Tuberculosis Exposure Research Articles

The impact of screening for tuberculosis exposure in the household in children with tuberculosis disease: A difficult riddle to solve.

Tuberculosis (TB) infection is transmitted by sharing the same airway with people with active TB. Children are often not considered the source of TB bacilli, and index case investigation is carried out after diagnosis. Here, we describe the impact of the presence of a household index case on childhood TB disease. The data of patients aged between 1 month and 18 years who were diagnosed with TB were collected. We compared patients according to whether they had an index case in the household or not. A total of 202 TB patients were enrolled, of whom 62 (30.7%) had a household index case. There was no significant difference in having a household index case between TB patients under the age of five (23.3%) and older children (33.8%) (p = .140). Pulmonary TB was present in 61.4% of the cases, and extrapulmonary TB was present in 38.6% of the cases. The rate of patients who had a household index case was significantly higher in pulmonary TB (46.8%) compared to extrapulmonary TB (5.1%) (p < .001). Pulmonary TB patients with a history of household contact were more likely to have diagnostic radiological findings (93.1%) compared to those without (75.8%) (p = .009). However, pulmonary TB patients without household contact history had a higher rate of diagnostic microbiological findings (59.1%) and constitutional symptoms (63.6%) (p = .019 and p = .013, respectively). Household contact research is an important epidemiological tool. However, considering the contact rates in the household, new and more comprehensive public health programs are required to prevent the spread of childhood tuberculosis.

Acute appendicitis due to extrapulmonary tuberculosis

Introduction and ImportanceTuberculous appendicitis is very infrequent, estimated to occur in only 0.1% of all appendectomies. Appendicular tuberculosis can manifest as either a primary or secondary infection. Primary appendicular tuberculosis is even more uncommon and occurs in the absence of any detectable primary focus elsewhere in the body. Case presentationIn this report, we present a challenging case of primary tuberculous appendicitis that does not appear to have originated from the lungs. This case highlights the importance of considering tuberculosis in the differential diagnosis of appendicitis, especially in regions where tuberculosis is endemic or in patients with a history of tuberculosis exposure. Clinical DiscussionDiagnosing tuberculous appendicitis can be challenging due to its rarity and the non-specific nature of its symptoms, which often mimic those of more common conditions such as acute appendicitis and because of these non-specific symptoms, tuberculous appendicitis is mostly diagnosed only after surgical intervention. ConclusionThis case underscores the need for a high index of suspicion and thorough diagnostic evaluation in patients with atypical presentations of appendicitis specifically in patients with chronic complaints. Treatment typically involves a combination of surgical intervention to remove the affected appendix and a prolonged course of anti-tuberculous medication to eradicate the infection and prevent recurrence.

Risk of tuberculosis after achieving HIV virological suppression on antiretroviral therapy: a Danish nationwide prospective cohort study.

In countries with low tuberculosis (TB) burden, the risk of TB in people with HIV (PWH) once HIV virological suppression is achieved is not fully understood. In a nationwide cohort, we included all adult PWH from the Danish HIV Cohort initiating antiretroviral therapy (ART) (1995-2017) without prior TB disease. We used Kaplan-Meier estimation and Poisson regression to calculate TB incidence rate (IR) after six months of ART, along with associated risk factors and mortality rates (MR). Among 6,849 PWH initiating ART (median follow-up 7.4 years), 84 developed TB (IR 1.4/1000 person-year [PY]), 54 of them beyond six months of ART initiation, IR 0.97/1000 PY (95%CI:1.17-1.79): 1.95 (95%CI:1.34-2.76) in non-Danish born, 0.36 (95%CI:0.21-0.62) in Danish-born without injection drug use (IDU), and 2.95 (95%CI:1.53-5.66) in Danish-born with IDU. Danish-born with suppressed viremia, and no IDU or known TB exposures had the lowest risk (IR 0.05/1000 PY).In the adjusted analysis, being non-Danish born (aIRR 4.27[95%CI:2.36-7.72]), IDU (aIRR 4.95[95%CI:2.55-9.62]), and previous AIDS-defining events (aIRR 2.05[95%CI:1.06-3.94]) raised TB risk, while suppressed HIV-RNA (aIRR 0.58[95%CI:0.34-0.99]) reduced it. The overall MR for HIV/TB co-infected post- ART was high, at 48.9/1000 PY (95%CI:30.4-78.7). The TB risk remains elevated in PWH beyond six months of ART initiation, especially among migrants, IDU, those without suppressed HIV-RNA, and individuals exposed to high TB endemic areas or with social risk determinants of health. Conversely, PWH without these risk factors have a TB risk similar to the general population and would not require targeted TB screening strategies.

Review Based Study of Prevalence and Association of Social Determinants with Tuberculosis in Doda Region of Jammu and Kashmir, India

Tuberculosis (TB) continues to rank among the world’s most serious health problems caused by Mycobacterium tuberculosis. There are several factors which are responsible for the exposure of tuberculosis among the communities. Human immunodeficiency virus (HIV) is one of the major factors for the exposure of tuberculosis disease among the persons. Worldwide, TB is one of the leading causes of death among people living with HIV. Tuberculosis is a serious health threat, especially for the people living with HIV. The socio-economic determinants such as unemployment, malnutrition and crowding play a significant role in increasing the rate of infection. In this article, we will discuss the socio-economic determinants of tuberculosis infection and disease. The rapidly growing consensus indicates that in the low and middle income country, the tuberculosis control programs are required with the investment in tuberculosis diagnostics and treatment in addition to action on the social determinants of tuberculosis. Tuberculosis is most common among the disadvantaged group which includes the poor, ethnic minorities as well as hungry.

Clinical Characteristics of Patients with Nontuberculous Mycobacterium Pulmonary Disease in Fuyang, China: A Retrospective Study.

We retrospectively review consecutive patients with nontuberculous mycobacterium (NTM) pulmonary disease reported from a designated hospital for infectious diseases in the Fuyang district of China to determine the clinical characteristics of these patients. This research enrolled 234 patients with NTM pulmonary disease between January 2018 and May 2023 in the Fuyang district of China. Data were collected from the electronic medical records. The NTM strain composition and clinical characteristics of NTM pulmonary disease were retrospectively analyzed. 73 (31.20%) patients had previous tuberculosis (TB) or TB exposure history and bronchiectasis. Mixed NTM infection accounted for 12.39%. Mycobacterium intracellulare strain was detected in 132 patients (49.62%). Women were found to be more affected by Mycobacterium avium infection, and men by Mycobacterium abscessus infection. Mycobacterium avium (34.21%) and Mycobacterium abscessus (33.33%) strains were most common in people with previous TB or TB exposure history. Among respiratory tract-related diseases, patients with bronchiectasis had the highest isolation rate of Mycobacterium avium (55.36%). Women were susceptible to bronchiectasis (P <0.01). The median of mononuclear-to-lymphocyte ratio (MLR) was higher in men than in women (P < 0.01). The serum albumin (ALB) level was lower in patients with TB or TB exposure history than in those without TB history (P = 0.034). The prognostic nutritional index (PNI) was lower in patients with TB or TB exposure history than in those without tuberculosis history (P = 0.021). Patients with NTM lung disease were poorly treated. Clinical symptoms of the disease were not species-specific. Mycobacterium intracellulare and Mycobacterium avium strains were predominant in the Fuyang district of China. Previous TB or TB exposure history immensely enhanced the risk of NTM disease.

SARS-CoV-2 coinfection in children with severe airway obstruction due to pulmonary tuberculosis.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic had a significant impact on tuberculosis (TB) control globally, with the number of new TB diagnoses decreasing. Coinfection with some viruses, especially measles, could aggravate TB in children. This is presumably a result of depressed cellular immunity. Reports on children with TB and SARS-CoV-2 coinfection are limited. A retrospective analysis of children up to 13 years old admitted to Tygerberg Hospital, Cape Town, South Africa, from March 2020 to December 2022 with suspected TB-induced airway compression requiring bronchoscopy. Children were included if they presented with severe intrathoracic airway obstruction and/or radiographic evidence of complicated TB. The patients were divided into two groups based on SARS-CoV-2 respiratory polymerase chain reaction results. Demographics, TB exposure, microbiology, SARS-CoV-2 laboratory data, imaging, inflammatory cytokine levels, and bronchoscopy data were collected. Statistical analyses compared SARS-CoV-2 positive and negative groups. Of the 50 children undergoing bronchoscopy for TB airway obstruction, 7 (14%) were SARS-CoV-2 positive. Cough was more prevalent in the SARS-CoV-2 positive group (p = 0.04). There was no difference in TB culture yield between groups. However, SARS-CoV-2 positive children showed slower radiological improvement at 1 month (p = 0.01), pleural effusions (p < 0.001), and a higher need for endoscopic enucleation (p < 0.001). FDG PET/CT scans indicated an ongoing inflammation in the SARS-CoV-2 positive group. Coinfection with SARS-CoV-2 in children with TB airway obstruction appears to complicate the disease course, necessitating more medical interventions and demonstrating a longer duration of the TB inflammatory process. Further research is needed to understand the impact of viral infections on TB progression and outcomes in pediatric patients.

Epigenetic programming of host lipid metabolism associated with resistance to TST/IGRA conversion after exposure to Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb) exposure leads to a range of outcomes including clearance, latent TB infection (LTBI), and pulmonary tuberculosis (TB). Some heavily exposed individuals resist tuberculin skin test (TST) and interferon-gamma (IFNγ) release assay (IGRA) conversion (RSTR), which suggests that they employ IFNγ-independent mechanisms of Mtb control. Here, we compare monocyte epigenetic profiles of RSTR and LTBI from a Ugandan household contact cohort. Chromatin accessibility did not differ between uninfected RSTR and LTBI monocytes. By contrast, methylation significantly differed at 174 CpG sites and across 63 genomic regions. Consistent with previous transcriptional findings in this cohort, differential methylation was enriched in lipid- and cholesterol-associated pathways including the genes APOC3, KCNQ1, and PLA2G3. In addition, methylation was enriched in Hippo signaling, which is associated with cholesterol homeostasis and includes CIT and SHANK2. Lipid export and Hippo signaling pathways were also associated with gene expression in response to Mtb in RSTR as well as IFN stimulation in monocyte-derived macrophages (MDMs) from an independent healthy donor cohort. Moreover, serum-derived high-density lipoprotein from RSTR had elevated ABCA1-mediated cholesterol efflux capacity (CEC) compared to LTBI. Our findings suggest that resistance to TST/IGRA conversion is linked to regulation of lipid accumulation in monocytes, which could facilitate early Mtb clearance among RSTR subjects through IFNγ-independent mechanisms.IMPORTANCETuberculosis (TB) remains an enduring global health challenge with millions of deaths and new cases each year. Despite recent advances in TB treatment, we lack an effective vaccine or a durable cure. While heavy exposure to Mycobacterium tuberculosis often results in latent TB latent infection (LTBI), subpopulations exist that are either resistant to infection or contain Mtb with interferon-gamma (IFNγ)-independent mechanisms not indicative of LTBI. These resisters provide an opportunity to investigate the mechanisms of TB disease and discover novel therapeutic targets. Here, we compare monocyte epigenetic profiles of RSTR and LTBI from a Ugandan household contact cohort. We identify methylation signatures in host lipid and cholesterol pathways with potential relevance to early TB clearance before the sustained IFN responses indicative of LTBI. This adds to a growing body of literature linking TB disease outcomes to host lipids.

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.

Village as Contextual Factors and Other Risk Factors Related with the Incidence of Clinical Tuberculosis in Children in Wonogiri, Central Java: A Multilevel Analysis

Background: Indonesia is in the second rank with the highest burden of tuberculosis (TB) in the world. Childhood is a period of rapid growth, the body still has a low immune system so it is susceptible to disease including tuberculosis in children which requires control efforts. This study aims to analyze the influence of risk factors and village contextual factors on the incidence of TB in children.Subjects and Method: Case-control study research was conducted in 82 villages in Wonogiri Regency, from November to December 2023. A sample of 200 children aged 0 to 4 years old was selected through fixed disease sampling. The dependent variable of this study was the incidence of TB in children. The independent variables in this study were stunting, contact history, exposure to cigarette smoke, home sanitation, gender, parental education, child age, parental income, BCG immunization status, and village contextual influences. Data on TB disease was obtained from the Tuberculosis Information System Application (SITB) at the Wonogiri District Health Service in 2023. Other data was collected through questionnaires. The data analysis was done through multilevel multiplelogistic regression.Results: The factors that increased the incidence of TB in children were stunting (OR= 10.94; CI 95%= 2.50 to 47.90; p= 0.001), contact history to TB (OR= 8.37; CI 95%= 1.60 to 43.83; p= 0.012), and exposure to cigarette smoke (OR= 7.36; CI 95%= 1.99 to 27.14; p= 0.003). The reducing factors were healthy sanitation (OR= 0.24; CI 95%= 0.08 to 0.78; p= 0.017), female children (OR= 0.40; CI 95%= 0.15 to 1.05; p= 0.062), and parents with ≥high school education (OR= 0.40; CI 95%= 0.15 to 1.05; p= 0.062). There was no relationship between age (OR= 0.93; CI 95%= 0.13 to 6.23; p= 0.940), parental income (OR= 1.14; CI 95%= 0.40 to 3.25; p= 0.807), and BCG immunization status (OR= 0.12; CI 95%= 0.00 to 105.98; p= 0.550). Village has a contextual influence on the incidence of clinical TB in children (ICC= 52.95%).Conclusion: The risk of clinical TB in children increased with stunting, a history of TB contact and exposure to cigarette smoke, it decreased with healthy home sanitation, female gender, parents with ≥high school education. There was no relationship between age, parental income, and BCG immunization status. The village has a contextual effect on the incidence of clinical TB in children.

Not Your Usual Exposure: Tuberculosis Contact Investigation Related to Contaminated Bone Allograft

Background: Mycobacterium tuberculosis transmission through contaminated bone allograft product is unusual and was first described in 2021 with a second outbreak in 2023. In July 2023, Michigan Medicine conducted contact tracing for healthcare personnel (HCP), patients, and visitors following exposure to an immunocompromised patient with surgical site infection and subsequent widely disseminated tuberculosis (bacteremia, pulmonary, lymphadenopathy) following spinal fusion with bone allograft in April 2023. The patient was in the emergency department, operating room (OR), and inpatient units for 9 days prior to initiation of Airborne Precautions (AP). Methods: Michigan Medicine is a 1,107 bed academic hospital. HCP are screened for tuberculosis with interferon-gamma release assay (IGRA) testing upon hire and following tuberculosis exposure. Exposure testing includes baseline IGRA testing and follow-up testing at 10-12 weeks post exposure. Exposure criteria for this investigation was defined as sharing room airspace with the tuberculosis patient prior to initiation of airborne precautions or Central Sterile Processing Department (CSPD) staff involved with instrument decontamination without the use of a respirator. Of note, universal masking with surgical masks was not required during this time for staff and patients/visitors, with the exception of CSPD and OR staff. Contact tracing was performed by Infection Prevention and Occupational Health Services managed all test results and conversions. Results: 176 employees from perioperative care areas (n=30), CSPD (n=7), OR (n=9) and inpatient units (n=130) were IGRA tested. Five employee conversions were identified: one surgeon, one circulating OR nurse, two CSPD decontamination staff, and one respiratory therapist. At time of detection, none of the conversions had evidence of active tuberculosis. Additionally, 46 patients and visitors were tested with zero conversions. HCP compliance with IGRA testing was initially 15% before engagement from hospital and unit leadership and human resources. With intervention, employee compliance reached 100%. Conclusion: Despite standard use of surgical masks for OR and CSPD staff, aerosolization of infected bone graft material played an important role in tuberculosis transmission during surgery and instrument cleaning. Respiratory therapy practices in the ICU setting likely also increased risk for pulmonary tuberculosis transmission. Achieving 100% HCP compliance for baseline and follow-up IGRA testing is challenging and requires engagement of both unit and hospital leadership and human resources to ensure all HCP are tested.

Host and pathogen factors that influence variability of Mycobacterium tuberculosis lipid body content in sputum from patients with tuberculosis: an observational study

High proportions of Mycobacterium tuberculosis cells in sputum containing triacylglycerol-rich lipid bodies have been shown to be associated with treatment failure or relapse following antituberculous chemotherapy. Although lipid body determination is a potential biomarker for supporting clinical trial and treatment decisions, factors influencing variability in sputum frequencies of lipid body-positive (%LB+) M tuberculosis in patients are unknown. We aimed to test our hypothesis that exposure to host-generated NO and M tuberculosis strains are factors associated with differences in sputum %LB+. In this observational study, we determined %LB+ frequencies before treatment by microscopy in patients with smear-positive tuberculosis from two separate prospective observational study settings (Gondar, Ethiopia, recruited between May 1, 2010, and April 30, 2011, and Fajara, The Gambia, who provided sputum samples before treatment between May 5, 2010, and Dec 22, 2011). In Ethiopia, fractional exhaled nitric oxide (FeNO) was measured as a biomarker of host NO, and M tuberculosis strain differences were determined by spoligotyping. Treatment response was assessed by percentage weight change after 7 months. In The Gambia, treatment responses were assessed as change in BMI and radiographic burden of disease after 6 months. Sputum Mtuberculosis isolates were studied invitro for their %LB+ and triacylglycerol synthase 1 (tgs1) mRNA responses to NO exposure. Propidium iodide staining was used as a measure of NO strain toxicity. Correlation between invitro %LB+ frequencies following NO exposure and those of the same strain in sputum was examined with linear regression and Dunnett's multiple comparison test. In Ethiopia, 73 patients who were smear positive for pulmonary tuberculosis were recruited (43 [59%] were male and 30 [41%] were female). Of these, the %LB+ in the sputum of 59 patients showed linear correlation with log10 FeNO (r2=0·28; p<0·0001) and an association with strain spoligotype was suggested. Seven Mtuberculosis strains from The Gambia showed different dose-responses to NO invitro, demonstrated by changing lipid body content, tgs1 transcription, and bacterial toxicity. In sputum %LB+ frequencies correlated with invitro %LB+ responses to NO of the corresponding isolate. In a subset of 34 patients across both cohorts, higher sputum %LB+ frequencies before treatment were associated with weaker responses to treatment than lower sputum %LB+ frequencies. M tuberculosis strain and exposure to host-generated NO are associated with sputum %LB+. Our results support the use of M tuberculosis strain-dependent sputum %LB+ as a predictive biomarker of treatment response. The Medical Research Council, the University of Leicester, and the University of Gondar.

The Tuberculous Synovitis of the Elbow: A Misunderstood Entity

We present the case of a 7-year-old child with a history of tuberculosis exposure, admitted to the pediatric surgery department due to a chronic swelling of the right elbow persisting for 3 years. Despite being afebrile, the patient experienced unspecified weight loss. Clinical examination revealed a painful fluctuating swelling of the right elbow, limited flexion, and a 12-degree valgus deformity of the ulna. Laboratory tests showed an elevated CRP level indicative of an inflammatory process. Standard radiographs exhibited soft tissue hypertrophy without bone lesions. MRI demonstrated synovial hypertrophy of the right elbow joint with adjacent bone marrow infiltration and deformation of the distal humerus. Biopsy revealed nonspecific chronic synovitis. Surgical removal of the synovial mass was performed, and histopathological examination revealed features suggestive of tuberculosis. Extension studies for tuberculosis were negative. The patient was treated with antituberculous therapy and physiotherapy, leading to the regression of symptoms. This case highlights the diagnostic utility of MRI in detecting synovial hypertrophy and bone marrow infiltration in cases of chronic elbow swelling, especially in the context of tuberculosis exposure.

Predictors of positive tuberculin skin test in neonates exposed to pulmonary tuberculosis.

Neonates are at risk of nosocomial tuberculosis (TB) infection from health care workers (HCWs) in neonatal care facilities, which can progress to severe TB diseases. Tuberculin skin test (TST) is commonly used for TB diagnosis, but its accuracy in neonates is influenced by various factors, including bacilli Calmette-Guérin (BCG) vaccination. This study aimed to identify predictors of positive TSTs in neonates exposed to HCWs with pulmonary TB. A retrospective observational study was conducted to compare the frequency of predictors between TST-positive and TST-negative neonates. Demographic, epidemiological, and clinical data of neonates exposed to TB, along with that of HCW and household contacts, were collected retrospectively through contact investigations with the Korean National TB Surveillance System (KNTSS) database. TSTs using 2 tuberculin units of purified protein derivative RT23 were performed on exposed neonates at the end of preventive TB treatment. Firth logistic regression was performed to identify predictors of TST positivity. Contact investigations revealed that 152 neonates and 54 HCWs were exposed to infectious TB index cases in 3 neonatal care facilities. Of 152 exposed neonates, 8 (5.3%) had positive TST results. Age of 6 days or more at the initial exposure is a statistically significant predictor of positive TST (Firth coefficient 2.1, 95% confidence interval 0.3-3.9, P = 0.024); BCG vaccination showed no statistical significance in both univariable and multivariable analysis. Sex, prematurity, exposure duration, duration from initial exposure to contact investigation, and isoniazid preventive treatment duration were not significant predictors. Age at the initial exposure is a significant predictor of positive TST in neonates exposed to active pulmonary TB. Given the complexities of TST interpretation, including false positives due to BCG vaccination, careful risk assessment is necessary for appropriate decision-making and resource allocation in the management of neonatal TB exposure.

Type 2 diabetes mellitus and recurrent Tuberculosis: A retrospective cohort in Peruvian military workers

BackgroundThe role played by type 2 diabetes mellitus (DM2) in the occurrence of recurrent tuberculosis is still uncertain. Military personnel are an occupational group with an increased risk for tuberculosis exposure due to their activities. Methods. We conducted a retrospective cohort to study the association between DM2 and recurrent TB in military workers who have been previously treated for tuberculosis at the Central Military Hospital in Lima, Peru, between 2016 and 2017. We evaluated the risk between DM2 and recurrent TB using Nelson-Aalen graphical analysis and Cox regression stratified by TB cured with hazard ratio (HR) calculation adjusted for confounders. Results. We evaluated 220 workers with a mean age of 23.2 ± 7.8 years (96.8 % male). DM2 and recurrent TB frequency were 11.8 % and 5.0 %, respectively. Those with DM (36.5 %) presented a greater proportion of recurrent TB than those without DM2 (10.5 %). The cumulative risk for recurrent TB increases faster among workers with DM2 (p = 0.025, LR chi-squared test). Cox regression stratified by type of cured TB did not show an association between DM2 and recurrent TB (HR: 3.67; 95 %CI: 1.00–13.46). Conclusion. The cumulative risk for recurrent TB increases faster in patients with DM than in those without DM2. DM2 is not associated with the time of apparition of recurrent TB in military workers.

Mycobacterium tuberculosis-dependent monocyte expression quantitative trait loci, cytokine production, and TB pathogenesis.

The heterogeneity of outcomes after Mycobacterium tuberculosis (Mtb) exposure is a conundrum associated with millennia of host-pathogen co-evolution. We hypothesized that human myeloid cells contain genetically encoded, Mtb-specific responses that regulate critical steps in tuberculosis (TB) pathogenesis. We mapped genome-wide expression quantitative trait loci (eQTLs) in Mtb-infected monocytes with RNAseq from 80 Ugandan household contacts of pulmonary TB cases to identify monocyte-specific, Mtb-dependent eQTLs and their association with cytokine expression and clinical resistance to tuberculin skin test (TST) and interferon-γ release assay (IGRA) conversion. cis-eQTLs (n=1,567) were identified in Mtb-infected monocytes (FDR<0.01), including 29 eQTLs in 16 genes which were Mtb-dependent (significant for Mtb:genotype interaction [FDR<0.1], but not classified as eQTL in uninfected condition [FDR≥0.01]). A subset of eQTLs were associated with Mtb-induced cytokine expression (n=8) and/or clinical resistance to TST/IGRA conversion (n=1). Expression of BMP6, an Mtb-dependent eQTL gene, was associated with IFNB1 induction in Mtb-infected and DNA ligand-induced cells. Network and enrichment analyses identified fatty acid metabolism as a pathway associated with eQTL genes. These findings suggest that monocyte genes contain Mtb-dependent eQTLs, including a subset associated with cytokine expression and/or clinical resistance to TST/IGRA conversion, providing insight into immunogenetic pathways regulating susceptibility to Mtb infection and TB pathogenesis.

Exposure of Mycobacterium tuberculosis to human alveolar lining fluid shows temporal and strain-specific adaptation to the lung environment

Upon infection, Mycobacterium tuberculosis (M.tb) reaches the alveolar space and comes in close contact with the lung mucosa or human alveolar lining fluid (ALF) for an uncertain period of time prior to its encounter with alveolar cells. We showed that homeostatic ALF hydrolytic enzymes modify the M.tb cell envelope, driving M.tb-host cell interactions. Still, the contribution of ALF during M.tb infection is poorly understood. Here, we exposed 4 M.tb strains with different levels of virulence, transmissibility, and drug resistance (DR) to physiological concentrations of human ALF for 15-min and 12-h, and performed RNA sequencing. Gene expression analysis showed a temporal and strain-specific adaptation to human ALF. Differential expression (DE) of ALF-exposed vs. unexposed M.tb revealed a total of 397 DE genes associated with lipid metabolism, cell envelope and processes, intermediary metabolism and respiration, and regulatory proteins, among others. Most DE genes were detected at 12-h post-ALF exposure, with DR-M.tb strain W-7642 having the highest number of DE genes. Interestingly, genes from the KstR2 regulon, which controls the degradation of cholesterol C and D rings, were significantly upregulated in all strains post-ALF exposure. These results indicate that M.tb-ALF contact drives initial bacterial metabolic and physiologic changes, which may have implications in the early events of M.tb infection.

Incidence and Risk Factors of Active Tuberculosis Among Hospitalized Patients with Latent Tuberculosis Infection in China: A Cohort Study.

The population with latent tuberculosis infection (LTBI) represents a potential pool of patients with active tuberculosis (ATB). T-SPOT.TB is an important test tool for screening LTBI. Owing to the large population of LTBI patients in China, it is necessary to identify a high-risk group for LTBI and enlarge tuberculosis preventive treatment (TPT) to reduce the incidence of ATB. Hospitalized patients with positive T-SPOT.TB results were recruited from January 2013 to December 2016. Patients with ATB were excluded. Basic information was collected and the development of ATBs was examined during follow-up. The life-table method was used to calculate cumulative incidence rates. Potential risk factors were analyzed through Cox regression analysis. A total of 1680 patients with LTBI were recruited in the follow-up cohort, and 377 (22.44%) patients dropped out. With a median follow-up time of 81 months [interquartile range (IQR):61-93], 19 of 1303 patients with LTBI developed ATB. The 1-year incidence of ATB was 614 per 100,000 individuals [95%confidence interval (95% CI):584-644]. Over 5-year period, the cumulative incidence of ATB was 1496 per 100,000 [95% CI:1430-1570], and the incidence density was 240 per 100,000 person-years[95% CI:144-375]. In the Cox regression model, exposure of pulmonary tuberculosis (PTB) [adjusted hazard ratio (aHR)=10.557, 95% CI:2.273-49.031], maximum daily dosage of glucocorticoids (GCs)≥ 50 mg/d (aHR=2.948, 95% CI:1.122-7.748), leflunomide (LEF) treatment (aHR=8.572, 95% CI:2.222 -33.070), anemia (aHR=2.565, 95% CI:1.015-6.479) and T-SPOT.TB level≥300SFCs/106 PBMCs (aHR=4.195, 95% CI:1.365-12.892) were independent risk factors for ATB development in LTBI patients. The incidence of ATB is significantly higher in hospitalized patients with LTBI than in the general population. The exposure history of PTB, maximum daily dosage of GCs≥ 50 mg/day, LEF treatment, anemia, and T-SPOT.TB level≥300SFCs/106PBMCs, were the risk factors of tuberculosis reactivation. Hospitalized LTBI patients with the above factors may need TPT.

Interferon-gamma release assay conversion after Mycobacterium tuberculosis exposure specifically associates with greater risk of progression to tuberculosis: A prospective cohort study in Leicester, UK

ObjectivesWe investigated whether quantifying the serial QuantiFERON-TB Gold (QFT) response improves tuberculosis (TB) risk stratification in pulmonary TB (PTB) contacts. MethodsA total of 297 untreated adult household PTB contacts, QFT tested at baseline and 3 months after index notification, were prospectively observed (median 1460 days). Normal variance of serial QFT responses was established in 46 extrapulmonary TB contacts. This informed categorisation of the response in QFT-positive PTB contacts as converters, persistently QFT-positive with significant increase (PPincrease), and without significant increase (PPno-increase). ResultsIn total, eight co-prevalent TB (disease ≤3 months after index notification) and 12 incident TB (>3 months after index notification) cases were diagnosed. Genetic linkage to the index strain was confirmed in all culture-positive progressors. The cumulative 2-year incident TB risk in QFT-positive contacts was 8.4% (95% confidence interval, 3.0-13.6%); stratifying by serial QFT response, significantly higher risk was observed in QFT converters (28%), compared with PPno-increase (4.8%) and PPincrease (3.7%). Converters were characterised by exposure to index cases with a shorter interval from symptom onset to diagnosis (median reduction 50.0 days, P = 0.013). ConclusionsQFT conversion, rather than quantitative changes of a persistently positive serial QFT response, is associated with greater TB risk and exposure to rapidly progressive TB.

Household air pollution exposure and risk of tuberculosis: a case–control study of women in Lilongwe, Malawi

IntroductionGlobally, 3–4 billion people rely on solid fuels for cooking, and 1 billion use kerosene to light their homes. While household air pollution (HAP) emitted from burning these fuels has...

Isoniazid preventive therapy during infancy does not adversely affect growth among HIV-exposed uninfected children: Secondary analysis of data from a randomized controlled trial.

Isoniazid preventive therapy (IPT) decreases risk of tuberculosis (TB) disease; impact on long-term infant growth is unknown. In a recent randomized trial (RCT), we assessed IPT effects on infant growth without known TB exposure. The infant TB Infection Prevention Study (iTIPS) trial was a non-blinded RCT among HIV-exposed uninfected (HEU) infants in Kenya. Inclusion criteria included age 6-10 weeks, birthweight ≥2.5 kg, and gestation ≥37 weeks. Infants in the IPT arm received 10 mg/kg isoniazid daily for 12 months, while the control trial received no intervention; post-trial observational follow-up continued through 24 months of age. We used intent-to-treat linear mixed-effects models to compare growth rates (weight-for-age z-score [WAZ] and height-for-age z-score [HAZ]) between trial arms. Among 298 infants, 150 were randomized to IPT, 47.6% were females, median birthweight was 3.4 kg (interquartile range [IQR] 3.0-3.7), and 98.3% were breastfed. During the 12-month intervention period and 12-month post-RCT follow-up, WAZ and HAZ declined significantly in all children, with more HAZ decline in male infants. There were no growth differences between trial arms, including in sex-stratified analyses. In longitudinal linear analysis, mean WAZ (β = 0.04 [95% CI:-0.14, 0.22]), HAZ (β = 0.14 [95% CI:-0.06, 0.34]), and WHZ [β = -0.07 [95% CI:-0.26, 0.11]) z-scores were similar between arms as were WAZ and HAZ growth trajectories. Infants randomized to IPT had higher monthly WHZ increase (β to 24 months 0.02 [95% CI:0.01, 0.04]) than the no-IPT arm. IPT administered to HEU infants did not significantly impact growth outcomes in the first two years of life.