Risk Of Tuberculosis Disease Research Articles

Risk of tuberculosis disease in Patients Receiving TNF-α Antagonist Therapy: A Meta-analysis of Randomized Controlled Trials

Risk of tuberculosis disease in Patients Receiving TNF-α Antagonist Therapy: A Meta-analysis of Randomized Controlled Trials

Facilitators and barriers to initiating and completing tuberculosis preventive treatment among children and adolescents living with HIV in Uganda: a qualitative study of adolescents, caretakers and health workers

IntroductionPeople living with HIV (PLHIV) have a 20-fold risk of tuberculosis (TB) disease compared to HIV-negative people. In 2021, the uptake of TB preventive treatment among the children and adolescents living with HIV at the Baylor-Uganda HIV clinic was 45%, which was below the national target of 90%. Minimal evidence documents the enablers and barriers to TB preventive treatment (TPT) initiation and completion among children and adolescents living with HIV(CALHIV). We explored the facilitators and barriers to TPT initiation and completion among CALHIV among adolescents aged 10-19years and caretakers of children below 18years.MethodsWe conducted a qualitative study from February 2022 to March 2023, at three paediatric and adolescent HIV treatment centers in Uganda. In-depth interviews were conducted at TPT initiation and after completion for purposively selected health workers, adolescents aged 10–19 years living with HIV, and caretakers of children aged below 18years.ResultsThe desire to avoid TB disease, previous TB treatment, encouragement from family members, and ministry of health policies emerged as key facilitators for the children and adolescents to initiate TPT. Barriers to TPT initiation included; TB and HIV-related stigma, busy carer and adolescent work schedules, reduced social support from parents and family, history of drug side effects, high pill burden and fatigue, and perception of not being ill. TPT completion was enabled by combined TPT and ART refill visits, delivery of ART and TPT within the community, and continuous education and counseling from health workers. Reported barriers to TPT completion included TB and HIV-related stigma, long waiting time. Non-disclosure of HIV status by caretakers to CALHIV and fear of side effects was cited by health workers as a barrier to starting TPT. Facilitators of TPT initiation and completion reported by healthcare workers included patient and caretaker health education, counselling about benefits of TPT and risk of TB disease, having same appointment for TPT and ART refill to reduce patient waiting time, adolescent-friendly services, and appointment reminder phone calls.ConclusionThe facilitators and barriers of TPT initiation and completion among CALHIV span from individual, to health system and structural factors. Health education about benefits of TPT and risk of TB, social support, adolescent-friendly services, and joint appointments for TPT and ART refill are major facilitators of TPT initiation and completion among CALHIV in Uganda.

Effects of the Beijing genotype on latent tuberculosis infection, TB disease risk, and clustering of TB cases

BackgroundThe Beijing genotype of Mycobacterium tuberculosis (Mtb) has sparked debate regarding its virulence and transmissibility. This study contributes to this discussion by assessing its effect on the risk of latent tuberculosis infection (LTBI), active tuberculosis (TB) disease among contacts, and clustering of known TB cases. MethodsWe conducted a retrospective cohort study using the records of 4457 culture-confirmed TB patients and their contacts (20,448) reported to the Florida Department of Health between 2009 and 2023. Univariate and multivariate analyses were used to evaluate the effect of the Beijing strain on LTBI, active TB risk among contacts, and case clustering. ResultsOur study revealed no significant difference in transmissibility between the Beijing and non-Beijing genotypes among contacts. LTBI prevalence was 19.9%, slightly higher in non-Beijing than Beijing genotypes (20.2% vs. 15.5%, p < 0.001). The prevalence of active TB was 1.8%, with no significant difference between the Beijing and non-Beijing genotypes (1.4% vs. 1.8%, p = 0.296). Increased LTBI risk was associated with older age, male sex, Hispanic ethnicity, multidrug-resistant TB exposure, household exposure, and a longer exposure duration. Active TB risk was higher for males, HIV-positive individuals, and contacts with more prolonged exposure to index cases. The Beijing genotype was associated with increased TB case clustering (aOR = 1.98, 95%CI: 1.53, 2.55, p < 0.001) as compared to the non-Beijing genotypes. US birthplace (aOR = 2.75, 95%CI: 2.37, 3.19, p < 0.001), pulmonary disease (aOR = 1.27, 95%CI: 1.04, 1.56, p < 0.020), cavitary TB (aOR = 1.25, 95% CI: 1.08, 1.44, p < 0.003), previous year alcohol use (aOR = 1.68, 95%CI: 1.38, 2.04, p < 0.001), and recreational drug use (aOR = 1.32, 95%CI: 1.04, 1.67, p < 0.024) were also associated with an increased risk of TB case clustering. ConclusionWhile the Beijing genotype did not increase the risk of LTBI or active TB among contacts, it showed a higher tendency for case clustering. Hence, interventions should prioritize populations where this genotype is prevalent.

Comparison of QuantiFERON Gold In-Tube Versus Tuberculin Skin Tests on the Initiation of Tuberculosis Preventive Therapy Among Patients Newly Diagnosed With HIV in the North West Province of South Africa (the Teko Study): A Cluster Randomized Trial.

Tuberculosis (TB) preventive therapy (TPT) reduces the risk of TB disease in people with human immunodeficiency virus (HIV), yet uptake has been suboptimal in many countries. We assessed whether QuantiFERON Gold In-Tube (QGIT) during routine HIV care increased TB infection (TBI) testing and TPT prescriptions. This parallel-arm, 1:1 cluster-randomized controlled trial compared the standard-of-care tuberculin skin test to QGIT in South Africa. We enrolled consenting, TPT-eligible adults diagnosed with HIV ≤30 days prior and used intention-to-treat analyses for the outcomes: proportion of patients with documented TBI results, proportion with documented TPT, and time from enrollment to outcomes. We enrolled 2232 patients across 14 clinics from November 2014 to May 2017 (58% in intervention clinics). At 24 months of follow-up, more participants in intervention clinics had TBI results (69% vs 2%, P < .001) and TPT prescriptions (45% vs 30%, P = .13) than control clinics. Controlling for baseline covariates, intervention clinics had 60% (95% confidence interval, 51-68; P < .001) more participants with TBI results and 12% (95% confidence interval, -6 to 31; P = .18) more with TPT prescriptions. Among participants with results, those in intervention clinics received results and TPT faster (intervention: median of 6 and 29 days after enrollment vs control: 21 and 54 days, respectively). In this setting, QGIT in routine HIV care resulted in more patients with TBI results. Clinicians also initiated more people with HIV on TPT in QGIT intervention clinics, and did so more quickly, than the control arm. NCT02119130.

Treatment preferences among people at risk of developing tuberculosis: A discrete choice experiment.

Diagnosing and treating people with bacteriologically-negative but radiologically-apparent tuberculosis (TB) may contribute to more effective TB care and reduce transmission. However, optimal treatment approaches for this group are unknown. It is important to understand peoples' preferences of treatment options for effective programmatic implementation of people-centred treatment approaches. We designed and implemented a discrete choice experiment (DCE) to solicit treatment preferences among adults (≥18 years) with TB symptoms attending a primary health clinic in Blantyre, Malawi. Treatment attributes included in the DCE were as follows: duration of treatment; number of tablets per dose; reduction in the risk of being unwell with TB disease; likelihood of infecting others; adverse effects from the treatment; frequency of follow up; and the annual travel cost to access care. Quantitative choice modelling with multinomial logit models estimated through frequentist and Bayesian approaches investigated preferences for the management of bacteriologically-negative, but radiographically-apparent TB. 128 participants were recruited (57% male, 43.8% HIV-positive, 8.6% previously treated for TB). Participants preferred to take any treatment compared to not taking treatment (odds ratio [OR] 5.78; 95% confidence interval [CI]: 2.40, 13.90). Treatments that reduced the relative risk of developing TB disease by 80% were preferred (OR: 2.97; 95% CI: 2.09, 4.21) compared to treatments that lead to a lower reduction in risk of 50%. However, there was no evidence for treatments that are 95% effective being preferred over those that are 80% effective. Participants strongly favoured the treatments that could completely stop transmission (OR: 7.87, 95% CI: 5.71, 10.84), and prioritised avoiding side effects (OR: 0.19, 95% CI: 0.12, 0.29). There was no evidence of an interaction between perceived TB disease risk and treatment preferences. In summary, participants were primarily concerned with the effectiveness of TB treatments and strongly preferred treatments that removed the risk of onward transmission. Person-centred approaches of preferences for treatment should be considered when designing new treatment strategies. Understanding treatment preferences will ensure that any recommended treatment for probable early TB disease is well accepted and utilized by the public.

Evaluation of immune profiles associated with control of mycobacterial growth in systemic lupus erythematosus (SLE) patients

Tuberculosis (TB) is an infectious disease with the burden concentrated in low- and middle-income countries. Systemic lupus erythematosus (SLE) is an autoimmune disease associated with widespread inflammation that is prevalent in some TB endemic areas including East Africa and parts of Southeast Asia. SLE patients are known to be at higher risk of becoming infected with M. tb, developing TB disease. However, the immune mechanisms underlying this susceptibility are not well understood, particularly in the absence of immunosuppressive drugs. We present a pilot study in which we have evaluated intracellular cytokine responses and ex vivo ability to control mycobacterial growth using peripheral blood mononuclear cells (PBMC) collected from SLE patients before and during SLE treatment. After six months of treatment, SLE patients had the highest frequencies of CD8+ T cells, NK cells and NKT cells producing IFN-γ and/or TNF-α. This group also showed superior control of mycobacterial growth, and proinflammatory cytokine-producing NK and NKT cells correlated with mycobacterial growth inhibition at the individual patient level. These findings contribute to a better understanding of autoimmune profiles associated with control of mycobacterial growth in SLE patients, which may inform intervention strategies to reduce risk of TB disease in this population.

Quantitative interferon-gamma releasing assay in predicting tuberculosis in South Korean military: a retrospective cohort study

ObjectiveThe interferon-gamma releasing assay (IGRA) has been widely used to diagnose latent tuberculosis infection (TBI). However, there are limited data on the association between performance in the IGRA and risk of tuberculosis disease (TBD), as well as on the appropriate IGRA threshold for initiating TBI treatment. MethodsThe analysis was performed using the IGRA results in the Korean Military Manpower Administration database (January 2017 to December 2021), and TBD cases reported to the Korean Military Medical Command (January 2017 to June 2023). All Korean candidates for 18-month military service underwent the IGRA in the pre-enlistment examination, and enlistees who tested positive (≥0.35 IU/mL) were advised to receive TBI treatment before enlistment. ResultsFrom 2017 to 2021, 1 647 941 individuals were screened, with 29 574 testing positive for IGRA. Excluding nonenlistees namely individuals with TBD before enlistment, 19 387 individuals were IGRA positive and 1 356 324 IGRA negative. Of the positives, 4351 were excluded due to discontinued or ongoing TBI treatment at or after enlistment. During follow-up of 9219 untreated and 5818 treated positive individuals and 1 356 324 negatives, TBD occurred in 22 of the IGRA-positive individuals (97.5/100 000 person-years [95% CI, 61.1–147.7]), predominantly in the untreated group (18 cases, 130.1/100 000 person-years [95% CI, 77.1–205.7]) compared to the treated group (4 cases, 45.9/100 000 person-years [95% CI 12.5 – 117.4]), whereas 57 cases occurred in the IGRA-negative group (2.8/100 000 person-years [95% CI, 2.2–3.6]). Elevating the cutoff of IGRA from 0.35 IU/mL to 1.33 IU/mL increased positive predictive value (0.2% vs. 0.4%, p 0.03), with insignificant loss of sensitivity (24% vs. 20%, p 0.69) and decreased numbers needing treatment from 790.5 to 415.3. DiscussionElevated IGRA levels before enlistment are associated with risk of TBD during military service. It is worth considering raising the IGRA threshold for treatment of TBI in cohorts of healthy, young military individuals.

Impaired Mycobacterium tuberculosis-specific T-cell memory phenotypes and functional profiles among adults with type 2 diabetes mellitus in Uganda.

Efforts to eradicate tuberculosis (TB) are threatened by diabetes mellitus (DM), which confers a 3-fold increase in the risk of TB disease. The changes in the memory phenotypes and functional profiles of Mycobacterium tuberculosis (Mtb)-specific T cells in latent TB infection (LTBI)-DM participants remain poorly characterised. We, therefore, assessed the effect of DM on T-cell phenotype and function in LTBI and DM clinical groups. We compared the memory phenotypes and function profiles of Mtb-specific CD4+ and CD8+ T cells among participants with LTBI-DM (n=21), LTBI-only (n=17) and DM-only (n=16). Peripheral blood mononuclear cells (PBMCs) were stimulated with early secretory antigenic 6 kDa (ESAT-6) and culture filtrate protein 10 (CFP-10) peptide pools or phytohemagglutinin (PHA). The memory phenotypes (CCR7/CD45RA), and functional profiles (HLA-DR, PD-1, CD107a, IFN-γ, IL-2, TNF, IL-13, IL-17A) of Mtb-specific CD4+ and CD8+ T cells were characterised by flow cytometry. Naïve CD4+ T cells were significantly decreased in the LTBI-DM compared to the LTBI-only participants [0.47 (0.34-0.69) vs 0.91 (0.59-1.05); (p<0.001)]. Similarly, CD8+ HLA-DR expression was significantly decreased in LTBI-DM compared to LTBI-only participants [0.26 (0.19-0.33) vs 0.52 (0.40-0.64); (p<0.0001)], whereas CD4+ and CD8+ PD-1 expression was significantly upregulated in the LTBI-DM compared to the LTBI-only participants [0.61 (0.53-0.77) vs 0.19 (0.10-0.28); (p<0.0001) and 0.41 (0.37-0.56) vs 0.29 (0.17-0.42); (p=0.007)] respectively. CD4+ and CD8+ IFN-γ production was significantly decreased in the LTBI-DM compared to the LTBI-only participants [0.28 (0.19-0.38) vs 0.39 (0.25-0.53); (p=0.030) and 0.36 (0.27-0.49) vs 0.55 (0.41-0.88); (p=0.016)] respectively. CD4+ TNF and CD8+ IL-17A production were significantly decreased in participants with LTBI-DM compared to those with LTBI-only [0.38 (0.33-0.50) vs 0.62 (0.46-0.87); (p=0.004) and 0.29 (0.16-0.42) vs 0.47 (0.29-0.52); (0.017)] respectively. LTBI-DM participants had significantly lower dual-functional (IFN-γ+IL-2+ and IL-2+TNF+) and mono-functional (IFN-γ+ and TNF+) CD4+ responses than LTBI-only participants. LTBI-DM participants had significantly decreased dual-functional (IFN-γ+IL-2+, IFN-γ+ TNF+ and IL-2+TNF+) and mono-functional (IFN-γ+, IL-2+ and TNF+) central and effector memory CD4+ responses compared to LTBI-only participants. Type 2 DM impairs the memory phenotypes and functional profiles of Mtb-specific CD4+ and CD8+ T cells, potentially indicating underlying immunopathology towards increased active TB disease risk.

Perinatal tuberculosis-An approach to an under-recognized diagnosis.

Tuberculosis (TB) in young infants (<3 months of age), often referred to as perinatal TB, is underdiagnosed, leading to severe morbidity and high mortality. Perinatal TB includes both congenital and postnatal transmission of Mycobacterium tuberculosis. We aimed to increase an awareness of TB in neonates and young infants and to provide guidance on the assessment and management when in contact with mothers with TB during or soon after pregnancy. Approximately 217,000 pregnant women develop TB annually; if they are not diagnosed and treated during pregnancy, their infants are at high risk of adverse birth outcomes and TB disease. Although safe and effective antituberculosis treatment regimens are available during pregnancy, the diagnosis of TB is challenging. Infants born to mothers newly diagnosed with TB, not receiving any effective treatment or with cultures not yet negative, should be assessed for TB disease or M. tuberculosis infection. TB preventive therapy should be instituted if the infant is clinically well but exposed to TB, while prompt initiation of TB treatment is essential if TB disease is presumed. HIV status of mother and infant should be considered as this will affect the management. Further research is needed for the diagnosis and prevention of TB during pregnancy, an early diagnosis of TB in infants, and antituberculosis drug pharmacokinetics in young infants.

Prevalence of bacteriologically-confirmed pulmonary tuberculosis in urban Blantyre, Malawi 2019-20: Substantial decline compared to 2013-14 national survey.

Recent evidence shows rapidly changing tuberculosis (TB) epidemiology in Southern and Eastern Africa, with need for subdistrict prevalence estimates to guide targeted interventions. We conducted a pulmonary TB prevalence survey to estimate current TB burden in Blantyre city, Malawi. From May 2019 to March 2020, 115 households in middle/high-density residential Blantyre, were randomly-selected from each of 72 clusters. Consenting eligible participants (household residents ≥ 18 years) were interviewed, including for cough (any duration), and offered HIV testing and chest X-ray; participants with cough and/or abnormal X-ray provided two sputum samples for microscopy, Xpert MTB/Rif and mycobacterial culture. TB disease prevalence and risk factors for prevalent TB were calculated using complete-case analysis, multiple imputation, and inverse probability weighting. Of 20,899 eligible adults, 15,897 (76%) were interviewed, 13,490/15,897 (85%) had X-ray, and 1,120/1,394 (80%) sputum-eligible participants produced at least one specimen, giving 15,318 complete cases (5,895, 38% men). 29/15,318 had bacteriologically-confirmed TB (189 per 100,000 complete-case (cc) / 150 per 100,000 with inverse weighting (iw)). Men had higher burden (cc: 305 [95% CI:144-645] per 100,000) than women (cc: 117 [95% CI:65-211] per 100,000): cc adjusted odds ratio (aOR) 2.70 (1.26-5.78). Other significant risk factors for prevalent TB on complete-case analysis were working age (25-49 years) and previous TB treatment, but not HIV status. Multivariable analysis of imputed data was limited by small numbers, but previous TB and age group 25-49 years remained significantly associated with higher TB prevalence. Pulmonary TB prevalence for Blantyre was considerably lower than the 1,014 per 100,000 for urban Malawi in the 2013-14 national survey, at 150-189 per 100,000 adults, but some groups, notably men, remain disproportionately affected. TB case-finding is still needed for TB elimination in Blantyre, and similar urban centres, but should focus on reaching the highest risk groups, such as older men.

Age-period-cohort analysis on tuberculosis cases in Japan, 1953-2022.

Age-period-cohort (APC) analysis has been employed to differentiate long-term trends in the incidences of communicable diseases, including tuberculosis (TB), into the effects of age, birth year, and calendar period. However, no such study was hitherto conducted for Japan, which has 70 years of surveillance data. Therefore, we conducted APC analysis for TB in Japan. The national TB data for 1953-2022 were analyzed using the log-transformed linear model of APC analysis. Annual age-and sex-standardized notification rates of TB peaked at 599.0 per 100 000 population in 1955 and fell by 99% to 4.5 in 2022. Adjusting for the effects of the birth cohort and period, the relative age-effect risk of TB peaked at 20-29 years and went down toward 60-69 years. Regarding the birth cohort effect, the TB risk showed a turning point in approximately 1913 for the central years of birth. Another change appeared in 1963 when the decline of the risk slightly stagnated; then, it started declining again at a rate as fast as in 1923-1953. Period effects showed a hump in the late 1950s and early 1960s, then sharply declined to the late 1970s, and reached a near plateau level until 2022. Our results highlight the continuing peak in TB disease risk for young adults and sharp decrease in disease risk in the 1960s and 70s. The introduction of anti-TB drugs in the 1950s and early 1970s had the most important impact on the epidemiology of TB in Japan.

Glycerol contributes to tuberculosis susceptibility in male mice with type 2 diabetes

Diabetes mellitus increases risk for tuberculosis disease and adverse outcomes. Most people with both conditions have type 2 diabetes, but it is unknown if type 1 and type 2 diabetes have identical effects on tuberculosis susceptibility. Here we show that male mice receiving a high-fat diet and streptozotocin to model type 2 diabetes, have higher mortality, more lung pathology, and higher bacterial burden following Mycobacterium tuberculosis infection compared to mice treated with streptozotocin or high-fat diet alone. Type 2 diabetes model mice have elevated plasma glycerol, which is a preferred carbon source for M. tuberculosis. Infection studies with glycerol kinase mutant M. tuberculosis reveal that glycerol utilization contributes to the susceptibility of the type 2 diabetes mice. Hyperglycemia impairs protective immunity against M. tuberculosis in both forms of diabetes, but our data show that elevated glycerol contributes to an additional adverse effect uniquely relevant to type 2 diabetes.

Burden of tuberculosis among vulnerable populations worldwide: an overview of systematic reviews

Tuberculosis is a communicable disease of public health concern that inequitably impacts the most vulnerable populations worldwide. Vulnerable populations are those with a high risk for tuberculosis disease and whose disadvantaged or marginalised socioeconomic position limits their access to the health system. We conducted an overview of reviews that aimed to assess the burden (ie, prevalence and incidence) of tuberculosis disease among 12 vulnerable populations globally. We did an overview of reviews using a systematic search in MEDLINE, Embase, and the Cochrane Database for Systematic Reviews for articles published in English, French, and Chinese, from Jan 1, 2010 to March 8, 2023. We did an initial search on Oct 28, 2021, and updated our search on March 8, 2023. We included systematic and scoping reviews reporting on the prevalence or incidence of active tuberculosis among 12 vulnerable populations. Evidence gaps were supplemented with primary or secondary database studies. Study characteristics and outcome data related to tuberculosis burden were tabulated, including prevalence ratios and incidence rate ratios, and evidence was synthesised narratively. This trial is registered with PROSPERO (CRD42022324421). We screened 13 169 citations and included 44 publications (23 reviews and 21 primary or database studies) in the final synthesis. The comprehensiveness and methodological quality of the evidence differed across population groups. Prevalence of more than 1000 cases per 100 000 were reported in all vulnerable populations. On the basis of pooled estimates, prevalence ratios were often more than 25 among people experiencing homelessness, incarcerated populations, refugees, asylum seekers, and people living with HIV compared with the general population. Incidence was infrequently reported, with the best-available incidence rate ratios documented for people who were incarcerated. There was scarce evidence specific to miners, nomadic populations, sex workers, men who have sex with men, and transgender individuals. The burden of tuberculosis is substantially higher among vulnerable populations than general populations, suggesting a need for improved integration of these groups, including dedicated efforts for their identification, targeted screening and prevention measures, as well as treatment support. WHO.

Preferences of healthcare workers using tongue swabs for tuberculosis diagnosis during COVID-19.

Healthcare workers (HCWs) who come into contact with tuberculosis (TB) patients are at elevated risk of TB infection and disease. The collection and handling of sputum samples for TB diagnosis poses exposure risks to HCWs, particularly in settings where aerosol containment is limited. An alternative sample collection method, tongue swabbing, was designed to help mitigate this risk, and is under evaluation in multiple settings. This study assessed risk perceptions among South African HCWs who used tongue swabbing in TB diagnostic research during the COVID-19 pandemic. We characterized their context-specific preferences as well as the facilitators and barriers of tongue swab use in clinical and community settings. Participants (n = 18) were HCWs with experience using experimental tongue swabbing methods at the South African Tuberculosis Vaccine Initiative (SATVI). We used key informant semi-structured interviews to assess attitudes toward two tongue swab strategies: Provider-collected swabbing (PS) and supervised self-swabbing (SSS). Responses from these interviews were analyzed by rapid qualitative analysis and thematic analysis methods. Facilitators included aversion to sputum (PS and SSS), perceived safety of the method (SSS), and educational resources to train patients (SSS). Barriers included cultural stigmas, as well as personal security and control of their work environment when collecting swabs in community settings. COVID-19 risk perception was a significant barrier to the PS method. Motivators for HCW use of tongue swabbing differed substantially by use case, and whether the HCW has the authority and agency to implement safety precautions in specific settings. These findings point to a need for contextually specific educational resources to enhance safety of and adherence to the SSS collection method.

Baseline Cytomegalovirus Viremia at Cryptococcal Meningitis Diagnosis Is Associated With Long-term Increased Incident TB Disease and Mortality in a Prospective Cohort of Ugandan Adults With HIV.

Adults with HIV-associated cryptococcal meningitis have overlapping burdens of cytomegalovirus (CMV) and tuberculosis (TB) coinfections. CMV infection/reactivation is strongly associated with CMV-specific memory T-cell activation and upregulation of type 1 interferons, which may lead to increased risk of TB disease and poor outcomes. We conducted a cohort study of 2-week survivors of cryptococcal meningitis during 2010-2021 to determine TB incidence and all-cause mortality over time stratified by baseline CMV status. We followed 497 Ugandans with HIV-associated cryptococcal meningitis for a median (interquartile range) of 4.6 (2.6-53.9) months. Overall, 42% (210/497) developed incident TB disease or died. One-fifth (98/497, 19.7%) developed incident TB disease, and 29% (142/497) of participants died during follow-up. Of 259 participants with CMV viral load measured at baseline, 37% (96/259) had concurrent CMV viremia (defined as anyone with detectable CMV DNA in plasma/serum by qualitative polymerase chain reaction [PCR] detection). Of 59 with measured CMV immunoglobulin G (IgG), 100% had positive CMV IgG antibody serology (≥10 enzyme-linked immunosorbent assay units/mL). CMV viremia was positively associated with higher HIV viral load (196 667 vs 73 295 copies/mL; P = .002) and higher cerebrospinal fluid fungal burden (68 500 vs 14 000 cfu/mL; P = .002) compared with those without. Participants with high-level CMV viremia (defined as CMV viral load ≥1000 IU/mL) had twice the risk of incident TB (subdistribution adjusted hazard ratio [aHR], 2.18; 95% CI, 1.11-4.27) and death (aHR, 1.99; 95% CI, 1.14-3.49) compared with participants with no or low-level CMV viremia. There was no association between the CMV IgG index and the incidence of TB/death (P = .75). CMV viremia >1000 IU/mL at meningitis diagnosis was associated with increased incident TB disease and mortality during long-term follow-up. Future studies to determine the causal relationship and potential for therapeutic intervention are warranted.

Is neglect of self-clearance biasing TB vaccine impact estimates?

BackgroundMathematical modelling has been used extensively to estimate the potential impact of new tuberculosis vaccines, with the majority of existing models assuming that individuals with Mycobacterium tuberculosis (Mtb) infection remain...

Risk of Tuberculosis Disease in People With Chronic Kidney Disease Without Kidney Failure: A Systematic Review and Meta-analysis.

Kidney failure is an established risk factor for tuberculosis (TB), but little is known about TB risk in people with chronic kidney disease (CKD) who have not initiated kidney replacement therapy (CKD without kidney failure). Our primary objective was to estimate the pooled relative risk of TB disease in people with CKD stages 3-5 without kidney failure compared with people without CKD. Our secondary objectives were to estimate the pooled relative risk of TB disease for all stages of CKD without kidney failure (stages 1-5) and by each CKD stage. This review was prospectively registered (PROSPERO CRD42022342499). We systematically searched MEDLINE, Embase, and Cochrane databases for studies published between 1970 and 2022. We included original observational research estimating TB risk among people with CKD without kidney failure. Random-effects meta-analysis was performed to obtain the pooled relative risk. Of the 6915 unique articles identified, data from 5 studies were included. The estimated pooled risk of TB was 57% higher in people with CKD stages 3-5 than in people without CKD (adjusted hazard ratio: 1.57; 95% CI: 1.22-2.03; I2 = 88%). When stratified by CKD stage, the pooled rate of TB was highest in stages 4-5 (incidence rate ratio: 3.63; 95% CI: 2.25-5.86; I2 = 89%). People with CKD without kidney failure have an increased relative risk of TB. Further research and modeling are required to understand the risks, benefits, and CKD cutoffs for screening people for TB with CKD prior to kidney replacement therapy.

Gene expression in cord blood and tuberculosis in early childhood: A nested case-control study in a South African birth cohort.

Transcriptomic profiling of adult tuberculosis patients has become increasingly common, predominantly for diagnostic and risk prediction purposes. However few studies have evaluated signatures in children, particularly in identifying those at risk for developing TB disease. We investigated the relationship between gene expression obtained from umbilical cord blood and both tuberculin skin test conversion as well as incident tuberculosis disease through the first 5 years of life. We conducted a nested case-control study in the Drakenstein Child Health Study, a longitudinal, population-based birth cohort in South Africa. We applied transcriptome-wide screens to umbilical cord blood samples from neonates born to a subset of selected mothers (n=131). Signatures identifying tuberculin conversion and risk of subsequent tuberculosis disease were identified from genome wide analysis of RNA expression. Gene expression signatures revealed clear differences predictive of tuberculin conversion (n=26) and tuberculosis disease (n=10); 114 genes were associated with tuberculin conversion and 30 genes were associated with the progression to tuberculosis disease among children with early infection. Co-expression network analysis revealed six modules associated with risk of tuberculosis infection or disease, including a module associated with neutrophil activation in immune response (p<0.0001) and defense response to bacterium (p<0.0001). These findings suggest multiple detectable differences in gene expression at birth which were associated with risk of tuberculosis infection or disease throughout early childhood. Such measures may provide novel insights into tuberculosis pathogenesis and susceptibility.

Ferritin as proinflamatory biomarker of iron metabolism in tuberculosis patients (review)

Traditional methods of tuberculosis (TB) diagnosis, including sputum microscopy and culture for Mycobacterium tuberculosis detection, are time-consuming or have unsatisfactory sensitivity. However, early diagnosis of TB with high accuracy and sensitivity is very important for disease outcomes and prevention. Therefore, there is an urgent need for new TB diagnostic methods based on TB-associated biomarkers, with rapid availability of results that do not require sputum analysis, are inexpensive, and have high sensitivity and specificity. Objective — to study the mechanisms of ferritin participation in the pathogenesis of tuberculosis basing on the literature data. Materials and methods. 242 literature sources were found in the PubMed system by the query «Ferritin AND Tuberculosis» and 40 of them were selected for further detailed study. Results and discussion. Studies have shown that serum iron and transferrin concentrations are lower and ferritin levels are higher in patients with TB compared to those without TB. These deviations in the concentration of ferritin and transferrin usually normalize after treatment. Lower transferrin levels are associated with both early and late TB progression, and higher ferritin and hepcidin levels are associated with a higher risk of early TB progression in TB contacts. In addition, the status of biomarkers of iron metabolism can be used as an indicator of treatment failure (low ferritin) and mortality (high ferritin). Finally, low levels of transferrin and serum iron, as well as high ferritin concentrations in HIV-infected patients predict an increased risk of TB disease and relapse. Conclusions. Iron metabolism between M. tuberculosis and the host organism is closely related and plays an important role in the pathogenesis of tuberculosis. Parameters of iron metabolism are promising markers of both the course and effectiveness of tuberculosis treatment. In particular, changes in the level of ferritin can be predictors of both the ineffectiveness of tuberculosis treatment and mortality from this disease, so the prognostic value of this marker requires further detailed study.

Risk of tuberculosis in children with rheumatologic diseases treated with biological agents: A cross-sectional cohort study.

This study aimed to evaluate the risk of tuberculosis (TB) disease in children receiving biological agents for rheumatologic diseases, focusing on appropriate screening tests in a high-priority country for TB control. One hundred nine children (56 females, 53 males; range, 3.4 to 16.2 years) who received any biological agent for rheumatologic diseases for more than two years between May 2012 and October 2021 were included in this retrospective study. Patients were screened for TB infection using tuberculin skin test (TST) or interferon-gamma release assay (IGRA). Following the initial evaluation, patients were clinically examined for TB every three months by a comprehensive medical history and physical examination, and every 12 months using TST or IGRA. At the initiation of the biological agent, the patients' mean age was 12.4±4.5 years. The average follow-up duration was 3.6±1.3 years (range, 2.6 to 10.2 years) for patients treated with biological agents. Each patient had a documented Bacillus Calmette-Guérin vaccination. Before the initiating of therapy, TST was performed alone in 45 (41.3%) patients and in combination with IGRA in 64 (58.7%) patients. In the 64 patients who underwent both TST and IGRA, IGRA revealed nine (14.1%) positive results. Six (66.7%) of these nine patients, however, had negative baseline TST. Four (7.3%) of the 55 individuals whose initial IGRA results were negative also had positive TST results. Overall, no TB disease was observed after a follow-up period. This study reveals that biological agents were not associated with an increased risk of TB disease in closely monitored children. Additionally, the concomitant use of TST and IGRA for screening of TB is reasonable in patients receiving biological agents.