Contacts Of Pulmonary Tuberculosis Cases Research Articles

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.

Factors Associated with Non-Adherence to Tuberculosis Preventive Treatment among Adult Contacts of Pulmonary Tuberculosis Cases with Latent Tuberculosis Infection in Catalonia, Spain, in 2019-2021.

The aim of this study was to identify factors associated with non-adherence to tuberculosis (TB) preventive treatment among contacts with latent TB infection for new cases of pulmonary TB cases reported in Catalonia in 2019-2021. All contacts aged 18 years or older with a latent TB infection who received a TB preventive treatment were included in the study. The Chi square test and the odds ratios (OR) were used to assess the association between non-adherence to TB preventive treatment and the study variables; a p < 0.05 was considered statistically significant. Multiple logistic regression analysis was used to detect the independent factors associated with TB preventive treatment non-adherence; a p < 0.05 was considered statistically significant. The percentage of non-adherence to TB preventive treatment found in this study was 23.7%. A multivariable logistic regression analysis determined that the following factors were significantly associated with TB preventive treatment non-adherence among adult contacts: "exposure at school or workplace" (aOR = 3.34), "exposure to an index case without laboratory confirmation of TB" (aOR = 2.07), "immigrant contact" (aOR = 1.81), "male gender" (aOR = 1.75) and "exposure duration < 6 h per week or sporadic" (aOR = 1.60. By contrast, the factor "short-term TB preventive treatment regimen" (aOR = 0.38) was significantly associated with a lower treatment non-adherence. Adherence to TB preventive treatment should be improved among adult contacts of TB pulmonary cases with latent TB infection by recommending short-term treatment regimens and by developing health education activities, with a greater focus on contacts with factors associated with treatment non-adherence.

Host blood-based biosignatures for subclinical TB and incipient TB: A prospective study of adult TB household contacts in Southern India.

A large proportion of the global tuberculosis (TB) burden is asymptomatic and not detectable by symptom-based screening, driving the TB epidemic through continued M. tuberculosis transmission. Currently, no validated tools exist to diagnose incipient and subclinical TB. Nested within a large prospective study in household contacts of pulmonary TB cases in Southern India, we assessed 35 incipient TB and 12 subclinical TB cases, along with corresponding household active TB cases (n=11), and household controls (n=39) using high throughput methods for transcriptional and protein profiling. We split the data into training and test sets and applied a support vector machine classifier followed by a Lasso regression model to identify signatures. The Lasso regression model identified an 11-gene signature (ABLIM2, C20orf197, CTC-543D15.3, CTD-2503O16.3, HLADRB3, METRNL, RAB11B-AS1, RP4-614C10.2, RNA5SP345, RSU1P1, and UACA) that distinguished subclinical TB from incipient TB with a very good discriminatory power by AUCs in both training and test sets. Further, we identified an 8-protein signature comprising b-FGF, IFNγ, IL1RA, IL7, IL12p70, IL13, PDGF-BB, and VEGF that differentiated subclinical TB from incipient TB with good and moderate discriminatory power by AUCs in the training and test sets, respectively. The identified 11-gene signature discriminated well between the distinct stages of the TB disease spectrum, with very good discriminatory power, suggesting it could be useful for predicting TB progression in household contacts. However, the high discriminatory power could partly be due to over-fitting, and validation in other studies is warranted to confirm the potential of the immune biosignatures for identifying subclinical TB.

Determinants of losses in the tuberculosis infection cascade of care among children and adolescent contacts of pulmonary tuberculosis cases: A Brazilian multi-centre longitudinal study

Approximately 10% of the global tuberculosis (TB) burden is in children. Identification, diagnosis, and early treatment of Mycobacterium tuberculosis infection (TBI) is critical to prevent progression to TB in children. The risk of TB, including severe disease, is highest in children <5 years old. We evaluated the cascade of TBI care among child and adolescent TB contacts to identify factors associated with losses in the cascade. Close contacts ≤ 18 years old of pulmonary TB patients enrolled between 2015 and 2019 in a multi-centre Brazilian cohort were followed for up to 24 months and classified according to age groups: <5 years, 5-9 years, 10-14 years and 15-18 years. Data on clinical investigation, radiographic examination, IGRA testing at baseline and 6 months, initiation and completion of TB preventive treatment (TPT) were collected. Multivariable regression analyses identified factors associated with TBI and losses in the cascade of care in children and adolescents. Among 1795 TB contacts initially identified, 530 (29·5%) were ≤18 years old. Losses for all steps in the cascade were especially high in children <5 years old (88%) because at this age all contacts are recommended to initiate TPT. As a proportion of all children, completion of TPT was low (between 10% and 13%) in all age-groups. Furthermore, multivariable regression revealed that younger age of contacts and TB index cases who were female, had pulmonary cavities, and persistent cough were independently associated with losses in the cascade of care among persons ≤18 years old. Losses in the TBI cascade were the highest among children <5 years, which was the group at highest risk for TB among the four age groups. The findings highlight the need to improve screening, initiation, and completion of TPT of young children who are close contacts of people with TB in Brazil. National Institutes of Allergy and Infectious Diseases.

Determinants of Losses in the Tuberculosis Infection Cascade of Care Among Children and Adolescent Contacts of Pulmonary Tuberculosis Cases in Brazil

Determinants of Losses in the Tuberculosis Infection Cascade of Care Among Children and Adolescent Contacts of Pulmonary Tuberculosis Cases in Brazil

Evaluation of Interleukin-2 to Detect Active and Latent Tuberculosis among Household Contacts of Pulmonary Tuberculosis Cases

Background: The interferon-gamma release assays (IGRAs) are the most important diagnostic approach to Mycobacterium tuberculosis infection diagnosis. However, they cannot discriminate between latent tuberculosis infection (LTBI) and active tuberculosis (TB). Some recent studies suggested that interleukin-2 (IL-2) response to M. tuberculosis could be utilized as a potential biomarker to discriminate active disease from LTBI. Objectives: The current study aimed at evaluating the potential role of IL-2 to detect both active TB and LTBI among household contacts of patients with pulmonary TB in two TB-endemic regions of Iran. Methods: A total of 650 household contacts of patients with TB were invited to participate in the current study. All subjects were diagnosed on extensive clinical evaluation of active TB and LTBI based on clinical manifestations and laboratory findings. The IGRA test was performed using QuantiFERON®-TB Gold Plus. The serum level of IL-2 was measured using the ELISA Development Kit. Results: A total of 237 household contacts entered the final analysis, including 132 patients with LTBI and three with active TB. In addition, 14 subjects were included as TB controls and 102 as TB-uninfected controls. The serum level of IL-2 was significantly higher in active TB and LTBI patients than TB-uninfected controls. The ROC curve was plotted between active TB and LTBI, revealing that the cutoff point of 25.5 pg/mL identifies the active form with 88.24% sensitivity and 36.36% specificity. Conclusions: The current study indicated that the IL-2 assay could not discriminate between active TB and LTBI with acceptable sensitivity.

Tuberculosis in children: screening, diagnosis and management.

The present review focuses on recent advances and current challenges in screening, diagnosis and management of tuberculosis (TB) in children, encompassing TB infection and TB disease, and public health priorities for screening and family engagement. Although awareness has improved in recent years that children in TB endemic areas suffer a huge disease burden, translation into better prevention and care remains challenging. Recent WHO guidelines have incorporated screening of all household contacts of pulmonary TB cases, but implementation in high incidence settings remains limited. Improved tests using noninvasive samples, such as the lateral flow urinary lipoarabinomannan assay and the new Xpert Ultra assay applied to induced sputum or stool in young children, are showing promise and further assessment is eagerly awaited. From a treatment perspective, child-friendly dispersible fixed dose combination tablets are now widely available with excellent acceptability and tolerance reported in young children. High-level government commitment to TB control as a public health priority and feasible strategies to achieve this are required to contain the global epidemic, whereas strong engagement of local TB clinics and affected families in TB prevention is essential to limit secondary cases and protect exposed children.

Latent tuberculosis among household contacts of pulmonary tuberculosis cases in Nairobi, Kenya.

IntroductionHousehold Contacts (HHCs) of Pulmonary Tuberculosis (PTB) patients have a higher risk of latent tuberculosis infection (LTBI). However, its prevalence and risk factors among adults living with PTB patients are poorly documented in Kenya.Objectiveto determine the prevalence and risk factors for LTBI among adult HHCs of PTB patients in Kenya.Methodsthis was an analytical cross-sectional study of HHCs of PTB patients in Nairobi, Kenya. Socio-demographic data was captured on questionnaires and blood samples drawn for Interferon gamma (IFN-γ) quantification. Univariate and multivariate analyses using the Statistical Package for Social Scientists (SPSS) was used to determine the prevalence of LTBI and risk factors at 95% Confidence Interval (CI).Resultsa total of 166 PTB patients yielded 175 HHCs of whom 29.7% (52/125) were males and 70.3% (123/125) were females. A majority of HHCs [65.7% (115/175)] lived in a single-room house with the patient and [37.7% (66/175)] were in the age group 30-39-years. The overall prevalence of LTBI was 55.7%, peaking among spouses of the patients [70.0% (14/20) and the 30-39 year age group [63.5% (42/66)]. Potential risk factors for LTBI included cohabiting with a PTB patient for 8 to 12 weeks [OR = 3.6 (0.70-18.5), p = 0.107], being a spouse of the patient [OR = 2.0 (0.72-5.47), p = 0.173] and sharing a single room with the patient [OR = 1.58 (0.84 - 2.97), p = 0.158].Conclusionthe high prevalence of LTBI among adult HHCs of PTB patients in this population demonstrates the need for targeted contact-screening programs in high TB transmission settings.

A population-based tuberculosis contact investigation in the country of Georgia

Setting: Identification and screening of contacts of patients with active tuberculosis (TB) is infrequent in low- and middle-income countries. Objective: To estimate the incidence, prevalence and risk factors of latent tuberculous infection (LTBI) and active TB among contacts of newly reported smear-positive TB patients. Design: A population-based contact investigation of sputum smear-positive pulmonary TB (PTB) cases diagnosed between April and December 2012 in Georgia was conducted. LTBI was assessed using the tuberculin skin test (TST). Contacts with active TB were identified from the National TB Program surveillance database. Results: Among 896 index patients with active TB, 3133 contacts were identified and 1157 (37%) underwent a TST, 34% of whom were positive. Most contacts were household contacts (86%) and female (58%). Among contacts, the 1-year period prevalence of active TB was 3.3% (95%CI 2.70-3.98); the incidence rate was 1101 per 100 000 person-years (95%CI 822-1443). In multivariable analysis, household contacts were more likely to have LTBI (adjusted OR [aOR] 2.28, 95%CI 1.49-3.49) than close contacts. Conclusions: A high prevalence of both LTBI and active TB was identified among contacts of PTB cases. Efforts aimed at active case finding among TB contacts should improve early case detection and enhance TB control efforts.

Tuberculosis contact-tracing among Syrian refugee populations: lessons from Jordan

BackgroundIn response to the influx of displaced Syrians since 2011, the Jordanian National Tuberculosis Program (NTP) implemented a specific Tuberculosis (TB) reduction strategy, including contact-tracing (CT). Contacts of all refugees diagnosed with pulmonary TB (PTB) were registered by the International Organization for Migration and screened for active & latent TB infection (LTBI) in 6 NTP centres.The objectives of this study were to assess prevalence of active TB and LTBI, risk factors for LTBI as well as program performance.MethodsWe performed a retrospective study among contacts (N = 481) of all PTB cases diagnosed between March 2011 and May 2014 (N = 76). CT was performed using verbal screening of TB-related symptoms, tuberculin skin test (TST) and chest X-ray.ResultsLTBI was diagnosed in 24.1% of contacts tested with TST while active TB was diagnosed in 2.1% of contacts. Main risk factors for positive TST included smear-positive index case (IC) (OR: 6.33) and previous TB infection in the family (OR: 4.94). Among children, the risk of LTBI was higher when their IC was a care-giving female (OR: 2.83). Prevalence of active TB was two times higher in children under five (U5 s) (5.3%) compared to adults (2.5%).ConclusionWe found a high prevalence of active TB and LTBI among contacts of PTB cases in the Syrian refugee population, emphasizing the urgent need for host countries to implement CT strategies for refugees. Our results underscore the vulnerability of U5s and contacts of smear-positive IC highlighting the need for specific actions focusing on those groups.

Latent Tuberculosis Infection among Household Contacts of Pulmonary Tuberculosis Cases in Central State, Sudan: Prevalence and Associated Factors

Introduction: Tuberculosis is a major health problem in developing countries including Sudan. Screening for TB cases through Household contacts (HHCs) investigation is an appropriate strategy to interrupt transmission of TB. Objectives: To determine the prevalence tuberculosis infection and risk factors for tuberculosis infection among household contacts in Wadimadani locality, Central State, Sudan, between November 2015 and April 2016. Methods: An analytical cross-sectional study conducted. During study period, to confirm TB diagnosis, all suspect contacts were tested through sputum samples, tuberculin skin test or chest X-ray. Structured questionnaire was used to collect socio-demographic and environmental factors. Results: One hundred forty six patients of smear-positive pulmonary tuberculosis were included in the study, 657 household contacts were identified and screened. Forty three new TB cases were detected from household contacts, yielding a prevalence of 6.5% (95% confidence interval = 0.05, 0.09) of latent tuberculosis infection (LTBI). Two factors were significantly associated with LTBI among HHCs: duration of contact with a TB patient ≤ 4 months (P = 0.03) and the educational status (P = 0.02). Conclusion: Screening of HHCs of index case of TB will contribute in early detection and treatment of new cases, and considered as a forward step towards eliminating TB.

Nutritional Status and Tuberculosis Risk in Adult and Pediatric Household Contacts

BackgroundStudies show obesity decreases risk of tuberculosis (TB) disease. There is limited evidence on whether high body mass index also protects against TB infection; how very high body mass indices influence TB risk; or whether nutritional status predicts this risk in children. We assessed the impact of body mass index on incident TB infection and disease among adults and children.Methods and FindingsWe conducted a prospective cohort study among household contacts of pulmonary TB cases in Lima, Peru. We determined body mass index at baseline and followed participants for one year for TB infection and disease. We used Cox proportional regression analyses to estimate hazard ratios for incident TB infection and disease. We enrolled 14,044 household contacts, and among 6853 negative for TB infection and disease at baseline, 1787 (26.1%) became infected. A total of 406 contacts developed secondary TB disease during follow-up. Body mass index did not predict risk of TB infection but overweight household contacts had significantly decreased risk of TB disease (HR 0.48; 95% CI 0.37–0.64; p <0.001) compared to those with normal weight. Among adults, body mass index ≥ 35 kg/m2 continued to predict a lower risk of TB disease (HR 0.30; 95% CI 0.12–0.74; p 0.009). We found no association between high body mass index and TB infection or disease among children under 12 years of age.ConclusionsHigh body mass index protects adults against TB disease even at levels ≥ 35 kg/m2. This protective effect does not extend to TB infection and is not seen in children.

M. tuberculosis DNA detection in nasopharyngeal mucosa can precede tuberculosis development in contacts.

The nasopharynx is a known gateway for some mycobacterial species such as Mycobacterium bovis and M. leprae. M. tuberculosis can cross lymphoepithelial barriers in vitro, but its ability to colonise the nasopharyngeal mucosa in vivo has not been established. To determine if M. tuberculosis can be transiently detected in nasopharyngeal mucosa of tuberculosis (TB) contacts as a preliminary step in the development of tuberculous infection. Exploratory study conducted among asymptomatic household contacts of pulmonary TB cases. A chest X-ray, QuantiFERON(®) TB-Gold or tuberculin skin test and a bilateral nasopharyngeal swab for Xpert(®) MTB/RIF and mycobacterial culture were performed at baseline and repeated 8-12 weeks later. Eighty-nine contacts were enrolled a median of 9 days after the diagnosis of the index case. At baseline, 29.9% were positive for latent tuberculous infection and one subject (1.1%) had a positive Xpert in the nasopharyngeal swab with a normal chest X-ray, negative QuantiFERON and negative induced sputum. After 12 weeks' follow-up, this subject developed a new cough and upper lobe infiltrates and M. tuberculosis grew in sputum. No other cases of active TB were detected at follow-up. The detection of M. tuberculosis DNA in the nasopharyngeal mucosa of contacts is an infrequent event that in this instance preceded the development of pulmonary TB. Its pathogenic role requires further investigation.

Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries.

Latent tuberculosis infection (LTBI) is characterised by the presence of immune responses to previously acquired Mycobacterium tuberculosis infection without clinical evidence of active tuberculosis (TB). Here we report evidence-based guidelines from the World Health Organization for a public health approach to the management of LTBI in high risk individuals in countries with high or middle upper income and TB incidence of <100 per 100 000 per year. The guidelines strongly recommend systematic testing and treatment of LTBI in people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor treatment, patients receiving dialysis, patients preparing for organ or haematological transplantation, and patients with silicosis. In prisoners, healthcare workers, immigrants from high TB burden countries, homeless persons and illicit drug users, systematic testing and treatment of LTBI is conditionally recommended, according to TB epidemiology and resource availability. Either commercial interferon-gamma release assays or Mantoux tuberculin skin testing could be used to test for LTBI. Chest radiography should be performed before LTBI treatment to rule out active TB disease. Recommended treatment regimens for LTBI include: 6 or 9 month isoniazid; 12 week rifapentine plus isoniazid; 3-4 month isoniazid plus rifampicin; or 3-4 month rifampicin alone.

Cough Aerosol Cultures of Mycobacterium tuberculosis: Insights on TST / IGRA Discordance and Transmission Dynamics.

RationaleThe diagnosis of latent tuberculosis (TB) infection (LTBI) is complicated by the absence of a gold standard. Discordance between tuberculin skin tests (TST) and interferon gamma release assays (IGRA) occurs in 10–20% of individuals, but the underlying mechanisms are poorly understood.MethodsWe analyzed data from a prospective household contact study that included cough aerosol culture results from index cases, environmental and contact factors. We assessed contacts for LTBI using TST and IGRA at baseline and six weeks. We examined TST/IGRA discordance in qualitative and quantitative analyses, and used multivariable logistic regression analysis with generalized estimating equations to analyze predictors of discordance.Measurements and ResultsWe included 96 TB patients and 384 contacts. Discordance decreased from 15% at baseline to 8% by six weeks. In adjusted analyses, discordance was related to less crowding (p = 0.004), non-cavitary disease (OR 1.41, 95% CI: 1.02–1.96; p = 0.03), and marginally with BCG vaccination in contacts (OR 1.40, 95% CI: 0.99–1.98, p = 0.06).ConclusionsWe observed significant individual variability and temporal dynamism in TST and IGRA results in household contacts of pulmonary TB cases. Discordance was associated with a less intense infectious exposure, and marginally associated with a BCG-mediated delay in IGRA conversion. Cough aerosols provide an additional dimension to the assessment of infectiousness and risk of infection in contacts.

Prevalence and risk factors of tuberculosis infection among child contacts of pulmonary tuberculosis cases

Prevalence and risk factors of tuberculosis infection among child contacts of pulmonary tuberculosis cases

The presence of a booster phenomenon among contacts of active pulmonary tuberculosis cases: a retrospective cohort

BackgroundAssuming a higher risk of latent tuberculosis (TB) infection in the population of Rio de Janeiro, Brazil, in October of 1998 the TB Control Program of Clementino Fraga Filho Hospital (CFFH) routinely started to recommend a two-step tuberculin skin test (TST) in contacts of pulmonary TB cases in order to distinguish a boosting reaction due to a recall of delayed hypersensitivity previously established by infection with Mycobacterium tuberculosis (M.tb) or BCG vaccination from a tuberculin conversion. The aim of this study was to assess the prevalence of boosted tuberculin skin tests among contacts of individuals with active pulmonary tuberculosis (TB).MethodsRetrospective cohort of TB contacts ≥ 12 years old who were evaluated between October 1st, 1998 and October 31st 2001. Contacts with an initial TST ≤ 4 mm were considered negative and had a second TST applied after 7–14 days. Boosting reaction was defined as a second TST ≥ 10 mm with an increase in induration ≥ 6 mm related to the first TST. All contacts with either a positive initial or repeat TST had a chest x-ray to rule out active TB disease, and initially positive contacts were offered isoniazid preventive therapy. Contacts that boosted did not receive treatment for latent TB infection and were followed for 24 months to monitor the development of TB. Statistical analysis of dichotomous variables was performed using Chi-square test. Differences were considered significant at a p < 0.05.ResultsFifty four percent (572/1060) of contacts had an initial negative TST and 79% of them (455/572) had a second TST. Boosting was identified in 6% (28/455). The mean age of contacts with a boosting reaction was 42.3 ± 21.1 and with no boosting was 28.7 ± 21.7 (p = 0.01). Fifty percent (14/28) of individuals whose test boosted met criteria for TST conversion on the second TST (increase in induration ≥ 10 mm). None of the 28 contacts whose reaction boosted developed TB disease within two years following the TST.ConclusionThe low number of contacts with boosting and the difficulty in distinguishing boosting from TST conversion in the second TST suggests that the strategy of two-step TST testing among contacts of active TB cases may not be useful. However, this conclusion must be taken with caution because of the small number of subjects followed.