Reactivation Of Latent Tuberculosis Infection Research Articles

Gene Regulatory Mechanism of Mycobacterium Tuberculosis during Dormancy.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) complex, is a zoonotic disease that remains one of the leading causes of death worldwide. Latent tuberculosis infection reactivation is a challenging obstacle to eradicating TB globally. Understanding the gene regulatory network of Mtb during dormancy is important. This review discusses up-to-date information about TB gene regulatory networks during dormancy, focusing on the regulation of lipid and energy metabolism, dormancy survival regulator (DosR), White B-like (Wbl) family, Toxin-Antitoxin (TA) systems, sigma factors, and MprAB. We outline the progress in vaccine and drug development associated with Mtb dormancy.

Late Tuberculosis Reactivation After Severe Covid-19.

Although there is no specific therapy for COVID-19, it is recommended that patients with severe SARS-CoV-2 infection are treated with corticosteroids and anti-IL-6 receptor monoclonal antibodies. Both COVID-19 itself and the treatment modalities mentioned above have suppressive effects on the immune system which may lead to an increased susceptibility to other infections. In patients with latent tuberculosis (TB) reactivation of TB infection after recovery from severe COVID-19 has been described. Most of these cases have occurred in parts of the world where tuberculosis is endemic. The patient is a female in her 70s who was born and raised in Southeast Asia and has lived in the Netherlands for more than 30 years. She was treated for a severe COVID-19 requiring mechanical ventilation for several weeks and pharmaceutical treatment with corticosteroids and anti-IL-6 receptor monoclonal antibodies (Sarilumab). She recovered well. Two years later she was readmitted with symptoms of a serious pulmonary infection and meningitis. Her condition deteriorated in a short time. An active TB infection was diagnosed. Despite adequate antibiotic treatment and supportive therapy her condition worsened and four days after admission to the ICU she deceased. Reactivation of latent TB after recovery from a severe COVID-19 has been described several times and may occur several months after the SARS-CoV-2 infection. In this case the reactivation presented two years after COVID-19. This case illustrates that long-term follow-up of patients with latent TB that recover from a severe COVID-19 may be indicated. Reactivation of latent tuberculosis infection in patients treated for a severe COVID-19 may occur even two years after recovery from SARS-CoV-2 infection.Most cases of reactivation of tuberculosis after COVID-19 are described in regions where tuberculosis is endemic. However, it may also occur in countries with a relatively low prevalence of tuberculosis infection. The exact incidence of tuberculosis reactivation after COVID-19 is unknown and probably underestimated.A long-term follow-up of patients after severe COVID-19 treated with corticosteroids and/or anti-IL-6 receptor monoclonal antibodies with a history of tuberculosis or patients migrated from countries where tuberculosis is endemic seems to be important.

IgG glycosylation associates with risk of progression from latent to active tuberculosis

Glycosylation motifs shape antibody structure, stability and antigen affinity and play an important role in antibody localization and function. Serum IgG glycosylation profiles are significantly altered in infectious diseases, including tuberculosis (TB), but have not been studied in the context of progression from latent to active TB. We performed a longitudinal study of paired bulk IgG glycosylation and transcriptomic profiling in blood from individuals with active TB (ATB) or latent TB infection (LTBI) before and after treatment. We identified that a combination of two IgG1 glycosylation traits were sufficient to distinguish ATB from LTBI with high specificity and sensitivity, prior to, and after treatment. Importantly, these two features positively correlated with previously defined cellular and RNA signatures of ATB risk in LTBI, namely monocyte to lymphocyte ratio and the expression of interferon (IFN)-associated gene signature of progression (IFN-risk signature) in blood prior to treatment. Additional glycosylation features at higher prevalence in LTBI individuals with high expression of the IFN-risk signature prior to treatment included fucosylation on IgG1, IgG2 and IgG3. Together, our results demonstrate that bulk IgG glycosylation features could be useful in stratifying the risk of LTBI reactivation and progression to ATB.

Latent Tuberculosis Infection Testing Practices in a Large US Integrated Healthcare System.

Tuberculosis (TB) is a public health threat, with >80% of active TB in the United States occurring due to reactivation of latent TB infection (LTBI). We may be underscreening those with high risk for LTBI and overtesting those at lower risk. A better understanding of gaps in current LTBI testing practices in relation to LTBI test positivity is needed. This study, conducted between 1 January 2008 and 31 December 2019 at Kaiser Permanente Southern California, included individuals aged ≥18 years without a history of active TB. We examined factors associated with LTBI testing and LTBI positivity. Among 3 816 884 adults (52% female, 37% White, 37% Hispanic, mean age 43.5 years [standard deviation, 16.1]), 706 367 (19%) were tested for LTBI, among whom 60 393 (9%) had ≥1 positive result. Among 1 211 971 individuals who met ≥1 screening criteria for LTBI, 210 025 (17%) were tested for LTBI. Factors associated with higher adjusted odds of testing positive included male sex (1.32; 95% confidence interval, 1.30-1.35), Asian/Pacific Islander (2.78, 2.68-2.88), current smoking (1.24, 1.20-1.28), diabetes (1.13, 1.09-1.16), hepatitis B (1.45, 1.34-1.57), hepatitis C (1.54, 1.44-1.66), and birth in a country with an elevated TB rate (3.40, 3.31-3.49). Despite being risk factors for testing positive for LTBI, none of these factors were associated with higher odds of LTBI testing. Current LTBI testing practices may be missing individuals at high risk of LTBI. Additional work is needed to refine and implement screening guidelines that appropriately target testing for those at highest risk for LTBI.

Incidence, risk factors for active tuberculosis infection and changes of IGRA in patients with Takayasu arteritis: a prospective cohort study

ABSTRACT There is limited evidence to support the association between tuberculosis (TB) and the occurrence of Takayasu arteritis (TAK). To investigate the incidence of active TB (ATB) in TAK and explore the impact of anti-rheumatic therapy on the occurrence of ATB or reactivation of Latent TB infection (LTBI) and their effect on interferon-γ release assay (IGRA) results, we conducted a prospective study based on the Chinese Registry for Systemic Vasculitis cohort. The standard incidence ratio (SIR) was calculated and stratified by age. Kaplan–Meier analysis was used to determine the effect of variables on ATB or LTBI reactivation in patients with TAK. Data from 825 patients with TAK in the registry were analysed. During a median follow-up of 5 years, 5 patients developed ATB with a crude incidence of 154 (95%CI:57–381) person-years/100,000. The SIR was 5.59 (95%CI:1.81–13.04). Glucocorticoids and conventional disease-modifying anti-rheumatic drugs (cDMARDs) did not increase the risk of ATB or LTBI reactivation (P > 0.05). However, the use of tumour necrosis factor inhibitor (TNFi) increased the risk of ATB in patients with LTBI (P < 0.001). Furthermore, the value of the IGRA assay decreased after treatment (P < 0.05). In conclusion, the incidence of TB infection is markedly increased in patients with TAK and patients with TAK are at high risk of developing ATB. Treatment with glucocorticoids and cDMARDs does not significantly increase the risk for ATB in patients with TAK. Moreover, IGRA may have limited effectiveness in monitoring ATB infection or LTBI reactivation in patients with TAK.

Reactivation Risk of Latent Tuberculosis or Inactive Hepatitis B Virus Infection and Effectiveness of Ustekinumab in Chinese Plaque Psoriasis Patients: A 28-Week Retrospective, Observational Study.

This study observed the effectiveness of ustekinumab and reactivation risk of concurrent latent tuberculosis infection (LTBI) and inactive hepatitis B virus (HBV) infection in Chinese mainland psoriasis patients on ustekinumab treatment. This retrospective, multicenter, observational study was conducted in three centers in China. Adult patients with moderate to severe plaque psoriasis were treated with ustekinumab for 28 weeks. The effectiveness endpoint included 75% and 90% improvement in Psoriasis Area Severity Index (PASI75/90) response rate, percentage of PASI improvement, change of absolute PASI score and body surface area involvement (BSA) score, absolute PASI ≤1/3 and Physicians' Global Assessment (PGA)=0/1, as well as Dermatology life quality index (DLQI)=0/1 response rate at week 4, 16 and 28. Screening of tuberculosis and hepatitis were performed at baseline and week 28. A total of 82 patients were enrolled between March 2021 and May 2023 and the number of patients combined with LTBI and inactive HBV infection was 20 and 21 respectively. The PASI75 and PASI90 response rate at week 28 was 95.1% and 81.7% respectively. The mean PASI score decreased from 14.93 ± 12.07 at baseline to 0.78 ± 1.86 at week 28, and the mean BSA score decreased from 21% ± 18% at baseline to 1% ± 2% at week 28 (both P<0.001 compared with baseline). DLQI 0/1 response rate at week 28 was 73.2%. No reactivation of LTBI and inactive HBV infection and also no new-onset tuberculosis and hepatitis B occurred in patients without LTBI and inactive HBV infection at baseline. Ustekinumab demonstrated great effectiveness in Chinese plaque psoriasis patients and good safety in psoriasis concurrent with LTBI and inactive HBV infection under the real-world setting.

Features of detection of latent tuberculosis infection in patients with inflammatory intestinal diseases

A quarter of the world’s population has latent tuberculosis infection (LTBI). Systemic immunosuppression is a risk factor for the reactivation of LTBI and the development of active tuberculosis, and such reactivation is associated with a substantial risk of morbidity and mortality. Despite the growing global prevalence of inflammatory bowel diseases (IBD) and the use of immunosuppressive therapies, current recommendations for LTBI testing and treatment in IBD patients lack a systematic approach due to a lack of evidence. Currently, the main challenge in accurately diagnosing inflammatory bowel diseases (IBD) is the high prevalence of conditions that lead to intestinal lesions mimicking IBD.

1869. Knowledge about and Perceptions of Latent Tuberculosis Infection (LTBI) among Physicians and Advanced Practice Providers at Tufts Medical Center

Abstract Background Mycobacterium Tuberculosis (TB) is a leading cause of infectious disease mortality worldwide. Most active TB cases result from reactivation of latent tuberculosis infection (LTBI). A large reservoir of latent TB is a major public health problem worldwide and in the United States. A better understanding of provider perspectives on LTBI could improve a sub-optimal LTBI care cascade. Methods A 13-question survey was fielded to attending physicians, fellows, and advanced practice providers working in the infectious disease, pulmonary/critical care, and general medicine departments at Tufts Medical Center (TMC), an academic tertiary care center in Boston, Massachusetts. Results The response rate of the survey was 33% (62/186). Only 17 (30.9%) providers were able to correctly identify all indications for screening. When asked how they decide who to treat, 26.8% (15/56) of providers selected that they would refer their patient to another specialist. Overall, provider confidence in LTBI management decreased along the care cascade (Figure 1). Infectious disease providers expressed more confidence in management than general medicine and pulmonary/critical care providers. The two most observed issues/barriers to care for patients were language, reported by 39 (76.5%) providers, and lack of knowledge or understanding about TB, reported by 39 (76.5%) providers. The two most selected interventions to improve LTBI care at TMC were use of in-person language interpreters, chosen by 37 (71.2%) providers, and information pamphlets available in patients’ preferred languages, chosen by 36 (69.2%) providers. Providers were asked “On a scale of 1-5, (“1” = not at all, and “5” = perfectly) “How confident are you in your ability to do the following” for the listed management tasks. Conclusion Results suggest that providers believe the largest barriers to patient LTBI treatment completion are due to a lack of patient comprehension about their infection. Improving patient understanding could be accomplished through in-person interpreters, information pamphlets about LTBI in patients’ preferred languages, and forming community partnerships to improve awareness and understanding of the risks of LTBI. Additionally, ensuring that providers feel confident in their ability to manage LTBI, are updated on screening guidelines, and have referral resources when needed, could help close the gaps in the LTBI care cascade. Disclosures All Authors: No reported disclosures

Latent tuberculosis infection in myasthenia gravis patients on immunosuppressive therapy: high incidence yet moderate reactivation rate

Background Immunosuppressive therapies (ISTs) are mainstays for management of myasthenia gravis (MG). Meanwhile, latent tuberculosis infection (LTBI) is common in the setting of high-burden countries. However, the prevalence of LTBI among MG patients and whether receiving ISTs for MG would aggravate LTBI reactivation remain unknown. Methods We retrospectively analyzed the frequency of LTBI via interferon-gamma release assay (IGRA) positivity among hospitalized MG patients from both rural and urban areas in a tertiary hospital, and those receiving ISTs were followed up to investigate the reactivation risk of LTBI. Results A total of 300 MG patients with determinate IGRA results were enrolled, where the frequency of LTBI was 35.0%. Male (OR = 1.910, 95% CI: 1.181–3.089, p = .008) and elderly (OR = 1.044, 95% CI: 1.027–1.061, p < .001) patients were prone to LTBI. Of those with LTBI, 78 individuals on ISTs were successfully followed up for a median duration of 18.3 (8.5–24.0) months, of which 25 (32.1%) received anti-tuberculosis (TB) treatments. The rate of various degrees of adverse events was 82.1% over the course of the follow-up, but was not different between individuals with and without therapies against TB (χ 2 < 0.001, p > .999). Only 1 patient eventually reported lymph node and intestinal TB, with the incidence rate of LTBI reactivation preliminarily estimated to be 0.81 per 100 person years. Conclusion The frequency of LTBI is high in our MG cohort, especially among those with advanced age and males. However, receiving immunosuppressives seems not to increase the risk of LTBI reactivation. LTBI screening is strongly recommended for all MG patients ready to receive ISTs, while preventive anti-TB chemotherapy should be prescribed after weighing potential benefits against the risk of side effects in those with LTBI. In-depth investigation is still entailed to further verify these findings due to the limitation of the retrospective single-center design of our study.

Single-Cell Transcriptomics of Mtb/HIV Co-Infection.

Tuberculosis (TB) and Human Immunodeficiency Virus (HIV) co-infection continues to pose a significant healthcare burden. HIV co-infection during TB predisposes the host to the reactivation of latent TB infection (LTBI), worsening disease conditions and mortality. There is a lack of biomarkers of LTBI reactivation and/or immune-related transcriptional signatures to distinguish active TB from LTBI and predict TB reactivation upon HIV co-infection. Characterizing individual cells using next-generation sequencing-based technologies has facilitated novel biological discoveries about infectious diseases, including TB and HIV pathogenesis. Compared to the more conventional sequencing techniques that provide a bulk assessment, single-cell RNA sequencing (scRNA-seq) can reveal complex and new cell types and identify more high-resolution cellular heterogeneity. This review will summarize the progress made in defining the immune atlas of TB and HIV infections using scRNA-seq, including host-pathogen interactions, heterogeneity in HIV pathogenesis, and the animal models employed to model disease. This review will also address the tools needed to bridge the gap between disease outcomes in single infection vs. co-infection. Finally, it will elaborate on the translational benefits of single-cell sequencing in TB/HIV diagnosis in humans.

Latent tuberculosis infection testing in a large integrated healthcare system

PurposeTuberculosis (TB) is a public health threat with >80% of active TB in the United States occurring due to reactivation of latent tuberculosis infection (LTBI). We may be under-screening those with high risk for LTBI and over-testing those at lower risk. A better understanding of gaps in current LTBI testing practices, particularly as it relates to LTBI test positivity, is needed. MethodsThis study, conducted between 01/01/2008 and 12/31/2019 at Kaiser Permanente Southern California, included individuals aged ≥18years without history of active TB. We examined factors associated with LTBI testing and LTBI positivity. ResultsAmong 3,816,884 adults (52% female, 37% White, mean age 43.5years [SD 16.1]), 706,367 (19%) were tested for LTBI, among whom 60,393 (9%) had ≥1 positive result. Among 1,211,971 individuals meeting ≥1 screening criteria for LTBI, 210,025 (17%) were tested for LTBI. Factors associated with higher odds of testing positive included male sex (OR:1.32, 95% CI:1.30–1.35), Asian/Pacific Islanders (2.78, 2.68–2.88), current smoking (1.24, 1.20–1.28), diabetes (1.13, 1.09–1.16), hepatitis B (1.45, 1.34–1.57), hepatitis C (1.54, 1.44–1.66), and birth in a TB endemic country (3.40, 3.31–3.49). Despite being risk factors for testing positive for LTBI, none of these factors were associated with higher odds of LTBI testing (Fig. 1). ConclusionsWe identified a mismatch between populations tested for LTBI and populations testing positive. Current LTBI testing practices may be missing individuals at high risk of LTBI. Additional work is needed to develop and implement screening guidelines that appropriately target testing for those at highest risk for LTBI.

Adverse Events of Latent Tuberculosis Treatment With Isoniazid in People Living With HIV: A Case-Control Study in a Resource-Rich Setting.

Introduction Multiple risk factors, such as human immunodeficiency virus (HIV) infection and immunosuppressive therapies, increase the odds of latent tuberculosis infection (LTBI) reactivation and progression to active tuberculosis. A six-to-nine-month preventive treatment with isoniazid (INH) decreases the risk of LTBI reactivation, but its effectiveness can be limited by its long duration and adverse events (AEs), including liver toxicity. Due to comorbidities and polypharmacy, people living with HIV (PLHIV) may be at increased risk of INH-associated AEs. Our study aimed to assess the prevalence of AEs among patients receiving INH treatment for LTBI, to identify risk factors for their occurrence, and to evaluate whether PLHIV have higher odds of developing INH-associated AEs. Methods We conducted a single-center retrospective case-control study, including 130 outpatients with LTBI treated with INH between July 2019 and March 2022. Participants who developed AE (cases) were compared to controls, and a subgroup of PLHIV was compared to HIV-negative participants. Demographics, socioeconomic variables, comorbidities, and clinical variables were compared between study groups. Patient data were obtained from institutional electronic medical records, and outcomes were measured at regularly scheduled appointments. Results We included 130 participants, of which 54 were PLHIV. The PLHIV subgroup was significantly younger (p = 0.01) and demonstrated significantly higher prevalences of chronic liver disease, previous viral hepatitis, daily alcohol consumption, and intravenous drug use (IDU). One-third of the participants had an AE (45 cases, 34.6%), with liver toxicity being the most common (22.3%). Participants who developed AEs were significantly older (p = 0.030) and had a higher prevalence of economic hardship (p = 0.037), as well as higher scores of the Charlson comorbidity index (p = 0.002) than the controls. INH withdrawal occurred in 17 participants (13.1%) and was mainly associated with liver toxicity (p < 0.01) and gastrointestinal symptoms (p = 0.022). In the adjusted effect model, an age ≥ 65 years, economic hardship, and excessive alcohol consumption were significantly associated with higher odds of AEs, while HIV infection decreased the odds by 68.4% (p = 0.033). Conclusions In our study, INH-associated AEs were common, with liver toxicity being the most frequent. Older age, economic hardship, and excessive alcohol consumption increased the odds of INH-associated AEs, while PLHIV had lower odds of developing INH-associated AEs, even when adjusting for other variables in the multivariate analysis. Further studies should be conducted to assess if these results are replicable in a larger population and in different settings.

Safety of secukinumab in the treatment of patients with axial spondyloarthritis and concurrent hepatitis B virus infection or latent tuberculosis infection.

To evaluate the safety of secukinumab (SEC) in the treatment of patients with axial spondyloarthritis (axSpA) and concurrent hepatitis B virus (HBV) infection or latent tuberculosis infection (LTBI). This is a retrospective cohort study. Adult axSpA patients with HBV infection or LTBI receiving SEC treatment for at least 3months from March 2020 to July 2022 in Guangdong Provincial People's Hospital were included. Patients were screened for HBV infection and LTBI before SEC treatment. During follow-up, reactivation of HBV infection and LTBI was monitored. Relevant data were collected and analyzed. A total of 43 axSpA patients with HBV infection or LTBI were included, of whom 37 were with HBV infection, 6 were with LTBI. Six out of thirty-seven (16.2%) patients with axSpA and concurrent HBV infection exhibited HBV reactivation after 9.0 ± 5.7months of SEC treatment. Among them, 3 patients had chronic HBV infection and received anti-HBV prophylaxis, 2 patients had chronic HBV infection but did not receive anti-HBV prophylaxis, and 1 patient had occult HBV infection and did not receive antiviral prophylaxis. None of the 6 axSpA patients with LTBI developed reactivation of LTBI, whether received anti-TB prophylaxis or not. HBV reactivation can occur in axSpA patients with different types of HBV infection undergoing SEC treatment, whether receive antiviral prophylaxis or not. Close monitoring of HBV reactivation in axSpA patients with HBV infection undergoing SEC treatment is mandatory. Anti-HBV prophylaxis may be beneficial. In contrast, SEC may be safe in axSpA patients with LTBI, even in patients not receiving anti-TB prophylaxis. Key Points •Currently, most evidence about the safety of SEC in patients with HBV infection and LTBI were from patients with psoriasis. Our study adds data about the safety of SEC in Chinese axSpA patients with concurrent HBV infection or LTBI in real-world clinical setting. •Our study showed that HBV reactivation can occur in axSpA patients with different types of HBV infection undergoing SEC treatment, whether receive antiviral prophylaxis or not. •Close monitoring of serum HBV markers, HBV DNA load, and liver function is mandatory in axSpA patients with chronic, occult, and resolved HBV infection undergoing SEC treatment. Anti-HBV prophylaxis may be beneficial in all HBsAg-positive patients and HBsAg-negative, HBcAb-positive patients at high risk of HBV reactivation who are receiving SEC therapy. •None of the axSpA patients with LTBI, whether received anti-TB prophylaxis or not, developed reactivation of LTBI in our study. SEC may be safe in axSpA patients with LTBI, even in patients not receiving anti-TB prophylaxis.

Inhibition of Mycobacterium tuberculosis resuscitation-promoting factor B (RpfB) by microbially derived natural compounds: a computational study

The majority of the world population (around 25%) has latent Mycobacterium tuberculosis (Mtb) infection, among which only 5–10% of individuals develop active tuberculosis (TB), and 90–95% continue to have latent tuberculosis infection. This makes it the biggest global health concern. It has been reported that the resuscitation-promoting factor B (RpfB) is an exciting potential target for tuberculosis drug discovery due to its significant role in the reactivation of latent TB infection to an active infection. Several attempts have been made to investigate potential inhibitors against RpfB utilizing in-silico approaches. The present study also utilized a computational approach to investigate microbially derived natural compounds against the Mtb RpfB protein which is a very cost-effective This evaluation used structure-based virtual screening (SBVS), drug-likeness profiling, molecular docking, molecular dynamics simulation, and free-binding energy calculations. Six potential natural compounds, viz. Cyclizidine I, Boremexin C, Xenocoumacin 2, PM-94128, Cutinostatin B, and (+)1-O-demethylvariecolorquinone A were selected, which displayed a potential binding affinity between −52.39 and −60.87 Kcal/mol MMGBSA score and docking energy between −7.307 Kcal/mol to −6.972 Kcal/mol. All the complexes showed acceptable stability (<2.7 Å RMSD) during 100 ns MD simulation time except the RpfB protein-xenocoumacin 2 complex. This result exhibited that the selected compounds have high efficiency in inhibiting the Mtb RpfB and can be taken into account for additional in vitro and in vivo experimental validation. Communicated by Ramaswamy H. Sarma

Patient-Reported Barriers to Treatment Initiation and Completion for Latent Tuberculosis Infection Among Patients Within a Large Integrated Health Care System in Southern California.

More than 80% of active tuberculosis in the United States is due to reactivation of latent tuberculosis infection (LTBI), which can be prevented via screening and treatment. Treatment initiation and completion rates are low for patients with LTBI in the United States, and the barriers to successful treatment are poorly understood. We conducted semistructured qualitative interviews with 38 patients who were prescribed LTBI treatment (9 months isoniazid, 6 months rifampin, or 3 months rifamycin-isoniazid short-course combinations). We used purposeful sampling employing a maximum variation approach to obtain diverse perspectives of patients who did not initiate treatment, who did not complete treatment, and who completed treatment (n = 14, n = 16, and n = 8, respectively). Patients were asked about LTBI knowledge, experience regarding treatment, interactions with providers, and barriers they faced. Using a team coding model (2 coders/analysts), we developed deductively derived (a priori) codes based on our central research questions and inductively derived codes that emerged directly from the data. Analysis of our coding categories and relationships generated a hierarchy of key themes and subthemes. Kaiser Permanente Southern California. Individuals 18 years or older who received a diagnosis of LTBI and prescribed treatment. LTBI knowledge, attitudes toward LTBI, attitudes toward LTBI treatment, attitudes toward providers, and explanation of barriers. Most patients reported having limited knowledge of LTBI. In addition to the duration of treatment, barriers to initiation and completion included perceived lack of support, uncomfortable side effects, and pervasive minimization of the positive impact of treatment on their health. Many patients felt there was little incentive to overcome barriers. Overall, patient experience with LTBI treatment initiation and completion could be improved with patient-centered treatment and more frequent follow-ups.

Estimated rates of progression to tuberculosis disease for persons infected with Mycobacterium tuberculosis in the United States.

In the United States, over 80% of tuberculosis (TB) disease cases are estimated to result from reactivation of latent TB infection (LTBI) acquired more than 2 years previously ("reactivation TB"). We estimated reactivation TB rates for the US population with LTBI, overall, by age, sex, race-ethnicity, and US-born status, and for selected comorbidities (diabetes, end-stage renal disease, and HIV). We collated nationally representative data for 2011-2012. Reactivation TB incidence was based on TB cases reported to the National TB Surveillance System that were attributed to LTBI reactivation. Person-years at risk of reactivation TB were calculated using interferon-gamma release assay (IGRA) positivity from the National Health and Nutrition Examination Survey, published values for interferon-gamma release assay sensitivity and specificity, and population estimates from the American Community Survey. For persons aged ≥6 years with LTBI, the overall reactivation rate was estimated as 0.072 (95% uncertainty interval: 0.047, 0.12) per 100 person-years. Estimated reactivation rates declined with age. Compared to the overall population, estimated reactivation rates were higher for persons with diabetes (adjusted rate ratio [aRR] = 1.6 [1.5, 1.7]), end-stage renal disease (aRR = 9.8 [5.4, 19]), and HIV (aRR = 12 [10, 13]). In our study, individuals with LTBI faced small, non-negligible risks of reactivation TB. Risks were elevated for individuals with medical comorbidities that weaken immune function.

The Bidirectional Relationship between Pulmonary Tuberculosis and Lung Cancer.

Lung cancer and pulmonary tuberculosis are two significant public health problems that continue to take millions of lives each year. They may have similar symptoms and, in some cases, are diagnosed simultaneously or may have a causal relationship. In tuberculosis disease, the chronic inflammation, different produced molecules, genomic changes, and fibrosis are believed to be important factors that may promote carcinogenesis. As a reverse reaction, the development of carcinogenesis and the treatment may induce the reactivation of latent tuberculosis infection. Moreover, the recently used checkpoint inhibitors are a debatable subject since they help treat lung cancer but may lead to the reactivation of pulmonary tuberculosis and checkpoint-induced pneumonitis. Pulmonary rehabilitation is an effective intervention in post-tuberculosis patients and lung cancer patients and should be recommended to improve outcomes in these pathologies.

Efficacy of light chain 3-fused protein multi epitope in protection of mice challenged with Mycobacterium tuberculosis.

The new strategy for vaccine development such as the fused protein multi-epitope capable of preventing the reactivation of latent tuberculosis infection (LTBi) can be an effective strategy for controlling tuberculosis (TB) worldwide. This study was conducted to evaluate the immunity of experimentally infected BALB/c mice with Mycobacterium tuberculosis after injection of DNA construct. Nineteen female BALB/c mice were divided into three groups and injected with 0.50 mL of M. tuberculosis. After 3 weeks, lung and spleen samples from the infected mice were examined. The protective effects of light chain 3-fused protein multi-epitope against TB were evaluated for post-exposure and therapeutic exposure. The lungs and spleens of the mice were aseptically removed after death for histopathology analysis. The bacterial colonies were counted, and the cells were stained after 3 weeks of incubation. No significant differences were observed between the post-exposure and therapeutic exposure groups. The pathological changes in the lung tissue of mice in these groups included an increase in the thickness of interalveolar septa, hyperemia, and intraparenchymal pulmonary hemorrhage centers (positive control), scattered hyperemic areas (negative control), and hyperemia in the interstitial tissue, scattered hyperemic areas in the lung parenchyma and lymphocytic infiltration centers (experimental group). Flow cytometry of the post-exposure and therapeutic exposure models showed insignificant changes in all three groups. It seems necessary to develop a post-exposure and therapeutic exposure vaccine strategy that focuses on LTBi to prevent the progression of the active disease. In this regard, multi-epitope vaccines should be designed to induce both cellular and humoral immunity.

B21 DNA vaccine expressing ag85b, rv2029c, and rv1738 confers a robust therapeutic effect against latent Mycobacterium tuberculosis infection.

Latent tuberculosis infection (LTBI) treatment is known to accelerate the decline in TB incidence, especially in high-risk populations. Mycobacterium tuberculosis (M. tb) expression profiles differ at different growth periods, and vaccines protective and therapeutic effects may increase when they include antigenic compositions from different periods. To develop a post-exposure vaccine that targets LTBI, we constructed four therapeutic DNA vaccines (A39, B37, B31, and B21) using different combinations of antigens from the proliferation phase (Ag85A, Ag85B), PE/PPE family (Rv3425), and latent phase (Rv2029c, Rv1813c, Rv1738). We compared the immunogenicity of the four DNA vaccines in C57BL/6j mice. The B21 vaccine stimulated the strongest cellular immune responses, namely Th1/Th17 and CD8+ cytotoxic T lymphocyte responses. It also induced the generation of strengthened effector memory and central memory T cells. In latently infected mice, the B21 vaccine significantly reduced bacterial loads in the spleens and lungs and decreased lung pathology. In conclusion, the B21 DNA vaccine can enhance T cell responses and control the reactivation of LTBI.

Dual latent tuberculosis screening with tuberculin skin tests and QuantiFERON-TB assays before TNF-α inhibitor initiation in children in Spain

Tumor-necrosis-factor-α inhibitors (anti-TNF-α) are associated with an increased risk of tuberculosis (TB) disease, primarily due to reactivation of latent TB infection (LTBI). We assessed the performance of parallel LTBI screening with tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube assays (QFT-GIT) before anti-TNF-α treatment in children with immune-mediated inflammatory disorders in a low TB-burden setting. We conducted a multicenter cohort study involving 17 pediatric tertiary centers in Spain. LTBI was defined as the presence of a positive TST and/or QFT-GIT result without clinical or radiological signs of TB disease. A total of 270 patients (median age:11.0 years) were included, mainly with rheumatological (55.9%) or inflammatory bowel disease (34.8%). Twelve patients (4.4%) were diagnosed with TB infection at screening (LTBI, n = 11; TB disease, n = 1). Concordance between TST and QFT-GIT results was moderate (TST+/QFT-GIT+, n = 4; TST−/QFT-GIT+, n = 3; TST+/QFT-GIT-, n = 5; kappa coefficient: 0.48, 95% CI: 0.36–0.60). Indeterminate QFT-GIT results occurred in 10 patients (3.7%) and were associated with young age and elevated C-reactive protein concentrations. Eleven of 12 patients with TB infection uneventfully completed standard LTBI or TB treatment. During a median follow-up period of 6.4 years, only 2 patients developed TB disease (incidence density: 130 (95% CI: 20–440) per 100,000 person-years), both probable de novo infections.Conclusion: A substantial number of patients were diagnosed with LTBI during screening. The dual strategy identified more cases than either of the tests alone, and test agreement was only moderate. Our data show that in children in a low TB prevalence setting, a dual screening strategy with TST and IGRA before anti-TNF-α treatment is effective.What is Known:• The optimal screening strategy for latent tuberculosis in children with immune-mediated inflammatory disorders remains uncertain.• Children receiving anti-TNF-α drugs are at increased risk of developing severe tuberculosis disease.What is New:• A dual screening strategy, using TST and an IGRA assay, identified more children with latent tuberculosis than either of the tests alone.• Identification and treatment of latent tuberculosis before initiation of anti-TNF-α therapy averted incident tuberculosis cases.