Tuberculosis Disease Severity Research Articles

Low-dose M.tb infection but not BCG or MTBVAC vaccination enhances heterologous antibody titres in non-human primates.

Mycobacteria are known to exert a range of heterologous effects on the immune system. The mycobacteria-based Freund's Complete Adjuvant is a potent non-specific stimulator of the immune response used in immunization protocols promoting antibody production, and Mycobacterium bovis Bacille Calmette Guérin (BCG) vaccination has been linked with decreased morbidity and mortality beyond the specific protection it provides against tuberculosis (TB) in some populations and age groups. The role of heterologous antibodies in this phenomenon, if any, remains unclear and under-studied. We set out to evaluate antibody responses to a range of unrelated pathogens following infection with Mycobacterium tuberculosis (M.tb) and vaccination with BCG or a candidate TB vaccine, MTBVAC, in non-human primates. We demonstrate a significant increase in the titer of antibodies against SARS-CoV-2, cytomegalovirus, Epstein-Barr virus, tetanus toxoid, and respiratory syncytial virus antigens following low-dose aerosol infection with M.tb. The magnitude of some of these responses correlated with TB disease severity. However, vaccination with BCG administered by the intradermal, intravenous or aerosol routes, or intradermal delivery of MTBVAC, did not increase antibody responses against unrelated pathogens. Our findings suggest that it is unlikely that heterologous antibodies contribute to the non-specific effects of these vaccines. The apparent dysregulation of B cell responses associated with TB disease warrants further investigation, with potential implications for risk of B cell cancers and novel therapeutic strategies.

Tuberculosis disease is associated with elevated plasma ribonuclease activity in antiretroviral treatment-naïve people with HIV.

The role of ribonucleases in tuberculosis (TB) among people with HIV (PWH) is unknown. We explored ribonuclease activity in plasma from PWH with and without TB. Participants were identified from a cohort of treatment-naïve PWH in Ethiopia who had been classified for TB disease (HIV+/TB + or HIV+/TB-). Ribonuclease activity in plasma was investigated by quantification of synthetic spike-in RNAs using sequencing and qPCR, and by a specific ribonuclease activity assay. Quantification of ribonuclease 1, 2, 3, 6, 7 and T2 proteins was performed by ELISA. Ribonuclease activity and protein concentrations were correlated with markers of TB and HIV disease severity and with concentrations of inflammatory mediators. Ribonuclease activity was significantly higher in plasma of HIV+/TB + (n = 51) compared to HIV+/TB- (n = 78), causing reduced stability of synthetic spike-in RNAs. concentrations of ribonucleases 2, 3 and T2 were also significantly increased in HIV+/TB + compared to HIV+/TB-. Ribonuclease activity was correlated with HIV viral load, and inversely correlated with CD4 count, mid-upper arm circumference and body mass index. Moreover, ribonuclease activity correlated with concentrations of interleukin-27, kynurenine/tryptophan ratio and procalcitonin. PWH with TB disease have elevated plasma ribonuclease activity, which is also associated with HIV severity and systemic inflammation.

The clinical significance of plasma sCD25 as valuable biomarker for progression and prognosis of tuberculosis

BackgroundsCD25 is an important immune molecule for T cell regulation. Tracking the detection of plasma sCD25 plays an important role in the evaluation of immune function, progression, and prognosis of tuberculosis (TB) patients. This study analyzed the association of plasma sCD25 levels with clinical, laboratory, CT imaging characteristics, and clinical outcome of TB patients.MethodsThe clinical data of 303 TB patients treated in the Fifth People’s Hospital of Suzhou from October 2019 to January 2022 were retrospectively analyzed. The levels of sCD25 in plasma were detected by ELISA. According to the cut-off threshold of plasma sCD25 levels, the patients were divided into a low-value group (Group TB1) and a high-value group (Group TB2). The association of plasma sCD25 levels with clinical, laboratory, and CT imaging characteristics of TB patients, as well as their TB treatment outcome were analyzed.ResultsThe levels of plasma sCD25 of patients with TB patients were higher than that of the healthy control group (P < 0.01). Among the 303 TB patients, the levels were increased in Group TB2 patients (0.602 ± 0.216 vs. 1.717 ± 0.604 ng/ml, P < 0.001), and there was a progressive reduction after anti-TB treatment. Furthermore, patients in Group TB2 showed higher positive rates in sputum smear (52.0% vs. 34.3%; P = 0.003), sputum culture (69.7% vs. 56.9%; P = 0.032), Xpert MTB/RIF (66.3% vs. 51.2%; P = 0.013) and TB-DNA (51.5% vs. 31.2%; P = 0.001) than those in Group TB1. Patients in Group TB2 had higher incidence in cough (78.8% vs. 62.3%; P = 0.004), expectoration (64.4% vs. 45.1%; P = 0.001), concomitant extrapulmonary TB (14.1% vs. 5.9%; P = 0.016), cavities (47.9% vs. 34.0%; P = 0.022), and unfavorable outcomes after anti-TB treatment.ConclusionThe clinical, laboratory and radiological manifestations of TB patients with high plasma sCD25 levels indicate that the disease is more severe. Tracking plasma sCD25 detection of TB patients has evident clinical significance. It is noteworthy that when the plasma sCD25 levels are significantly elevated, patients should be cautious of the TB progression and disease severity.

Applicability of artificial intelligence-based computer-aided detection (AI–CAD) for pulmonary tuberculosis to community-based active case finding

BackgroundArtificial intelligence-based computer-aided detection (AI–CAD) for tuberculosis (TB) has become commercially available and several studies have been conducted to evaluate the performance of AI–CAD for pulmonary tuberculosis (TB) in clinical settings. However, little is known about its applicability to community-based active case-finding (ACF) for TB.MethodsWe analysed an anonymized data set obtained from a community-based ACF in Cambodia, targeting persons aged 55 years or over, persons with any TB symptoms, such as chronic cough, and persons at risk of TB, including household contacts. All of the participants in the ACF were screened by chest radiography (CXR) by Cambodian doctors, followed by Xpert test when they were eligible for sputum examination. Interpretation by an experienced chest physician and abnormality scoring by a newly developed AI–CAD were retrospectively conducted for the CXR images. With a reference of Xpert-positive TB or human interpretations, receiver operating characteristic (ROC) curves were drawn to evaluate the AI–CAD performance by area under the ROC curve (AUROC). In addition, its applicability to community-based ACFs in Cambodia was examined.ResultsTB scores of the AI–CAD were significantly associated with the CXR classifications as indicated by the severity of TB disease, and its AUROC as the bacteriological reference was 0.86 (95% confidence interval 0.83–0.89). Using a threshold for triage purposes, the human reading and bacteriological examination needed fell to 21% and 15%, respectively, detecting 95% of Xpert-positive TB in ACF. For screening purposes, we could detect 98% of Xpert-positive TB cases.ConclusionsAI–CAD is applicable to community-based ACF in high TB burden settings, where experienced human readers for CXR images are scarce. The use of AI–CAD in developing countries has the potential to expand CXR screening in community-based ACFs, with a substantial decrease in the workload on human readers and laboratory labour. Further studies are needed to generalize the results to other countries by increasing the sample size and comparing the AI–CAD performance with that of more human readers.

Inflammatory immune profiles associated with disease severity in pulmonary tuberculosis patients with moderate to severe clinical TB or anemia.

Immune control of Mycobacterium tuberculosis (Mtb) infection is largely influenced by the extensive disease heterogeneity that is typical for tuberculosis (TB). In this study, the peripheral inflammatory immune profile of different sub-groups of pulmonary TB patients was explored based on clinical disease severity, anemia of chronic disease, or the radiological extent of lung disease. Plasma samples were obtained from n=107 patients with active pulmonary TB at the time of diagnosis and after start of standard chemotherapy. A composite clinical TB symptoms score, blood hemoglobin status and chest X-ray imaging were used to sub-group TB patients into 1.) mild and moderate-severe clinical TB, 2.) anemic and non-anemic TB, or 3.) limited and extensive lung involvement. Plasma levels of biomarkers associated with inflammation pathways were assessed using a Bio-Plex Magpix 37-multiplex assay. In parallel, Th1/Th2 cytokines were quantified with a 27-multiplex in matched plasma and cell culture supernatants from whole blood stimulated with M. tuberculosis-antigens using the QuantiFERON-TB Gold assay. Clinical TB disease severity correlated with low blood hemoglobin levels and anemia but not with radiological findings in this study cohort. Multiplex protein analyses revealed that distinct clusters of inflammation markers and cytokines separated the different TB disease sub-groups with variable efficacy. Several top-ranked markers overlapped, while other markers were unique with regards to their importance to differentiate the TB disease severity groups. A distinct immune response profile defined by elevated levels of BAFF, LIGHT, sTNF-R1 and 2, IP-10, osteopontin, chitinase-3-like protein 1, and IFNα2 and IL-8, were most effective in separating TB patients with different clinical disease severity and were also promising candidates for treatment monitoring. TB patients with mild disease displayed immune polarization towards mixed Th1/Th2 responses, while pro-inflammatory and B cell stimulating cytokines as well as immunomodulatory mediators predominated in moderate-severe TB disease and anemia of TB. Our data demonstrated that clinical disease severity in TB is associated with anemia and distinct inflammatory immune profiles. These results contribute to the understanding of immunopathology in pulmonary TB and define top-ranked inflammatory mediators as biomarkers of disease severity and treatment prognosis.

The impact of HIV co-infection on presentation and outcome in adults with tuberculous pericarditis: Findings from the IMPI trial

Background. Little is known about the impact of HIV infection on clinical presentation, complications, and morbid pericarditis-relatedoutcomes of tuberculous pericarditis and its predictors.Objective. To assess the impact of HIV infection on presentation and outcomes in the multicountry Investigation of the Management of Pericarditis (IMPI) randomised controlled trial of immunotherapy in tuberculous pericarditis conducted in sub-Saharan Africa.Methods. We compared clinical features and outcomes of 1 370 adult patients treated for tuberculous pericarditis (939 and 431 HIVinfected and uninfected, respectively) enrolled in the IMPI trial. Cox proportional hazards models were used to determine independent predictors of outcomes of HIV-associated tuberculous pericarditis.Results. At presentation, HIV-infected (v. uninfected) patients were younger (median age 34.0 years v. 47.7 years), had lower body mass (mean weight 56 kg v. 60 kg), higher prevalence of tachycardia (58.5% v. 51.9%), hypotension (9.4% v. 3.9%), anaemia (65.9% v. 26.8%), and radiographic pulmonary infiltrates compatible with tuberculosis (35.4% v. 27.4%), but had lower rates of peripheral oedema (37.1% v. 48.3%). HIV-infected (v. uninfected) patients were less likely to develop constrictive pericarditis (4.1% v. 10.0% at 1 year, p&lt;0.0001 (hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.27 - 0.63, p&lt;0.0001)). However, there was no difference in case fatality rate at 1 year (14.9% v. 12.2%, respectively, p=0.09; (HR 1.20, 95%CI 0.90 - 1.59, p=0.22)). Among HIV-infected patients, heart failure New York Heart Association (NYHA) class III - IV, low body mass, hypotension, and peripheral oedema were independently associated with death.Conclusion. HIV infection alters the cardiovascular presentation and reduces the incidence of constrictive pericarditis, but does notincrease case fatality. Mortality in HIV-infected patients is independently predicted by markers of pericardial and tuberculosis diseaseseverity.

Nonadherence Predictors to Tuberculosis Medications among TB Patients in Gambella Region of Ethiopia.

Background Global tuberculosis (TB) disease deaths rise comparable to the one seen in 2015 (by 200,000) or even in 2012 (by 400,000) as a result of the potential impact of the COVID-19 pandemic. Ethiopia's Gambella region is leading for years in terms of TB cases and its comorbidities. The TB control program effectiveness depends on in large on the patients completing the appropriate treatment regimen. Hence, the objective of this study was to determine the determinants of nonadherence to anti-TB drug treatment among patients in Gambella regional state of Ethiopia. Methods A case-control study was conducted on cohorts of TB patients sampled from four public health facilities in Gambella Region from January 2019 to 2020, followed by 18 months of follow-up. The total sample size was 296 patients (74 cases and 222 controls) with a response rate of 97.3% (288 : 72 nonadhered cases and 216 controls). Cases (nonadhered) were TB patients who missed 10% of the doses while controls were patients, who completed 90% or more doses. Results TB patients, who perceived stigma [AOR = 2.7 at 95% CI (1.1–6.6) with P value <0.05], failed to receive any counseling during the treatment course [AOR = 65.24 at 95% CI (11.69–363.95) with P value <0.01], patients who used to smoking during treatment [AOR = 15.4 at 95% CI (7.7–30) with P value <0.01], taking TB medications regularly has no benefits [AOR = 6.8 at 95% CI (1.8–24.9) with P value <0.05], and patients believing TB disease as not severe [AOR = 8.38 at 95% CI (2.0–34.6) with P value <0.05] were significantly or highly significantly associated with nonadherence to anti-TB drugs medications. Conclusion The determinants of nonadherence to anti-TB treatment among TB patients in the Gambella region during the study period were the absence of counselling services, and patients' behavior (smoking habits, undermining the severity of TB disease, lack of trust in the outcomes of regular medications, and perceived stigmatization). Accordingly, capacitating healthcare providers and workers at all TB clinics for effective counseling , preventing perceived stigma by protecting the patient's secrecy, and routine health education has paramount importance for effective TB control in Gambella.

Tobacco smoking impact on tuberculosis treatment outcome: an observational study from West Africa

ObjectiveBoth tuberculosis (TB) and tobacco smoking are preventable health hazards. Few studies have examined the relationship between TB and tobacco smoking in an African setting, where the two health burdens collide heavily. This study aimed to describe the severity of TB disease and treatment outcomes among smokers with TB compared with nonsmokers with TB in Guinea-Bissau. MethodsWe conducted a prospective follow-up study between 2003-2017 in Guinea-Bissau, enrolling adult patients with TB classified as nonsmokers or smokers. Disease severity was assessed using the Bandim TBscore. Multivariate logistic and Cox proportional hazard regressions were used to analyse treatment outcomes. ResultsOf 1780 included patients, 385 were smokers who had smoked for a median 10 years (interquartile range [IQR] 5-20). No difference in disease severity at the time of diagnosis was observed. Smokers were not significantly more prone to a nonsuccessful treatment outcome, although a trend was seen (adjusted odds ratio [OR] 1.24, 95% confidence interval [CI] 0.91-1.70), and smokers tended to be more often lost to follow-up, but this also was not a significant finding (adjusted hazard ratio [HR] 2.09, 95% CI 0.89-4.94). ConclusionIn a TB high-endemic setting with few tobacco smokers, smoking was not associated with disease severity or worse outcome, possibly because of socioeconomic confounders.

Exploring the Role of Low-Density Neutrophils During Mycobacterium tuberculosis Infection.

Tuberculosis (TB) is caused by infection with the bacterium Mycobacterium tuberculosis (Mtb), which primarily infects the lungs but can also cause extrapulmonary disease. Both the disease outcome and the pathology of TB are driven by the immune response mounted by the host. Infection with Mtb elicits inflammatory host responses that are necessary to control infection, but can also cause extensive tissue damage when in excess, and thus must be precisely balanced. In particular, excessive recruitment of neutrophils to the site of infection has been associated with poor control of Mtb infection, prompting investigations into the roles of neutrophils in TB disease outcomes. Recent studies have revealed that neutrophils can be divided into subpopulations that are differentially abundant in TB disease states, highlighting the potential complexities in determining the roles of neutrophils in Mtb infection. Specifically, neutrophils can be separated into normal (NDN) and low-density neutrophils (LDNs) based on their separation during density gradient centrifugation and surface marker expression. LDNs are present in higher numbers during active TB disease and increase in frequency with disease progression, although their direct contribution to TB is still unknown. In addition, the abundance of LDNs has also been associated with the severity of other lung infections, including COVID-19. In this review, we discuss recent findings regarding the roles of LDNs during lung inflammation, emphasizing their association with TB disease outcomes. This review highlights the importance of future investigations into the relationship between neutrophil diversity and TB disease severity.

Spontaneous Control of SIV Replication Does Not Prevent T Cell Dysregulation and Bacterial Dissemination in Animals Co-Infected with M. tuberculosis.

ABSTRACTIndividuals co-infected with HIV and Mycobacterium tuberculosis (Mtb) are more likely to develop severe tuberculosis (TB) disease than HIV-naive individuals. To understand how a chronic pre-existing Simian immunodeficiency virus (SIV) infection impairs the early immune response to Mtb, we used the Mauritian cynomolgus macaque (MCM) model of SIV/Mtb co-infection. We examined the relationship between peripheral viral control and Mtb burden, Mtb dissemination, and T cell function between SIV+ spontaneous controllers, SIV+ non-controllers, and SIV-naive MCM who were challenged with a barcoded Mtb Erdman strain 6 months post-SIV infection and necropsied 6 weeks post-Mtb infection. Mycobacterial burden was highest in the SIV+ non-controllers in all assessed tissues. In lung granulomas, the frequency of TNF-α-producing CD4+ T cells was reduced in all SIV+ MCM, but IFNγ-producing CD4+ T cells were only lower in the SIV+ non-controllers. Further, while all SIV+ MCM had more PD1+ and TIGIT+ T cells in the lung granulomas relative to SIV-naive MCM, SIV+ controllers exhibited the highest frequency of cells expressing these markers. To measure the effect of SIV infection on within-host bacterial dissemination, we sequenced the molecular barcodes of Mtb present in each tissue and characterized the Mtb population complexity. While Mtb population complexity was not associated with SIV infection group, lymph nodes had increased complexity when compared with lung granulomas across all groups. These results provide evidence that SIV+ animals, independent of viral control, exhibit a dysregulated T cell immune response and enhanced dissemination of Mtb, likely contributing to the poor TB disease course across all SIV/Mtb co-infected animals.IMPORTANCE HIV and TB remain significant global health issues, despite the availability of treatments. Individuals with HIV, including those who are virally suppressed, are at an increased risk to develop and succumb to severe TB disease when compared with HIV-naive individuals. Our study aims to understand the relationship between the extent of SIV replication, mycobacterial growth, and T cell function in the tissues of co-infected Mauritian cynomolgus macaques during the first 6 weeks of Mtb infection. Here we demonstrate that increased viral replication is associated with increased bacterial burden in the tissues and impaired T cell responses, and that the immunological damage attributed to virus infection is not fully eliminated when animals spontaneously control virus replication.

Ifnar gene variants influence gut microbial production of palmitoleic acid and host immune responses to tuberculosis.

Both host genetics and the gut microbiome have important effects on human health, yet how host genetics regulates gut bacteria and further determines disease susceptibility remains unclear. Here, we find that the gut microbiome pattern of participants with active tuberculosis is characterized by a reduction of core species found across healthy individuals, particularly Akkermansia muciniphila. Oral treatment of A. muciniphila or A. muciniphila-mediated palmitoleic acid strongly inhibits tuberculosis infection through epigenetic inhibition of tumour necrosis factor in mice infected with Mycobacterium tuberculosis. We use three independent cohorts comprising 6,512 individuals and identify that the single-nucleotide polymorphism rs2257167 'G' allele of type I interferon receptor 1 (encoded by IFNAR1 in humans) contributes to stronger type I interferon signalling, impaired colonization and abundance of A. muciniphila, reduced palmitoleic acid production, higher levels of tumour necrosis factor, and more severe tuberculosis disease in humans and transgenic mice. Thus, host genetics are critical in modulating the structure and functions of gut microbiome and gut microbial metabolites, which further determine disease susceptibility.

Prevalence of anaemia and associated factors among people with pulmonary tuberculosis in Uganda.

Anaemia predicts delayed sputum conversion and mortality in tuberculosis (TB). We determined the prevalence and factors associated with anaemia among people with TB at the National Tuberculosis Treatment Centre in Uganda. People with bacteriologically confirmed TB were consecutively enrolled in a cross-sectional study between August 2017 and March 2018. Blood samples were tested for a full blood hemogram, HIV infection, and CD4+ and CD8+ T-cell counts. Anaemia was defined as a haemoglobin level of <13.0 grams per decilitre (g/dl) for males and <12.0 g/dl for females. Of 358 participants, 210 (58.7%, 95% confidence interval (CI) 53.4-63.8) had anaemia. Anaemia was associated with night sweats, a longer duration of fever, low body mass index (BMI), hyperthermia, high sputum bacillary loads, HIV co-infection, and low CD4 and CD8 counts at bivariate analysis. Factors associated with anaemia at multivariable analysis were low BMI (odds ratio (OR) 2.93, 95% CI 1.70-5.05, P < 0.001), low CD4:CD8 ratio (OR 2.54, 95% CI 1.07-6.04, P = 0.035) and microcytosis (OR 4.23, 95% CI 2.17-8.25, P < 0.001). Anaemia may be associated with the features of severe TB disease and should be considered in TB severity scores.

Tuberculosis Infection in Children and Adolescents: Testing and Treatment

Tuberculosis (TB) remains an important problem among children in the United States and throughout the world. There is no diagnostic reference standard for latent tuberculosis infection (also referred to as tuberculosis infection [TBI]). The tuberculin skin test (TST) has many limitations, including difficulty in administration and interpretation, the need for a return visit by the patient, and false-positive results caused by cross-reaction with Mycobacterium bovis-bacille Calmette-Guerin vaccines and many nontuberculous mycobacteria. Interferon-gamma release assays (IGRAs) are blood tests that use antigens specific for M tuberculosis; as a result, IGRAs yield fewer false-positive results than the TST. Both IGRAs and the TST have reduced sensitivity in immunocompromised children, including children with severe TB disease. Both methods have high positive predictive value when applied to children with risk factors for TBI, especially recent contact with a person who has TB disease. The advantages of using IGRAs and diminished experience with the placement and interpretation of the TST favor expanded use of IGRAs in children in the United States. There are now several effective and safe regimens for the treatment of TBI in children. For improved adherence to therapy, the 3 rifamycin-based regimens are preferred because of their short duration. Daily isoniazid can be used if there is intolerance or drug interactions with rifamycins. A TB specialist should be involved when there are questions regarding testing interpretation, selection of an appropriate treatment regimen, or management of adverse effects.

Diabetes-Associated Susceptibility to Tuberculosis: Contribution of Hyperglycemia vs. Dyslipidemia.

Diabetes is a major risk factor for tuberculosis (TB). Diabetes increases the risk of the progression from latent tuberculosis infection (LTBI) to active pulmonary TB and TB patients with diabetes are at greater risk of more severe disease and adverse TB treatment outcomes compared to TB patients without co-morbidities. Diabetes is a complex disease, characterised not only by hyperglycemia but also by various forms of dyslipidemia. However, the relative contribution of these underlying metabolic factors to increased susceptibility to TB are poorly understood. This review summarises our current knowledge on the epidemiology and clinical manifestation of TB and diabetes comorbidity. We subsequently dissect the relative contributions of body mass index, hyperglycemia, elevated cholesterol and triglycerides on TB disease severity and treatment outcomes. Lastly, we discuss the impact of selected glucose and cholesterol-lowering treatments frequently used in the management of diabetes on TB treatment outcomes.

Differential effects of asymptomatic Ascaris lumbricoides, Schistosoma mansoni or hook worm infection on the frequency and TGF-beta-producing capacity of regulatory T cells during active tuberculosis

Helminth induced expansion of regulatory T cells (Tregs) may take part in suppressing protective host responses during tuberculosis (TB), although Tregs functionality and link to TB disease severity remains unexplored. We investigated the species-specific effect of helminths on frequency and TGF-β producing capacity of Tregs, and possible connection to TB disease severity. 89 pulmonary TB patients (PTB) and 69 community controls (CCs) from Gondar, Ethiopia, were included. Clinical disease severity was graded by TB score, and flow cytometry used to characterize Treg frequency and functionality measured as their TGF-β-producing capacity. In helminth positive PTB patients (Helminth+PTB+) compared to helminth negative PTB or CCs, TGF-β+ Tregs were significantly increased mainly in hookworm coinfection whereas S. mansoni increased TGF-β+ Tregs in CCs. Treatment of TB and helminths decreased TGF-β+ Tregs in Helminth+PTB+ at 2 months follow-up. There were no overall differences in the frequency of Tregs in CCs or PTB unless stratification on TB disease severity was performed. At inclusion Helminth+PTB+ had increased frequency of Tregs already at low disease severity, and TGF-β+ Tregs correlated to intermediate-to-high disease severity. In conclusion, helminth specific increase of TGF-β+ Tregs in PTB patients was correlated to TB disease severity and was restored following anti-helminth treatment.

PMN-MDSC Frequency Discriminates Active Versus Latent Tuberculosis and Could Play a Role in Counteracting the Immune-Mediated Lung Damage in Active Disease.

Tuberculosis (TB), due to Mycobacterium tuberculosis infection, is still the principal cause of death caused by a single infectious agent. The balance between the bacillus and host defense mechanisms reflects the different manifestations of the pathology. Factors defining this variety are unclear and likely involve both mycobacterial and immunological components. Myeloid derived suppressor cells (MDSC) have been shown to be expanded during TB, but their role in human TB pathogenesis is not clear. We evaluated the frequency of circulating MDSC by flow-cytometry in 19 patients with active TB, 18 with latent TB infection (LTBI), and 12 healthy donors (HD) as control. Moreover, we investigated the capacity of MDSC to modulate the mycobactericidal activity of monocytes. The association between MDSC level and TB chest X-ray severity score was analyzed. We observed that, unlike active TB, polymorphonuclear (PMN)-MDSC are not expanded in LTBI patients, and, by performing a receiver operating characteristic (ROC) curve analysis, we found that PMN-MDSC frequency supported the discrimination between active disease and LTBI. Interestingly, we observed an association between PMN-MDSC levels and the severity of TB disease evaluated by chest X-ray. Specifically, PMN-MDSC frequency was higher in those classified with a low/mild severity score compared to those classified with a high severity score. Moreover, PMN-MDSC can impact mycobacterial growth by inducing ROS production in Bacillus Calmette et Guerin (BCG)-infected monocytes. This effect was lost when tested with M. tuberculosis (MTB), In conclusion, our data indicate that the elevated frequency of PMN-MDSC in IGRA-positive individuals is associated with active TB. Our findings also pointed out a beneficial role of PMN-MDSC during human active TB, most likely associated with the limitation of inflammation-induced tissue damage.

Radiologist observations of computed tomography (CT) images predict treatment outcome in TB Portals, a real-world database of tuberculosis (TB) cases

The TB Portals program provides a publicly accessible repository of TB case data containing multi-modal information such as case clinical characteristics, pathogen genomics, and radiomics. The real-world resource contains over 3400 TB cases, primarily drug resistant cases, and CT images with radiologist annotations are available for many of these cases. The breadth of data collected offers a patient-centric view into the etiology of the disease including the temporal context of the available imaging information. Here, we analyze a cohort of new TB cases with available radiologist observations of CTs taken around the time of initial registration of the case into the database and with available follow up to treatment outcome of cured or died. Follow up ranged from 5 weeks to a little over 2 years consistent with the longest treatment regimens for drug resistant TB and cases were registered within the years 2008 to 2019. The radiologist observations were incorporated into machine learning pipelines to test various class balancing strategies on the performance of predictive models. The modeling results support that the radiologist observations are predictive of treatment outcome. Moreover, inferential statistical analysis identifies markers of TB disease spread as having an association with poor treatment outcome including presence of radiologist observations in both lungs, swollen lymph nodes, multiple cavities, and large cavities. While the initial results are promising, further data collection is needed to incorporate methods to mitigate potential confounding such as including additional model covariates or matching cohorts on covariates of interest (e.g. demographics, BMI, comorbidity, TB subtype, etc.). Nonetheless, the preliminary results highlight the utility of the resource for hypothesis generation and exploration of potential biomarkers of TB disease severity and support these additional data collection efforts.

Tuberculosis contact investigation results among paediatric contacts in low-incidence settings in Finland

Tuberculosis (TB) risk is highest immediately after primary infection, and young children are vulnerable to rapid and severe TB disease. Contact tracing should identify infected children rapidly and simultaneously target resources effectively. We conducted a retrospective review of the paediatric TB contact tracing results in the Hospital District of Helsinki and Uusimaa from 2012 to 2016 and identified risk factors for TB disease or infection. Altogether, 121 index cases had 526 paediatric contacts of whom 34 were diagnosed with TB disease or infection. The maximum delay until first contact investigation visit among the household contacts under 5 years of age with either TB disease or infection was 7 days. The yield for TB disease or infection was 4.6% and 12.8% for household contacts, 0.5% and 0% for contacts exposed in a congregate setting and 1.4% and 5.0% for other contacts, respectively. Contacts born in a TB endemic country (aOR 3.07, 95% CI 1.10–8.57), with household exposure (aOR 2.96, 95% CI 1.33–6.58) or a sputum smear positive index case (aOR 3.96, 95% CI 1.20–13.03) were more likely to have TB disease or infection.Conclusions: Prompt TB investigations and early diagnosis can be achieved with a well-organised contact tracing structure. The risk for TB infection or disease was higher among contacts with household exposure, a sputum smear positive index case or born in a TB endemic country. Large-scale investigations among children exposed in congregate settings can result in a very low yield and should be cautiously targeted.What is Known:• Vulnerable young children are a high priority in contact tracing and should be evaluated as soon as possible after TB exposureWhat is New:• Prompt investigations for paediatric TB contacts and early diagnosis of infected children can be achieved with a well-organised contact tracing structure• Large-scale investigations among children exposed in congregate settings can result in a very low yield and should be cautiously targeted

Closing the loop in child TB contact management: completion of TB preventive therapy outcomes in western Kenya

SettingChildren especially those <5 years of age exposed to pulmonary tuberculosis (TB) are at a high risk of severe TB disease and death. Isoniazid preventive therapy (IPT) has been shown...

Dysglycemia is associated with Mycobacterium tuberculosis lineages in tuberculosis patients of North Lima-Peru.

This study was performed to investigate the role of dysglycemia on the genetic diversity of Mycobacterium tuberculosis (MTB) among pulmonary tuberculosis (TB) patients to build scientific evidence about the possible mechanisms of TB transmission. MTB isolates obtained of patients affected by pulmonary tuberculosis from health care facilities of North Lima—Peru, were analyzed using whole genome sequencing and 24-locus mycobacterial interspersed repetitive-unit -variable-number tandem repeats (MIRU-VNTR). Subsequently, clinical and epidemiological characteristics were associated with clustering, lineages and comorbid conditions. The analysis carried out 112 pulmonary TB patients from various health centers in North Lima, 17 (15%) had diabetes mellitus (DM) and 33 (29%) had pre-diabetes (PDM). Latin American-Mediterranean, Haarlem and Beijing were the most frequent MTB lineages found in those patients. Previous TB (adjusted odds ratio [aOR] = 3.65; 95%CI: 1.32–17.81), age (aOR = 1.12; 95%CI: 1.03–1.45) and Beijing lineage (aOR = 3.53; 95%CI: 1.08–13.2) were associated with TB-DM comorbidity. Alcoholism (aOR = 2.92; 95%CI: 1.10–8.28), age (aOR = 1.05; 95%CI: 1.03–1.12) and Haarlem lineage (aOR = 2.54; 95%CI: 1.04–6.51) were associated with TB-PDM comorbidity. Beijing and Haarlem lineages were independently associated with TB-DM and TB-PDM comorbidities, respectively. Although these findings may be surprising, we must be cautious to suggest that dysglycemia could be associated with a highly clustering and predisposition of MTB lineages related to a serious impact on the severity of TB disease, which requires further research.