BALC containing particulate matter, that interferes with fluorescence-based flow cytometry data analysis. Based on light microscopy differential cell counting, our findings suggest that there are differences in the cell yields and cellular composition of the BALF between TB patients, healthy community controls and patients with other lung diseases. We also report on subject characteristics and demographic factors, namely gender and age, that have the potential to affect cell yields and cellular data of BALF. Conclusions These findings will serve as a valuable reference for appropriate planning and design of studies involving clinical bronchoscopies for TB and lung disease research.

Tuberculous granulomas that develop in response to Mycobacterium tuberculosis (M. tuberculosis) infection are highly dynamic entities shaped by the host immune response and disease kinetics. Within this microenvironment, immune cell recruitment, polarization, and activation are driven not only by coexisting cell types and multicellular interactions but also by M. tuberculosis-mediated changes involving metabolic heterogeneity, epigenetic reprogramming, and rewiring of the transcriptional landscape of host cells. There is an increased appreciation of the in vivo complexity, versatility, and heterogeneity of the cellular compartment that constitutes the tuberculosis (TB) granuloma and the difficulty in translating findings from animal models to human disease. Here, we describe a novel biomimetic in vitro three-dimensional (3D) human lung spheroid granuloma model, resembling early “innate” and “adaptive” stages of the TB granuloma spectrum, and present results of histological architecture, host transcriptional characterization, mycobacteriological features, cytokine profiles, and spatial distribution of key immune cells. A range of manipulations of immune cell populations in these spheroid granulomas will allow the study of host/pathogen pathways involved in the outcome of infection, as well as pharmacological interventions. IMPORTANCE TB is a highly infectious disease, with granulomas as its hallmark. Granulomas play an important role in the control of M. tuberculosis infection and as such are crucial indicators for our understanding of host resistance to TB. Correlates of risk and protection to M. tuberculosis are still elusive, and the granuloma provides the perfect environment in which to study the immune response to infection and broaden our understanding thereof; however, human granulomas are difficult to obtain, and animal models are costly and do not always faithfully mimic human immunity. In fact, most TB research is conducted in vitro on immortalized or primary immune cells and cultured in two dimensions on flat, rigid plastic, which does not reflect in vivo characteristics. We have therefore conceived a 3D, human in vitro spheroid granuloma model which allows researchers to study features of granuloma-forming diseases in a 3D structural environment resembling in vivo granuloma architecture and cellular orientation.

The development of a non-sputum-based, point-of-care diagnostic test for tuberculosis (TB) is a priority in the global effort to combat this disease, particularly in resource-constrained settings. Previous studies have identified host biomarker signatures which showed potential, but there is a need to validate and refine these for development as a test. We recruited 1,403 adults presenting with symptoms suggestive of pulmonary TB at primary healthcare clinics in six countries from West, East and Southern Africa. Of the study cohort, 326 were diagnosed with TB and 787 with other respiratory diseases, from whom we randomly selected 1005 participants. Using Luminex® technology, we measured the levels of 20 host biomarkers in serum samples which we used to evaluate the diagnostic accuracy of previously identified and novel bio-signatures. Our previously identified seven-marker bio-signature did not perform well (sensitivity: 89%, specificity: 60%). We also identified an optimal, two-marker bio-signature with a sensitivity of 94% and specificity of 69% in patients with no history of previous TB. This signature performed slightly better than C-reactive protein (CRP) alone. The cut-off value for a positive diagnosis differed for human immuno-deficiency virus (HIV)-positive and -negative individuals. Notably, we also found that no signature was able to diagnose TB adequately in patients with a prior history of the disease. We have identified a two-marker, pan-African bio-signature which is more robust than CRP alone and meets the World Health Organization (WHO) target product profile requirements for a triage test in both HIV-negative and HIV-positive individuals. This signature could be incorporated into a point-of-care device, greatly reducing the necessity for expensive confirmatory diagnostics and potentially reducing the number of cases currently lost to follow-up. It might also potentially be useful with individuals unable to provide sputum or with paucibacillary disease. We suggest that the performance of TB diagnostic signatures can be improved by incorporating the HIV-status of the patient. We further suggest that only patients who have never had TB be subjected to a triage test and that those with a history of previous TB be evaluated using more direct diagnostic techniques.

Summary Background Direct bronchial spread of tuberculosis was extensively described in pre-antibiotic human pathology literature but this description has been overlooked in the post-antibiotic era, in which most pathology data come from animal models that emphasise the granuloma. Modern techniques, such as [18F]2-fluoro-2-deoxy-D-glucose (FDG) PET-CT scans, might provide further insight. Our aim was to understand normal early tuberculosis resolution patterns on pulmonary PET-CT scans in treated patients with tuberculosis who were subsequently cured. Methods In this observational analysis, we analysed data from PredictTB, an ongoing, prospective, randomised clinical trial that examined sequential baseline and week 4 FDG-PET-CT scans from participants successfully treated (sputum culture negative 18 months after enrolment) for drug-susceptible pulmonary tuberculosis in South Africa and China. Participants who were aged 18–75 years, GeneXpert MTB/RIF positive for tuberculosis and negative for rifampicin resistance, had not yet started tuberculosis treatment, had not been treated for active tuberculosis within the previous 3 years, and met basic safety laboratory criteria were included and participants with diabetes, HIV infection, or with extrapulmonary tuberculosis including pleural tuberculosis were excluded. Scans were assessed by two readers for the location of tuberculosis lesions (eg, cavities and consolidations), bronchial thickening patterns, and changes from baseline to week 4 of treatment. Findings Among the first 124 participants (enrolled from June 22, 2017, to Sept 27, 2018) who were successfully treated, 161 primarily apical cavitary lesions were identified at baseline. Bronchial thickening and inflammation linking non-cavitary consolidative lesions to cavities were observed in 121 (98%) of 124 participants' baseline PET-CT scans. After 4 weeks of treatment, 21 (17%) of 124 participants had new or expanding lesions linked to cavities via bronchial inflammation that were not present at baseline, particularly participants with two or more cavities at baseline and participants from South Africa. Interpretation In participants with pulmonary tuberculosis who were subsequently cured, the location of cavitary and non-cavitary lesions at baseline and new lesions at week 4 of treatment suggest a cavitary origin of disease and bronchial spread through the lungs. Bronchial spread from cavities might play a larger role in the spread of pulmonary tuberculosis than has been appreciated. Elucidating cavity lesion dynamics and Mycobacterium tuberculosis viability within cavities might better explain treatment outcomes and why some patients are cured and others relapse. Funding Bill & Melinda Gates Foundation, European and Developing Countries Clinical Trials Partnership, China Ministry of Science and Technology, National Natural Science Foundation of China, and National Institutes of Health. Translations For the Chinese, Afrikaans and Xhosa translations of the abstract see Supplementary Materials section.

Background Inequality is rife throughout South Africa. The first wave of COVID-19 may have affected people in lower socioeconomic groups worse than the affluent. The SARS-CoV-2 seroprevalence and the specificity of anti-SARS-CoV-2 antibody tests in South Africa is not known. Methods We tested 405 volunteers representing all socioeconomic strata from the workforce of a popular shopping and tourist complex in central Cape Town with the Abbott SARS-CoV-2 IgG assay. We assessed the association between antibody positivity and COVID-19 symptom status, medical history, and sociodemographic variables. We tested 137 serum samples from healthy controls collected in Cape Town prior to the COVID-19 pandemic, to confirm the specificity of the assay in the local population. Results Of the 405 volunteers tested one month after the first peak of the epidemic in Cape Town, 96(23.7%) were SARS-CoV-2 IgG positive. Of those who tested positive, 46(47.9%) reported no symptoms of COVID-19 in the previous 6 months. Seropositivity was significantly associated with living in informal housing, residing in a subdistrict with low income-per household, and having a low-earning occupation. The specificity of the assay was 98.54%(95%CI 94.82%-99.82%) in the pre-COVID controls. Conclusions There is a high background seroprevalence in Cape Town, particularly in people of lower socioeconomic status. Almost half of cases are asymptomatic, and therefore undiagnosed by local testing strategies. These results cannot be explained by low assay specificity.

Background: The diagnosis of TB remains one of the major challenges in the control of the disease, due to limitations in the currently available diagnostic tests. There is an urgent need for new, accurate, rapid, and affordable diagnostic tests. The aim of the present study was to use mass spectrometry to identify new candidate TB diagnostic protein biomarkers in saliva obtained from individuals with TB, and patients with other respiratory diseases (ORD).Methods: Saliva samples were collected from 22 individuals who self-presented with symptoms requiring investigation for TB as part of a larger TB biomarker project. Eleven of the participants were finally diagnosed with TB using routine clinical, radiological and laboratory tests and 11 with ORD. Salivary proteins were concentrated and purified, followed by tryptic digestion. Peptides were analyzed using a QExactive Orbitrap MS coupled to a Dionex liquid chromatography system. Raw files were processed using MaxQuant software against the database of human proteins. Identified proteins were subjected to gene ontology and ingenuity pathway analysis for functional enrichment analysis.Results: We identified 1176 protein groups across all samples, of which 46 (3.91%) were contaminants, 12 (1.02%) were reverse hits and 170 (14.46%) were single-peptide protein groups. After removal of the contaminants, reverse hits and protein groups represented by single peptides, 26 of the remaining 948 proteins significantly discriminated individuals with TB from those with ORD after Benjamini Hochberg correction, with five of these proteins diagnosing TB with AUC ³ 0.80. A 5-protein biosignature comprising of P01011, Q8NCW5, P28072, A0A2Q2TTZ9 and Q99574 diagnosed TB with an AUC of 1.00 (95% CI, 1.00-1.00), sensitivity of 100% (95% CI, 76.2-100%) and specificity of 90.9% (95% CI, 58.7-99.8%) after leave-one-out cross validation. Conclusions: We identified novel salivary protein biomarkers and biosignatures with strong potential as TB diagnostic candidates. Our results are preliminary and require validation in larger studies.

Mycobacterium tuberculosis (Mtb) is extremely recalcitrant to antimicrobial chemotherapy requiring 6 months to treat drug-sensitive tuberculosis (TB). Despite this, 4–10% of cured patients will develop recurrent disease within 12 months after completing therapy. Reasons for relapse in cured TB patients remains speculative, attributed to both pathogen and host factors. Populations of dormant bacilli are hypothesized to cause relapse in initially cured TB patients however, development of tests to convincingly demonstrate their presence at the end of anti-TB treatment has been challenging. Previous studies have indicated the utility of culture filtrate supplemented media (CFSM) to detect differentially culturable tubercle bacilli (DCTB). Here, we show that 3/22 of clinically cured patients retained DCTB in induced sputum and bronchoalveolar lavage fluid (BALF), with one DCTB positive patient relapsing within the first year of completing therapy. We also show a correlation of DCTB status with “unresolved” end of treatment FDG PET-CT imaging. Additionally, 19 end of treatment induced sputum samples from patients not undergoing bronchoscopy were assessed for DCTB, identifying a further relapse case with DCTB. We further show that induced sputum is a less reliable source for the DCTB assay at the end of treatment, limiting the utility of this assay in a clinical setting. We next investigated the host proteome at the site of disease (BALF) using multiplexed proteomic analysis and compared these to active TB cases to identify host-specific factors indicative of cure. Distinct signatures stratified active from cured TB patients into distinct groups, with a DCTB positive, subsequently relapsing, end of treatment patient showing a proteomic signature closer to active TB disease than cure. This exploratory study offers evidence of live Mtb, undetectable with conventional culture methods, at the end of clinically successful treatment and putative host protein biomarkers of active disease and cure. These findings have implications for the assessment of true sterilizing cure in TB patients and opens new avenues for targeted approaches to monitor treatment response.

Pulmonary tuberculosis (PTB) is characterized by lung granulomas, inflammation and tissue destruction. Here we used within-subject peripheral blood gene expression over time to correlate with the within-subject lung metabolic activity, as measured by positron emission tomography (PET) to identify biological processes and pathways underlying overall resolution of lung inflammation. We used next-generation RNA sequencing and [18F]FDG PET-CT data, collected at diagnosis, week 4, and week 24, from 75 successfully cured PTB patients, with the [18F]FDG activity as a surrogate for lung inflammation. Our linear mixed-effects models required that for each individual the slope of the line of [18F]FDG data in the outcome and the slope of the peripheral blood transcript expression data correlate, i.e., the slopes of the outcome and explanatory variables had to be similar. Of 10,295 genes that changed as a function of time, we identified 639 genes whose expression profiles correlated with decreasing [18F]FDG uptake levels in the lungs. Gene enrichment over-representation analysis revealed that numerous biological processes were significantly enriched in the 639 genes, including several well known in TB transcriptomics such as platelet degranulation and response to interferon gamma, thus validating our novel approach. Others not previously associated with TB pathobiology included smooth muscle contraction, a set of pathways related to mitochondrial function and cell death, as well as a set of pathways connecting transcription, translation and vesicle formation. We observed up-regulation in genes associated with B cells, and down-regulation in genes associated with platelet activation. We found 254 transcription factor binding sites to be enriched among the 639 gene promoters. In conclusion, we demonstrated that of the 10,295 gene expression changes in peripheral blood, only a subset of 639 genes correlated with inflammation in the lungs, and the enriched pathways provide a description of the biology of resolution of lung inflammation as detectable in peripheral blood. Surprisingly, resolution of PTB inflammation is positively correlated with smooth muscle contraction and, extending our previous observation on mitochondrial genes, shows the presence of mitochondrial stress. We focused on pathway analysis which can enable therapeutic target discovery and potential modulation of the host response to TB.

Summary Background Targeted preventive therapy for individuals at highest risk of incident tuberculosis might impact the epidemic by interrupting transmission. We tested performance of a transcriptomic signature of tuberculosis (RISK11) and efficacy of signature-guided preventive therapy in parallel, using a hybrid three-group study design. Methods Adult volunteers aged 18–59 years were recruited at five geographically distinct communities in South Africa. Whole blood was sampled for RISK11 by quantitative RT-PCR assay from eligible volunteers without HIV, recent previous tuberculosis (ie

Early bactericidal activity studies monitor daily sputum bacterial counts in individuals with tuberculosis (TB) for 14 days during experimental drug treatment. The rate of change in sputum bacterial load over time provides an informative, but imperfect, estimate of drug activity and is considered a critical step in development of new TB drugs. In this clinical study, 160 participants with TB received isoniazid, pyrazinamide, or rifampicin, components of first-line chemotherapy, and moxifloxacin individually and in combination. In addition to standard bacterial enumeration in sputum, participants underwent 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography and computerized tomography ([18F]FDG-PET/CT) at the beginning and end of the 14-day drug treatment. Quantitating radiological responses to drug treatment provided comparative single and combination drug activity measures across lung lesion types that correlated more closely with established clinical outcomes when combined with sputum enumeration compared to sputum enumeration alone. Rifampicin and rifampicin-containing drug combinations were most effective in reducing both lung lesion volume measured by CT imaging and lesion-associated inflammation measured by PET imaging. Moxifloxacin was not superior to rifampicin in any measure by PET/CT imaging, consistent with its performance in recent phase 3 clinical trials. PET/CT imaging revealed synergy between isoniazid and pyrazinamide and demonstrated that the activity of pyrazinamide was limited to lung lesion, showing the highest FDG uptake during the first 2 weeks of drug treatment. [18F]FDG-PET/CT imaging may be useful for measuring the activity of single drugs and drug combinations during evaluation of potential new TB drug regimens before phase 3 trials.

Tuberculosis (TB) is a global health concern. Treatment is prolonged, and patients on anti-TB therapy (ATT) often experience treatment failure for various reasons. There is an urgent need to identify signatures for early detection of failure and initiation of a treatment switch. We investigated how gene biomarkers and/or basic patient characteristics could be used to define signatures for treatment outcomes in Indian adult pulmonary-TB patients treated with standard ATT. Using blood samples at baseline, a 12-gene signature combined with information on gender, previously-diagnosed TB, severe thinness, smoking and alcohol consumption was highly predictive of treatment failure at 6 months. Likewise a 4-protein biomarker signature combined with the same patient characteristics was almost as highly predictive of treatment failure. Combining biomarkers and basic patient characteristics may be useful for predicting and hence identification of treatment failure at an early stage of TB therapy., Sivakumaran et al. show that a 12-gene signature combined with gender, previously diagnosed tuberculosis (TB), severe thinness, smoking, and alcohol consumption predict the treatment outcome at 6 months. This study suggests that the combination of biomarkers and basic patient characteristics may better predict the treatment failure at an early stage of TB therapy.

Objective To investigate the potential of host urinary biomarkers as diagnostic candidates for tuberculosis (TB). Methods Adults self-presenting with symptoms requiring further investigation for TB were enrolled in Cape Town, South Africa. Participants were later classified as having TB or other respiratory diseases (ORD) using results from TB confirmatory tests. The concentrations of 29 analytes were evaluated in urine samples from participants using the Luminex platform, and their diagnostic potential was assessed using standard statistical approaches. Results Of the 151 study participants, 34 (22.5%) were diagnosed with TB and 26 (17.2%) were HIV-positive. Seven biomarkers showed potential as TB diagnostic candidates, with accuracy improving (in HIV-positives) when stratified according to HIV status (area under the receiver operating characteristics curve; AUC ≥0.80). In HIV-positive participants, a four-marker biosignature (sIL6R, MMP-9, IL-2Ra, IFN-γ) diagnosed TB with AUC of 0.96, sensitivity of 85.7% (95% confidence interval (CI) 42.1–99.6%), and specificity of 94.7% (95% CI 74.0–99.9%). In HIV-negatives, the most promising was a two-marker biosignature (sIL6R and sIL-2Ra), which diagnosed TB with AUC of 0.76, sensitivity of 53.9% (95% CI 33.4–73.4%), and specificity of 79.6% (95% CI 70.3–87.1%). Conclusions Urinary host inflammatory biomarkers possess TB diagnostic potential but may be influenced by HIV infection. The results of this study require validation in larger studies.

Type 2 diabetes (T2D) is a prevalent risk factor for tuberculosis (TB), but most studies on TB-T2D have focused on TB patients, been limited to one community, and shown a variable impact of T2D on TB risk or treatment outcomes. We conducted a cross-sectional assessment of sociodemographic and metabolic factors in adult TB contacts with T2D (versus no T2D), from the Texas-Mexico border to study Hispanics, and in Cape Town to study South African Coloured ethnicities. The prevalence of T2D was 30.2% in Texas-Mexico and 17.4% in South Africa, with new diagnosis in 34.4% and 43.9%, respectively. Contacts with T2D differed between ethnicities, with higher smoking, hormonal contraceptive use and cholesterol levels in South Africa, and higher obesity in Texas-Mexico (p < 0.05). PCA analysis revealed striking differences between ethnicities in the relationships between factors defining T2D and dyslipidemias. Our findings suggest that screening for new T2D in adult TB contacts is effective to identify new T2D patients at risk for TB. Furthermore, studies aimed at predicting individual TB risk in T2D patients, should take into account the heterogeneity in dyslipidemias that are likely to modify the estimates of TB risk or adverse treatment outcomes that are generally attributed to T2D alone.

Most infections with Mycobacterium tuberculosis (Mtb) manifest as a clinically asymptomatic, contained state, known as latent tuberculosis infection, that affects approximately one-quarter of the global population(1). Although fewer than one in ten individuals eventually progress to active disease(2), tuberculosis is a leading cause of death from infectious disease worldwide(3). Despite intense efforts, immune factors that influence the infection outcomes remain poorly defined. Here we used integrated analyses of multiple cohorts to identify stage-specific host responses to Mtb infection. First, using high-dimensional mass cytometry analyses and functional assays of a cohort of South African adolescents, we show that latent tuberculosis is associated with enhanced cytotoxic responses, which are mostly mediated by CD16 (also known as FcγRIIIa) and natural killer cells, and continuous inflammation coupled with immune deviations in both T and B cell compartments. Next, using cell-type deconvolution of transcriptomic data from several cohorts of different ages, genetic backgrounds, geographical locations and infection stages, we show that although deviations in peripheral B and T cell compartments generally start at latency, they are heterogeneous across cohorts. However, an increase in the abundance of circulating natural killer cells in tuberculosis latency, with a corresponding decrease during active disease and a return to baseline levels upon clinical cure are features that are common to all cohorts. Furthermore, by analysing three longitudinal cohorts, we find that changes in peripheral levels of natural killer cells can inform disease progression and treatment responses, and inversely correlate with the inflammatory state of the lungs of patients with active tuberculosis. Together, our findings offer crucial insights into the underlying pathophysiology of tuberculosis latency, and identify factors that may influence infection outcomes.

BackgroundDiabetes mellitus (DM) increases active tuberculosis (TB) risk and worsens TB outcomes, jeopardizing TB control especially in TB-endemic countries with rising DM prevalence rates. We assessed DM status and clinical correlates in TB patients across settings in Indonesia, Peru, Romania, and South Africa.MethodsAge-adjusted DM prevalence was estimated using laboratory glycated hemoglobin (HbA1c) or fasting plasma glucose in TB patients. Detailed and standardized sociodemographic, anthropometric, and clinical measurements were made. Characteristics of TB patients with or without DM were compared using multilevel mixed-effect regression models with robust standard errors.ResultsOf 2185 TB patients (median age 36.6 years, 61.2% male, 3.8% human immunodeficiency virus–infected), 12.5% (267/2128) had DM, one third of whom were newly diagnosed. Age-standardized DM prevalence ranged from 10.9% (South Africa) to 19.7% (Indonesia). Median HbA1c in TB–DM patients ranged from 7.4% (Romania) to 11.3% (Indonesia). Compared to those without DM, TB–DM patients were older and had a higher body mass index (BMI) (P value < .05). Compared to those with newly diagnosed DM, TB patients with diagnosed DM had higher BMI and HbA1c, less severe TB, and more frequent comorbidities, DM complications, and hypertension (P value < .05).ConclusionsWe show that DM prevalence and clinical characteristics of TB–DM vary across settings. Diabetes is primarily known but untreated, hyperglycemia is often severe, and many patients with TB–DM have significant cardiovascular disease risk and severe TB. This underlines the need to improve strategies for better clinical management of combined TB and DM.

Improved tuberculosis diagnostics and tools for monitoring treatment response are urgently needed. We developed a robust and simple, PCR-based host-blood transcriptomic signature, RISK6, for multiple applications: identifying individuals at risk of incident disease, as a screening test for subclinical or clinical tuberculosis, and for monitoring tuberculosis treatment. RISK6 utility was validated by blind prediction using quantitative real-time (qRT) PCR in seven independent cohorts.Prognostic performance significantly exceeded that of previous signatures discovered in the same cohort. Performance for diagnosing subclinical and clinical disease in HIV-uninfected and HIV-infected persons, assessed by area under the receiver-operating characteristic curve, exceeded 85%. As a screening test for tuberculosis, the sensitivity at 90% specificity met or approached the benchmarks set out in World Health Organization target product profiles for non-sputum-based tests. RISK6 scores correlated with lung immunopathology activity, measured by positron emission tomography, and tracked treatment response, demonstrating utility as treatment response biomarker, while predicting treatment failure prior to treatment initiation. Performance of the test in capillary blood samples collected by finger-prick was noninferior to venous blood collected in PAXgene tubes. These results support incorporation of RISK6 into rapid, capillary blood-based point-of-care PCR devices for prospective assessment in field studies.

The evaluation of new tuberculosis (TB) therapies is limited by the paucity of biomarkers to monitor treatment response. Previous work detected an uncharacterized urine metabolite with a molecular mass of 874.3547 Da that showed promise as a biomarker for successful TB treatment. Using mass spectrometry combined with enzymatic digestions, the metabolite was structurally characterized as a seryl-leucine core 1 O-glycosylated peptide (SLC1G) of human origin. Examination of SLC1G in urine revealed a significant abundance increase in individuals with active TB versus their household contacts and healthy controls. Moreover, differential decreases in SLC1G levels were observed by week one in TB patients during successful treatment versus those that failed treatment. The SLC1G levels were also associated with clinical parameters used to measure bacterial burden (GeneXpert) and inflammation (positron emission tomography-computed tomography (PET-CT)). These results demonstrate the importance of metabolite identification and provide strong evidence for applying SLC1G as a biomarker of TB treatment response.

Conventional anti-tuberculosis (TB) therapies comprise lengthy antibiotic treatment regimens, exacerbated by multi-drug resistant and extensively drug resistant mycobacterial strains. We assessed the ability of all-trans retinoic acid (ATRA), as repurposed compound serving as host-directed therapy (HDT), to counteract the suppressive effects of myeloid-derived suppressor cells (MDSCs) obtained from active TB cases (untreated or during week one of treatment) on T-cell responsiveness. We show for the first time that MDSCs suppress non-specific T-cell activation and production of interleukin (IL)-2, IL-4, IL-13 and GM-CSF via contact-dependent mechanisms. ATRA treatment decreases MDSC frequency, but fails to mature MDSCs to non-suppressive, terminally differentiated myeloid cells and does not restore T-cell function or cytokine production in the presence of MDSCs. The impact of ATRA treatment on improved immunity, using the concentration tested here, is likely to be minimal, but further identification and development of MDSC-targeting TB host-directed therapies are warranted.

Standard treatment of drug-sensitive pulmonary tuberculosis requires six months of treatment. Several randomized clinical trials have attempted to shorten treatment to four months using various strategies but thus far all have failed. The PredictTB trial is an ongoing international randomized clinical trial testing a treatment shortening strategy whereby only drug-sensitive pulmonary TB patients who meet the study early treatment completion criteria are randomized to four vs. six months of treatment. The PredictTB early treatment completion criteria were developed based on a cohort of 92 pulmonary tuberculosis patients treated programmatically through the local tuberculosis treatment program in Cape Town, South Africa, with FDG-PET/CT scans also performed at baseline and week 4 of treatment. Patients were followed for one year after the end of therapy for programmatic treatment outcomes. This methodology paper describes how the PET/CT scans and GeneXpert cycle threshold data of this cohort were analyzed to develop the early treatment completion algorithm currently being used in the PredictTB trial.

Background There is a growing interest in the use of 18F-FDG PET-CT to monitor tuberculosis (TB) treatment response. However, TB causes complex and widespread pathology, which is challenging to segment and quantify in a reproducible manner. To address this, we developed a technique to standardise uptake (Z-score), segment and quantify tuberculous lung lesions on PET and CT concurrently, in order to track changes over time. We used open source tools and created a MATLAB script. The technique was optimised on a training set of five pulmonary tuberculosis (PTB) cases after standard TB therapy and 15 control patients with lesion-free lungs. Results We compared the proposed method to a fixed threshold (SUV > 1) and manual segmentation by two readers and piloted the technique successfully on scans of five control patients and five PTB cases (four cured and one failed treatment case), at diagnosis and after 1 and 6 months of treatment. There was a better correlation between the Z-score-based segmentation and manual segmentation than SUV > 1 and manual segmentation in terms of overall spatial overlap (measured in Dice similarity coefficient) and specificity (1 minus false positive volume fraction). However, SUV > 1 segmentation appeared more sensitive. Both the Z-score and SUV > 1 showed very low variability when measuring change over time. In addition, total glycolytic activity, calculated using segmentation by Z-score and lesion-to-background ratio, correlated well with traditional total glycolytic activity calculations. The technique quantified various PET and CT parameters, including the total glycolytic activity index, metabolic lesion volume, lesion volumes at different CT densities and combined PET and CT parameters. The quantified metrics showed a marked decrease in the cured cases, with changes already apparent at month one, but remained largely unchanged in the failed treatment case. Conclusions Our technique is promising to segment and quantify the lung scans of pulmonary tuberculosis patients in a semi-automatic manner, appropriate for measuring treatment response. Further validation is required in larger cohorts.

Contains fulltext : 196372.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To describe the characteristics and management of Diabetes mellitus (DM) patients from low- and middle-income countries (LMIC). METHODS: We systematically characterised consecutive DM patients attending public health services in urban settings in Indonesia, Peru, Romania and South Africa, collecting data on DM treatment history, complications, drug treatment, obesity, HbA1c and cardiovascular risk profile; and assessing treatment gaps against relevant national guidelines. RESULTS: Patients (median 59 years, 62.9% female) mostly had type 2 diabetes (96%), half for >5 years (48.6%). Obesity (45.5%) and central obesity (females 84.8%; males 62.7%) were common. The median HbA1c was 8.7% (72 mmol/mol), ranging from 7.7% (61 mmol/mol; Peru) to 10.4% (90 mmol/mol; South Africa). Antidiabetes treatment included metformin (62.6%), insulin (37.8%), and other oral glucose-lowering drugs (34.8%). Disease complications included eyesight problems (50.4%), EGFR

To evaluate the performance of diagnostic tools for diabetes mellitus, including laboratory methods and clinical risk scores, in newly-diagnosed pulmonary tuberculosis patients from four middle-income countries.In a multicentre, prospective study, we recruited 2185 patients with pulmonary tuberculosis from sites in Indonesia, Peru, Romania and South Africa from January 2014 to September 2016. Using laboratory-measured glycated haemoglobin (HbA1c) as the gold standard, we measured the diagnostic accuracy of random plasma glucose, point-of-care HbA1c, fasting blood glucose, urine dipstick, published and newly derived diabetes mellitus risk scores and anthropometric measurements. We also analysed combinations of tests, including a two-step test using point-of-care HbA1cwhen initial random plasma glucose was ≥ 6.1 mmol/L.The overall crude prevalence of diabetes mellitus among newly diagnosed tuberculosis patients was 283/2185 (13.0%; 95% confidence interval, CI: 11.6-14.4). The marker with the best diagnostic accuracy was point-of-care HbA1c (area under receiver operating characteristic curve: 0.81; 95% CI: 0.75-0.86). A risk score derived using age, point-of-care HbA1c and random plasma glucose had the best overall diagnostic accuracy (area under curve: 0.85; 95% CI: 0.81-0.90). There was substantial heterogeneity between sites for all markers, but the two-step combination test performed well in Indonesia and Peru.Random plasma glucose followed by point-of-care HbA1c testing can accurately diagnose diabetes in tuberculosis patients, particularly those with substantial hyperglycaemia, while reducing the need for more expensive point-of-care HbA1c testing. Risk scores with or without biochemical data may be useful but require validation.Évaluer la performance des outils de diagnostic du diabète sucré, et notamment les méthodes de laboratoire et les cotes de risque clinique, chez les patients souffrant d'une tuberculose pulmonaire récemment diagnostiquée dans quatre pays à revenu intermédiaire.Dans le cadre d'une étude multicentrique et prospective, nous avons recruté 2185 patients atteints de tuberculose pulmonaire dans différents endroits en Afrique du Sud, en Indonésie, au Pérou et en Roumanie entre janvier 2014 et septembre 2016. En utilisant comme référence l'hémoglobine glyquée (HbA1c) mesurée en laboratoire, nous avons évalué la précision diagnostique de la glycémie aléatoire, de l'HbA1c sur le lieu d'intervention, de la glycémie à jeun, de la bandelette urinaire, des cotes de risque déjà publiées et récemment obtenues pour le diabète sucré et des mesures anthropométriques. Nous avons également analysé des combinaisons de tests, et notamment un test en deux étapes qui utilise l'HbA1c sur le lieu d'intervention lorsque la glycémie aléatoire initiale est ≥ 6,1 mmol/L.La prévalence brute générale du diabète sucré chez les patients souffrant d'une tuberculose récemment diagnostiquée était de 283/2185 (13,0%; intervalle de confiance, IC, à 95%: 11,6–14,4). Le marqueur fournissant la meilleure précision diagnostique était l'HbA1c sur le lieu d'intervention (aire sous la courbe ROC: 0,81; IC à 95%: 0,75–0,86). La meilleure précision diagnostique générale a été obtenue à l'aide d'une cote de risque calculée au moyen de l'âge, de l'HbA1c sur le lieu d'intervention et de la glycémie aléatoire (aire sous la courbe ROC: 0,85; IC à 95%: 0,81–0,90). Une forte hétérogénéité entre les différents endroits a été constatée pour tous les marqueurs, mais le test en deux étapes a donné de bons résultats en Indonésie et au Pérou.L'utilisation de la glycémie aléatoire suivie de l'HbA1c sur le lieu d'intervention permet de diagnostiquer avec précision le diabète chez les patients atteints de tuberculose, en particulier lorsqu'ils souffrent d'une importante hyperglycémie, tout en diminuant le besoin de tests HbA1c sur le lieu d'intervention, plus coûteux. Les cotes de risque associées ou non à des données biochimiques peuvent être utiles, mais doivent être validées.Evaluar el rendimiento de las herramientas de diagnóstico para la diabetes mellitus, incluidos los métodos de laboratorio y los índices de riesgo clínico, en pacientes recién diagnosticados con tuberculosis pulmonar de cuatro países de ingresos medios.En un estudio prospectivo multicéntrico, se seleccionaron 2185 pacientes con tuberculosis pulmonar de algunas regiones de Indonesia, Perú, Rumanía y Sudáfrica entre enero de 2014 y septiembre de 2016. Usando hemoglobina glicosilada medida en laboratorio (HbA1c) como el patrón de excelencia, se midió la precisión diagnóstica de glucosa plasmática al azar, estando HbA1c en el punto de atención, glucemia en sangre en ayunas, tira reactiva de orina, índices de riesgo de diabetes mellitus publicados recientemente y medidas antropométricas. También se analizaron combinaciones de pruebas, incluida una prueba de dos pasos con HbA1c en el punto de atención cuando la glucosa plasmática aleatoria inicial fue ≥ 6,1mmol/L.La prevalencia general cruda de diabetes mellitus entre los pacientes con tuberculosis recién diagnosticados fue de 283/2185 (13,0 %, intervalo de confianza del 95 %, IC: 11,6–14,4). El marcador con la mejor precisión diagnóstica fue la HbA1c en el punto de atención (área bajo la curva característica operativa del receptor: 0,81; IC del 95 %: 0,75–0,86). Un índice de riesgo derivado de la edad, la HbA1c en el punto de atención y la glucosa plasmática al azar obtuvieron la mejor precisión diagnóstica general (área bajo la curva: 0,85; IC del 95 %: 0,81–0,90). Hubo una heterogeneidad sustancial entre las regiones para todos los marcadores, pero la prueba combinada de dos pasos funcionó de manera correcta en Indonesia y Perú.La glucosa plasmática al azar seguida de la prueba de HbA1c en el punto de atención puede diagnosticar con precisión la diabetes en pacientes con tuberculosis, particularmente en aquellos con hiperglucemia sustancial, mientras se reduce la necesidad de pruebas más costosas de HbA1c en el punto de atención. Los índices de riesgo con o sin datos bioquímicos pueden ser útiles, pero requieren validación.تقييم أداء أدوات تشخيص مرض السكري، بما في ذلك الطرق المختبرية ودرجات المخاطر السريرية، لدى المرضى الذين تم تشخيص إصابتهم حديثاً بالسل الرئوي من أربعة بلدان متوسطة الدخل.في دراسة استباقية متعددة المراكز، قمنا بالاستعانة بـ 2185 مريضًا بمرض السل الرئوي من مواقع في إندونيسيا وبيرو وجنوب إفريقيا ورومانيا من يناير/كانون ثاني 2014 إلى سبتمبر/أيلول 2016. وعن طريق قياس الهيموغلوبين الغليكوزيلاتي في المختبر (HbA1c) كمعيار أساسي، قمنا بقياس مدى دقة تشخيص كل من جلوكوز البلازما العشوائي، واختبار HbA1c في أماكن الرعاية، وجلوكوز الدم أثناء الصيام، ومقياس البول، ودرجات المخاطر المنشورة والمستنبطة حديثا من داء السكري، والقياسات الأنثروبومترية. قمنا أيضا بتحليل مجموعات من الاختبارات، بما في ذلك اختبار من خطوتين باستخدام اختبار HbA1c في أماكن الرعاية عندما كان مستوى جلوكوز البلازما العشوائي أكبر من أو يساوي 6.1 مليمول/ لتر.كان معدل الانتشار الكلي لمرض السكري بين المرضى الذين تم تشخيص إصابتهم حديثًا بالسل هو 283/2185 (13.0%؛ بفاصل ثقة 95%، فاصل ثقة: 11.6 إلى 14.4).كانت العلامة ذات أفضل دقة تشخيصية هي اختبار HbA1c في أماكن الرعاية (المساحة تحت منحنى خاصية التشغيل للمستقبِل: 0.81؛ بفاصل ثقة 95%: 0.75 إلى 0.86). كانت درجة الخطر المشتقة باستخدام العمر، واختبار HbA1c في أماكن الرعاية، وجلوكوز البلازما العشوائي، هي أفضل دقة تشخيصية عامة (المساحة تحت المنحنى: 0.85؛ بفاصل ثقة 95%: 0.81 إلى 0.90). كانت هناك عدم تجانس واضح بين المواقع لكل العلامات، إلا أن الاختبار المكون من خطوتين قدم أداءً جيدًا في إندونيسيا وبيرو.يمكن لاختبار جلوكوز البلازما العشوائي، ويليه اختبار HbA1c في أماكن الرعاية، تشخيص مرض السكري بدقة في مرضى السل، وخاصة أولئك الذين يعانون من ارتفاع شديد في سكر الدم، مع تقليل الحاجة إلى اختبار HbA1c الأكثر تكلفة في أماكن الرعاية. قد تكون درجات الخطر مفيدة، سواء مع بيانات كيميائية حيوية أو بدونها، ولكنها تتطلب التحقق من الصحة.评估用于四个中等收入国家新诊断结核病患者的糖尿病诊断工具的表现，其中包括实验室方法和临床风险评分。.在这项多中心、前瞻性的研究中，自 2014 年 1 月起至 2016 年 9 月，我们从秘鲁、罗马尼亚、南非和印度尼西亚各地招募了 2185 名肺结核患者。使用实验室测量的糖化血红蛋白 (HbA1c) 为黄金标准，我们测量了随机血糖、糖化血红蛋白 (HbA1c) 床旁检测、空腹血糖、尿液常规检查、已发表的和新导出的糖尿病风险评分以及人体测量法的诊断准确度。我们还对组合检测法进行了分析，其中包括两步检测法：即在初始随机血糖为临界值 ≥6.1 mmol/L 时，进行糖化血红蛋白 (HbA1c) 床旁检测。.新诊断结核病患者中，糖尿病的整体患病率为 283/2185（13.0％；95％ 置信区间，CI：11.6–14.4）。最准确的诊断指标是糖化血红蛋白 (HbA1c) 床旁检测（受试者工作特征曲线下的区域：0.81；95％ 置信区间，CI：0.75-0.86）。使用年龄、糖化血红蛋白 (HbA1c) 床旁检测和随机血糖得出的风险评分整体诊断准确度最佳（受试者工作特征曲线下的区域：0.85；95％ 置信区间，CI：0.81-0.90）。不同地点的指标之间存在显著的异质性，但两步组合检测法在秘鲁和印度尼西亚表现良好。.在随机血糖检测后再进行糖化血红蛋白 (HbA1c) 床旁检测可以准确诊断结核病患者是否患有糖尿病（尤其针对患有严重高血糖的患者），同时减少对更为昂贵的糖化血红蛋白 (HbA1c) 床旁检测的需求。内附或未附生化指标的风险评分可能有用，但仍需验证。.Оценить эффективность инструментов диагностики сахарного диабета (включая лабораторные методы и показатели клинического риска) у пациентов с недавно диагностированным туберкулезом легких из четырех стран со средним уровнем доходов.С января 2014 года по сентябрь 2016 года авторы провели многоцентровое проспективное исследование, в котором приняли участие 2185 пациентов с туберкулезом легких, проживающих в Индонезии, Перу, Румынии и Южной Африке. Используя измеренный в лаборатории гликозилированный гемоглобин (HbA1c) в качестве общепринятого стандарта, авторы измерили диагностическую точность выборочного определения уровня глюкозы в плазме; уровня HbA1c, определяемого в месте предоставления медицинской помощи; уровня глюкозы в крови натощак и определения сахара в моче с помощью индикаторной полоски с учетом опубликованных и недавно полученных оценок риска заболевания сахарным диабетом и антропометрических измерений. Мы также проанализировали комбинации тестов, в том числе двухэтапный тест с использованием HbA1c, измеренного в месте предоставления медицинской помощи, при начальном случайном уровне глюкозы в плазме ≥ 6,1 ммоль/л.Общая распространенность сахарного диабета среди пациентов с недавно выявленным туберкулезом составила 283 случая на 2185 человек (13,0%, 95%-й доверительный интервал, ДИ: 11,6–14,4). Маркер с наибольшей диагностической точностью — HbA1c, измеренный в месте предоставления медицинской помощи (область под кривой ROC: 0,81; 95%-й ДИ: 0,75–0,86). Оценка риска в зависимости от возраста, HbA1c, измеренного в месте предоставления медицинской помощи, и выборочного определения глюкозы в плазме имела наилучшую общую диагностическую точность (область под кривой: 0,85; 95%-й ДИ: 0,81–0,90). В различных местах наблюдалась существенная гетерогенность всех маркеров, при этом двухступенчатый комбинированный тест дал хорошие показатели для Индонезии и Перу.Выборочно определяемый уровень глюкозы в плазме с последующим тестированием HbA1c в месте предоставления медицинской помощи может точно диагностировать диабет у пациентов с туберкулезом, особенно у пациентов с существенной гипергликемией, уменьшая необходимость в более дорогостоящем тестировании HbA1c в месте предоставления медицинской помощи. Оценки риска по данным биохимического анализа крови или без них могут быть полезными, но нуждаются в проверке.