Latent Infection Research Articles

Diseases Caused by and Behaviors Associated with Toxoplasma gondii Infection

Toxoplasma gondii is an Apicomplexan parasite that is estimated to infect at least one-third of the global human population. T. gondii infection may be transmitted horizontally or vertically. The main risk factors for transmission to humans are related to diet, especially the consumption of undercooked meat, along with soil contact. In immunocompetent persons, the acute infection may go undetected as it typically produces minor, non-specific symptoms that are self-limited. After infection is established, recurrent retinochoroiditis is the most common clinical disease. In contrast, severe systemic or cerebral toxoplasmosis may be life-threatening for immunocompromised individuals. Furthermore, congenital toxoplasmosis acquired in utero may have devastating consequences if not recognized and promptly treated. A growing body of research has identified associations between latent T. gondii infection, and personality traits and risk-taking behaviors. Other studies have documented associations between latent infection and psychiatric conditions that include schizophrenia and bipolar affective disorder. With no current treatment regimens being curative of T. gondii infection, effective prevention measures at both the public health and individual levels are vitally important.

The Crosstalk Between HIV-TB Co-Infection and Associated Resistance in the Indian Population

Extensive research on tuberculosis (TB) and HIV co-infection reveals the diverse prevalence and co-epidemic patterns across populations, necessitating tailored public health strategies. Co-infection is bidirectional; individuals with HIV are more susceptible to TB, and vice versa. Antiretroviral therapy (ART) and antituberculosis treatment (ATT) are critical for managing these conditions, but pose risks due to drug–pathogen and drug–drug interactions, potentially leading to immune reconstitution inflammatory syndrome (IRIS) in patients with HIV/AIDS. IRIS, often triggered by highly active antiretroviral therapy (HAART), can exacerbate HIV progression, increase drug resistance, and deteriorate patients’ quality of life. Approximately one-third of the global population with HIV is also infected with TB, with extensive drug-resistant (XDR) and multidrug-resistant (MDR) strains posing significant challenges. Latent TB infection (LTBI) further complicates the scenario, as it can progress to active TB, particularly in individuals with both conditions. The global and Indian mortality rates for TB-HIV co-infection remain high, emphasizing the need for new strategies. Additionally, unreported cases and inadequate post-treatment monitoring contribute to the high mortality rate, particularly among patients with LTBI. The complexity of managing HIV-TB co-infection, especially with LTBI, underscores the urgency of addressing these challenges to improve the outcomes for the affected populations.

Specific human gene expression in response to infection is an effective marker for diagnosis of latent and active tuberculosis.

RNA sequencing and microarray analysis revealed transcriptional markers expressed in whole blood can differentiate active pulmonary TB (ATB) from other respiratory diseases (ORDs), and latent TB infection (LTBI) from healthy controls (HC). Here we describe a streamlined reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) assay that could be applied at near point-of-care for diagnosingand distinguishing ATB from ORDs and LTBI from HC. A literature review was undertaken to identify the most plausible host-gene markers (HGM) of TB infection. Primers, and dual labelled hydrolysis probes were designed and analytically evaluated for accuracy in an in-vitro model of infection using a lung fibroblast cell-line. Best performing genes were multiplexed into panels of 2-4 targets and taken forward for clinical evaluation. Mycobacteria Growth Indicator Tube and QuantiFERON-TB Gold Plus were used as reference tests for ATB and LTBI respectively. A total of 16 HGM were selected and incorporated into five multiplex RT-qPCR panels. PCR assay efficiency of all evaluated targets was ≥ 90% with a median analytical sensitivity of 292 copies/µl [IQR: 215.0-358.3 copies/µl], and a median limit of quantification of 61.7 copies/µl [IQR: 29.4-176.3 copies/µl]. Clinically, ATB was characterised by higher gene expression than ORDs, while LTBI was associated with lower gene expression than HC, Kruskal-Wallis p < 0.0001. Crucially, BATF2, CD64, GBP5, C1QB, GBP6, DUSP3, and GAS6 exhibited high differentiative ability for ATB from ORDs, LTBI or HC while KLF2, PTPRC, NEMF, ASUN, and ZNF296 independently discriminated LTBI from HC. Our results show that different HGM maybe required for ATB and LTBI differentiation from ORDs or HC respectively and demonstrate the feasibility of host gene-based RT-qPCR to diagnose ATB and LTBI at near point-of-care.

Novel tuberculosis skin tests for detecting latent tuberculosis infection.

Dear Editor, We are impressed by the article titled "Latent tuberculosis diagnostics: current scenario and review" by Gupta et al. published in your journal. The authors have reviewed the tests used for diagnosis of latent tuberculosis infection and have given a detailed overview of the purified protein derivative-based tuberculin skin test and interferon γ release assays. We would like to draw attention to the fact that in 2022, the World Health Organization has also recommended the use of Mycobacterium tuberculosis antigen-based skin tests for the diagnosis of latent tuberculosis (conditional recommendation, very low certainty of evidence).

Streptococcus canis transcriptomic modifications in host cell entry environments of human keratinocytes

BackgroundStreptococcus canis is a commensal bacterium in companion animals. This microorganism can infect humans who have been in deep contact with or bitten by pet dogs, suggesting that the skin/soft tissue is one of infection entry sites. To understand pathological process in human cells, we aimed to determine S. canis transcriptomic changes in invasive environments of human keratinocytes.MethodsWe selected one isolate from candidates with whole-genome sequences, based on re-obtained cell invasion ability (CIA) data into human keratinocytes along with bacterial cytotoxicity. RNA-sequencing was conducted for the samples at baselines and 2 h/5 hr post-inoculation using NovaSeq 6000. Global/differential gene expression analyses [principal component analysis (PCA)/k-means clustering analysis/differentially expressed gene (DEG) analyses] were performed. We classified DEGs into their functional categories. To validate transcriptomic results, we did quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assays.ResultsFU1 isolate was selected from seven candidates, based on re-obtained CIA data with less cytotoxicity. Total read bases of 6.17–9.02 Gbp were obtained by RNA-sequencing. PCA and k-means clustering analysis indicated clustering according to their inoculation times. Volcano plots and Venn diagrams revealed that S. canis invasion into keratinocytes produced altered distributions of many genes. Gene ontology enrichment analysis showed most of the gene expressions were downregulated. DEG functional analysis showed the downregulated DEGs belonging to energy production and conversion/carbohydrate transport and metabolism/amino acid transport and metabolism/nucleotide transport and metabolism, with the upregulated DEGs belonging to transcription. qRT-PCR assays for downregulated/upregulated expressions of four genes (pgk–slo/opuAA–kdpB) validated transcriptomic results.ConclusionOur observations suggest that S. canis can downregulate its metabolism-associated gene expressions in human keratinocyte environments. The observed gene expression changes can imply the latent infection in human cells. Further investigation is needed to elucidate the underlying mechanisms for the latent infection.

Reasons for acceptance or nonparticipation in iAdhere: a trial of latent TB infection treatment.

<sec><title>BACKGROUND</title>Understanding the motivations behind clinical trial participation can help enhance recruitment strategies and determine the generalizability of trial results. This study focuses on the reasons for participating in or declining the Tuberculosis Trials Consortium Study 33 (iAdhere), a clinical trial on the treatment of latent tuberculosis infection (LTBI).</sec><sec><title>METHODS</title>A quantitative evaluation was conducted among screened patients to ascertain their reasons for participating or not in the iAdhere trial. The study gathered data from enrolled participants and those who chose not to enroll.</sec><sec><title>RESULTS</title>Among 1,002 enrolled individuals, 290 participants provided 749 reasons for enrolling. The most common reasons included access to shorter treatment regimens (56%), avoiding progression to TB disease (45%), and improving health (21%). Of the 670 eligible persons who chose not to enroll, 551 individuals provided 800 reasons, with the most common being a preference for standard therapy (17%), disinterest in study medication or TB therapy (both 13%), and the inconvenience of daily observed treatment (12%).</sec><sec><title>CONCLUSION</title>The desire for shorter treatment options and preventing active disease motivates participation in LTBI trials. The diverse reasons for declining enrolment suggest the importance of developing targeted recruitment strategies. These findings support exploring shorter treatment regimens and can guide future recruitment efforts.</sec>.

Development of KSHV vaccine platforms and chimeric MHV68-K-K8.1 glycoprotein for evaluating the in vivo immunogenicity and efficacy of KSHV vaccine candidates.

Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8 is an etiological agent of Kaposi's Sarcoma, multicentric Castleman's disease, and primary effusion lymphoma. Considering the high seroprevalence reaching up to 80% in sub-Saharan Africa, an effective vaccine is crucial for preventing KSHV infection. However, vaccine development has been limited due to the lack of an effective animal model that supports KSHV infection. Murine Herpesvirus 68 (MHV68), a natural mouse pathogen persisting lifelong post-infection, presents a promising model for KSHV infection. In this study, we developed KSHV vaccine and a chimeric MHV68 carrying the KSHV glycoprotein, serving as a surrogate challenge virus for testing KSHV vaccines in a mouse model. Among KSHV virion glycoproteins, K8.1 is the most abundant envelope glycoprotein with the highest immunogenicity. We developed two K8.1 vaccines: K8.1 mRNA-lipid nanoparticle (LNP) vaccine and K8.126-87-Ferritin (FT) nanoparticle vaccines. Both induced humoral responses in immunized mice, whereas K8.1 mRNA LNP also induced T cell responses. Using BACmid-mediated homologous recombination, the MHV68 M7 (gp150) gene was replaced with KSHV K8.1 gene to generate chimeric MHV68-K-K8.1. MHV68-K-K8.1 established acute and latent infection in the lungs and spleens of infected mice, respectively. Mice immunized with K8.1 mRNA LNP or K8.126-87-FT showed a reduction of MHV68-K-K8.1 titer but not MHV68 wild type (WT) titer in the lung. In addition, viral reactivation of MHV68-K-K8.1 was also significantly reduced in K8.1 mRNA LNP-immunized mice. This study demonstrates the effectiveness of two vaccine candidates in providing immunity against KSHV K8.1 and introduces a surrogate MHV68 system for evaluating vaccine efficacy in vivo.IMPORTANCEKaposi's sarcoma-associated herpesvirus (KSHV) is a prevalent virus that establishes lifelong persistent infection in humans and is linked to several malignancies. While antiretroviral therapy has reduced Kaposi's Sarcoma (KS) complications in people with HIV, KS still affects individuals with well-controlled HIV, older men without HIV, and transplant recipients. Despite its significant impact on human health, however, research on KSHV vaccine has been limited, mainly due to the lack of interest and the absence of a suitable animal model. This study addresses these challenges by developing KSHV K8.1 vaccine with two platforms, mRNA lipid nanoparticle (LNP) and FT nanoparticle. Additionally, chimeric virus, MHV68-K-K8.1, was created to evaluate KSHV vaccine efficacy in vivo. Vaccination of K8.1 mRNA LNP or K8.126-87-FT significantly reduced MHV68-K-K8.1 titers. Developing an effective KSHV vaccine requires an innovative approach to ensure safety and efficacy, especially for the immunocompromised population and people with limited healthcare resources. This study could be a potential blueprint for future KSHV vaccine development.

A modified multiple-criteria decision-making approach based on a protein-protein interaction network to diagnose latent tuberculosis

BackgroundDNA microarrays provide informative data for transcriptional profiling and identifying gene expression signatures to help prevent progression of latent tuberculosis infection (LTBI) to active disease. However, constructing a prognostic model for distinguishing LTBI from active tuberculosis (ATB) is very challenging due to the noisy nature of data and lack of a generally stable analysis approach.MethodsIn the present study, we proposed an accurate predictive model with the help of data fusion at the decision level. In this regard, results of filter feature selection and wrapper feature selection techniques were combined with multiple-criteria decision-making (MCDM) methods to select 10 genes from six microarray datasets that can be the most discriminative genes for diagnosing tuberculosis cases. As the main contribution of this study, the final ranking function was constructed by combining protein-protein interaction (PPI) network with an MCDM method (called Decision-making Trial and Evaluation Laboratory or DEMATEL) to improve the feature ranking approach.ResultsBy applying data fusion at the decision level on the 10 introduced genes in terms of fusion of classifiers of random forests (RF) and k-nearest neighbors (KNN) regarding Yager’s theory, the proposed algorithm reached a sensitivity of 0.97, specificity of 0.90, and accuracy of 0.95. Finally, with the help of cumulative clustering, the genes involved in the diagnosis of latent and activated tuberculosis have been introduced.ConclusionsThe combination of MCDM methods and PPI networks can significantly improve the diagnosis different states of tuberculosis.Clinical trial numberNot applicable.

Isoniazid Prophylaxis Based on Tuberculosis Risk Factors in Living Kidney Transplantation Recipients: A Retrospective Cohort Study

BackgroundTuberculosis (TB) is a major and severe opportunistic infection among solid organ transplant recipients. Chemoprophylaxis is advised for those with latent tuberculosis infection (LTBI). However, the effectiveness of an isoniazid (INH) prophylactic approach based on TB risk factors remains uncertain. MethodsThis study included all living-donor kidney transplant recipients (KTRs) between January 2016 and December 2022. The recipients were categorized into three groups: the risk group with isoniazid (R-INH), the risk group without isoniazid (R-NINH), and the non-risk group (NR), based on the presence of TB risk factors and INH usage. The R-INH group received a 6-month INH prophylactic regimen to prevent post-transplant TB infection. The incidence of active TB among the groups was assessed. ResultsA total of 1348 patients were divided into R-INH (n=108), R-NINH (n=371), and NR (n=869). Forty-seven patients (3.49%) developed TB with an incidence rate of 16.0 per 1000 person-years. Compared to NR, the TB incidence in R-INH was not statistically different (HR, 0.55, 95% CI, 0.07-4.21, P = 0.564), whereas it was significantly higher in R-NINH (HR, 5.04, 95% CI, 2.64-9.62, P < 0.001). The median time from transplantation to TB was 19 months (IQR: 6-39), and 18 patients (38.3%) were diagnosed within one year of transplantation. Ninety-four patients (87.0%) completed INH prophylaxis, with adverse events including two cases of hepatotoxicity (1.85%) and one case of peripheral neuritis (0.93%). ConclusionsA 6-month INH regimen based on TB risk factors is effective and well tolerated for preventing post-transplant TB in KTRs

Study of immune response in a latent tuberculosis infection model

A simple mathematical model describing the immune response during the stage latent tuberculosis infection is established and analyzed. The main purpose of this study is to explore the sustained immune response of the immune system against invaded Mycobacterium tuberculosis in the stage of latent tuberculosis infection. First, the threshold R0 is defined to determine the occurrence of sustained immune response. Then, stability conditions are derived to show that the sustained immune response may converge to a constant or to a stable periodical oscillation, implying that the Mycobacterium tuberculosis, the infected macrophages, the activated uninfected macrophages, and the immune cells coexist to form the tuberculous granuloma structure. This structure may appear calcified if the system solution converges to a constant, or maintains a dynamic balance if the system solution undergoes a periodical oscillation. These findings well demonstrate the process of sustained immune response in the latent tuberculosis infection as the Mycobacterium tuberculosis is changing. Numerical examples are presented to illustrate the theoretical predictions.

Role of dormancy survival regulator and resuscitation-promoting factors antigens in differentiating between active and latent tuberculosis: a systematic review and meta-analysis

BackgroundDormancy survival regulator (DosR) and resuscitation-promoting factor (Rpf) antigens of Mycobacterium tuberculosis are activated during dormant phase of tuberculosis (TB). This study evaluates the differential immunogenicity potentials of DosR and Rpf antigens in individuals with latent tuberculosis infection (LTBI) and active TB patients.MethodsAfter a literature search in electronic databases, studies were selected by following precise eligibility criteria. Outcomes were synthesized systematically, and meta-analyses were performed to estimate standardized mean differences (SMDs) in interferon-gamma (IFNγ) levels, and IFNγ positive immune cells between individuals with LTBI and active TB patients.ResultsTwenty-six studies (1278 individuals with LTBI and 1189 active TB patients) were included. DosR antigens Rv0569 (Standardized mean difference; SMD 2.44 [95%CI: 1.21, 3.66]; p < 0.0001), Rv1733c (SMD 0.60 [95%CI: 0.14, 1.07]; p = 0.011), Rv1735c (SMD 1.16 [95%CI: 0.44, 1.88]; p = 0.002), Rv1737c (SMD 1.26 [95%CI: 0.59, 1.92]; p < 0.0001), Rv2029c (SMD 0.89 [95%CI: 0.35, 1.42]; p = 0.002), RV2626c (SMD 1.24 [95%CI: 0.45, 2.02); p = 0.002), and Rv2628 (SMD 0.65 [95%CI: 0.38, 0.91]; p < 0.0001) and Rpf antigens Rv0867c (SMD 1.33 [95%CI: 0.48, 2.18]; p = 0.002), Rv1009 (SMD 0.65 [95%CI: 0.05, 1.25]; p = 0.034), and Rv2450c (SMD 1.54 [95%CI: 0.92, 2.16]; p < 0.0001) elicited higher IFNγ levels in individuals with LTBI in comparison with active TB patients. IFNγ-positive immunoresponsive cells were significantly higher in individuals with LTBI than in active TB patients for antigens Rv1733c (SMD 1.02 [95%CI: 0.15, 1.88]; p = 0.021), Rv2029c (SMD 0.57 [95%CI: 0.05, 1.09]; p = 0.031), and Rv2628 [SMD 0.38 [95%CI: 0.15, 0.61]; p = 0.001).ConclusionDosR antigens Rv0569, Rv1733c, Rv1735c, Rv1737c, RV2626c, Rv2628, and Rv2029c, and Rpf antigens Rv0867c, Rv1009, and Rv2450c are found to elicit immune responses differently in individuals with LTBI and active TB patients.

Antiviral immune response against HTLV-1 invalidates T-SPOT.TB® results in patients with HTLV-1-positive rheumatic diseases

BackgroundT-SPOT.TB®, one of the screening tests for latent tuberculosis infection (LTBI), yields invalid results in human T-cell leukemia virus type 1 (HTLV-1)-positive patients with rheumatoid arthritis. However, the detailed mechanisms behind this invalidation are unclear. Additionally, it remains unclear whether T-SPOT.TB® or QuantiFERON-TB (QFT) is more useful in HTLV-1-positive patients with rheumatic disease (RD).MethodAmong all of the HTLV-1-positive RD patients who visited our department between August 2012 and December 2022, 44 patients who were screened using T-SPOT.TB® were included in the analysis. QFT testing was performed in 33 of the 44 patients, and the results were compared with that of T-SPOT.TB®. Furthermore, we performed a culture experiment mimicking T-SPOT.TB® using peripheral blood mononuclear cells (PBMCs) obtained from HTLV-1-positive patients with RD. Additionally, T-cell subsets with autonomous product IFN-γ were analyzed using a flow cytometer.ResultsOf the included patients, 13 (29.5%) were invalid for T-SPOT.TB® because of the increased number of negative control spots. The median HTLV-1 proviral load in the invalid group was higher than that in the valid group (2.45 vs. 0.49 copies/100 PBMCs, respectively, p = 0.002). QFT was performed in all 33 patients, including 13 patients who were invalid in T-SPOT.TB®. The main source of IFN-γ production was CD8+ T-cells in the T-SPOT.TB® mimic experiment. Furthermore, Tax-expressing CD4+ T-cells and Tax-specific cytotoxic CD8+ T-cells were more frequently observed in patients with invalid results than in patients with valid results. CD4+ T-cell depletion in the T-SPOT.TB® mimic experiment reduced the population of IFN-γ producing CD8+ T cells.ConclusionT-SPOT.TB® may be invalidated by the interaction between Tax-expressing CD4+ T-cells and cytotoxic CD8+ T-cells. Moreover, HTLV-1-associated immune reactions due to contact between these cells may be unlikely to occur in QFT using whole blood. Therefore, our results reveal the superiority of QFT over T-SPOT.TB® as a screening test for LTBI in HTLV-1-positive patients with RD.

Latent tubercolosis infection in the migrant population: an Italian surveillance experience

Abstract Background The Special Reception Center (“Centro Accoglienza Straordinario” or CAS in Italian) concept was born in Italy in 2014 to receive the large number of migrants arriving in Italy. There are around 3100 centres are in Italy, of which 200+ in Tuscany. Each Center’s objective is to support migrants’ social integration through Italian language and job orientation courses. On arrival at a facility, migrants undergo diagnostic and lab tests to highlight potentially infectious diseases; among these, tuberculosis is one of the most frequently encountered. Therefore, the objective of the study is to estimate the prevalence of Latent Tuberculosis Infections (LTBIs) among migrants hosted in CAS centers. Methods From May-December 2023, Amiata Senese, Val d’Orcia and Valdichiana Senese Public Health Unit staff, according to national and departmental guidelines, implemented a number of health surveillance protocols, with close attention to latent tuberculosis infection. This protocol includes the Mantoux TB skin test at the CAS: in case of positivity, subjects are directed to further exams (chest X-ray, TB-IGRA blood test, infectious disease specialist consultation) in order to implement a therapy. Results From May-December 2023, 259 migrants (241 males and 18 females) received the TB skin tests. Average subject age was 26. Pakistan was the most represented nation of origin with 130 migrants (50%), followed by Bangladesh (9.7%) and Ivory Coast (7.3%). 77 migrants showed a positive TB skin test result (29.7%): of these 56 (i.e. 21.6% of the migrants screened) were also positive to the TB-IGRA blood test and treated for LTBI. Conclusions The high prevalence of LTBIs found in the referenced CAS indicates the need to continue/extend these surveillance protocols. Implementing successfully this procedure requires the involvement of a range of professionals from the socio-health sector within a process necessarily coordinated by the Disease Prevention Department. Key messages • Screening and surveillance of infectious diseases among migrant population represent a major public health issue for European health systems. • Detection and treatment of Latent Tubercolosis Infections require a multiprofessional and integrated approach, coordinated by the Disease Prevention Department.

The impacts of tobacco and nicotine on HIV-1 infection, inflammation, and the blood-brain barrier in the central nervous system

Human immunodeficiency virus (HIV-1) remains a persistent global health crisis. Even while successfully virologically suppressed, people with HIV (PWH) experience a higher risk for inflammatory disorders such as HIV-associated neurocognitive disorder (HAND). Tobacco use puts PWH at higher risk for neurocognitive symptoms resulting from HIV-associated neuroinflammation. The NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome has been implicated as a driver of HIV-associated inflammation, including HAND. Nicotine, the psychoactive component of tobacco smoke, has also been shown to signal through the NLRP3 inflammasome and modulate inflammatory signaling in the CNS. Here, we explore the impacts of nicotine and tobacco on the complex neurobiology of HAND, including effects on cognition, inflammation, viral latency, and blood-brain barrier integrity. We outline nicotine’s role in the establishment of active and latent infection in the brain and posit the NLRP3 inflammasome as a common pathway by which HIV-1 and nicotine promote neuroinflammation in PWH.

Changes in TB contact tracing during the COVID-19 pandemic. An Irish single centre experience

Abstract Contact tracing following the diagnosis of tuberculosis (TB) is a crucial process in the identification and treatment of both secondary TB cases and also infected contacts who may require treatment for latent TB infection. During the COVID-19 pandemic, Public Health and Respiratory teams in the St Vincent’s University Hospital (SVUH) TB clinic in Dublin, Ireland, noted anecdotally that there appeared to be fewer contacts screened by public health services per index active TB case identified. To investigate this, we performed a retrospective review of the TB contact tracing service in SVUH, examining and comparing contact tracing of active TB cases in the 3 years prior to the pandemic (2017-2019) and four years thereafter (2020-2023). Results from 2017-2019 calendar years, prior to the COVID-19 pandemic noted an average of 4.77 contacts per index TB case (total 107 index cases and 510 contacts). In comparison, our data from 2020-2022 noted an average of 3.03 contacts per index TB case (total 59 index cases and 179 contacts). As pandemic restrictions were lifted again, we found our 2023 data to be more comparable to that of pre-pandemic times, noting 4.54 contacts per index case (total 22 index cases and 100 contacts). The reduction in TB contacts per index cases noted during the COVID-19 pandemic may reflect work and lifestyle changes over that time, particularly an increase in remote work but also social distancing. It is interesting that as the population emerged from the isolation measures of the pandemic, contact numbers returned quickly to pre-pandemic levels. In line with global concerns, our data highlights the ongoing workload of TB contact tracing locally and the importance of resource allocation for these services. Key messages • Our Irish centre experienced a notable but temporary reduction in contacts requiring screening by public health services, per index active TB case, during the COVID-19 pandemic. • In line with global concerns, our data highlights the ongoing workload of TB contact tracing locally and the importance of resource allocation for these services.

A prolonged outbreak of tuberculosis associated with an intellectual disability daycentre in Ireland

Abstract One of the factors impeding tuberculosis elimination in low burden countries is its persistence and concentration in vulnerable populations. This is a complex, prolonged Tuberculosis (TB) outbreak in a daycentre for adults with intellectual disability in Ireland. This is a particularly vulnerable population with special considerations for Public Health (PH) management. There are eight cases of active TB, 46 cases of Latent TB Infection (LTBI) and a cumulative total of 116 contacts associated with this outbreak, with diagnosis spanning 15 years. The last three cases were identical on Whole Genome Sequencing. The index case was an Irish-born, Caucasian, social care worker, with smear positive pulmonary TB, who was symptomatic in the facility for three months prior to diagnosis. Case 2 was a household contact of the index case and the other 6 cases were Service Users (SUs) at the facility. At least five of the subsequent seven cases are secondary cases of the index case. Significant to this outbreak was the change in Irish guidance, 2010, relating to the management of contacts of cases. Following the notification of the most recent case, July 2023, the Outbreak Control Team decided a retrospective review be conducted of all SU contacts of the seven cases associated with the facility. The contacts were stratified according to hierarchical risk. A total of six contacts met the criteria for review and offered screening, re-screening or treatment as appropriate. In this outbreak 21.8% of the total contacts and 16.1% of SU contacts completed treatment for LTBI. The significance of this outbreak lies in its duration, infectivity of the index case and particular vulnerabilities of the SUs. There were issues with overcrowding and difficulties in relation to symptom recognition, diagnosis and treatment. The PH team tailored their approach to meet the SU needs, demonstrating the importance of person-centred contact tracing in the disruption of transmission. Key messages • A factor impeding tuberculosis elimination in low burden countries is it’s persistence and concentration in vulnerable populations. • Adapting a patient-centred approach to contact tracing can lead to higher participation rate and the disruption of infection transmission.

European guidelines for the management of tuberculosis screening in migrants: a systematic review

Abstract Background This systematic review assesses the current available evidence across the WHO European region on the effectiveness and cost-effectiveness of the different approaches used for TB screening and also explores the facilitators and barriers that migrants face during screening programs. Methods We conducted an extensive, comprehensive, and systematic literature search across multiple databases, including MEDLINE, Cochrane, Scopus, and ISI Web of Knowledge, without any restrictions on publication date or language. In addition, we reviewed grey literature and reports from WHO. The data were meticulously analyzed using RStudio, with a focus on screening effectiveness indicators, such as infection and disease detection rates, uptake, coverage, and cost-effectiveness economic analyses. Results Our review included 43 studies covering over 8 million migrants from 11 countries. The findings demonstrate that while screening uptake was high, coverage varied, and completion rates for preventive treatments were low. Economic analyses supported the high cost-effectiveness of the screening programs, particularly when integrating both active TB and LTBI screening strategies. Conclusions The implementation of uniform screening protocols could potentially streamline efforts, reduce TB transmission, and offer substantial public health and economic benefits, making this research highly relevant for policymakers and healthcare providers. Key messages • An important strength of this study lies in its pioneering approach of current recommendations regarding screening for latent tuberculosis infection and active TB within the WHO European region. • This is the first study that provides a comprehensive overview of screening interventions across 11 countries and incorporates studies with large sample sizes (n &amp;gt; 8 million migrants).

Latent cytomegalovirus infection associates with impairments in myocardial reperfusion, left-ventricular function, and quality of life after ST-elevation myocardial infarction

Abstract Introduction Cytomegalovirus (CMV) is a ubiquitous herpesvirus affecting the majority of adults in European countries. CMV influences T-lymphocyte biology throughout life. We have previously associated CMV status with adverse left ventricular (LV) remodeling after ST-elevation myocardial infarction (STEMI) in a single-centre study. In this study, we aimed to assess the external validity of these findings. Methods This study is a retrospective analysis of 354 patients presenting with STEMI, who were recruited to A Trial of Low-Dose Adjunctive Alteplase During Primary PCI (T-TIME) and had blood samples archived. The participants underwent immediate coronary angiography and percutaneous coronary intervention (PCI), serial cardiovascular magnetic resonance (CMR) imaging at 2-7 days and 3 months post-STEMI, and serial assessment of health-related quality of life with the standardised EQ-5D visual analogue scale (VAS). CMV IgG titre was measured in cryopreserved samples from each patient, and patients were categorised as CMV negative, low-positive or high-positive. All analyses were adjusted for infarct location. Results Of 354 patients, 175 (49.4%) were CMV IgG titre negative, 89 (25.1%) were low-positive and 90 (25.4%) were high-positive. CMV+ patients were older (62.5 vs 58.7 years) and more likely to be non-White (6.7% vs 2.3%). CMV+ patients displayed several adverse outcomes. First, myocardial reperfusion was impaired. Thrombolysis in myocardial infarction (TIMI) flow grade 3 after PCI, indicating complete reperfusion, was less common in CMV+ patients (76.0% vs 84.6%; p=0.042). CMV+ patients also had a higher TIMI frame count after PCI (p=0.021), and non-significantly less ST-segment resolution at 60 minutes (38.8% vs 48.4%; p=0.066). Impaired myocardial reperfusion appeared to lead to impaired LV function, with LV ejection fraction (LVEF) measured on early CMR lower in CMV+ patients (42.6% vs 45.3%, p=0.004). At 3 months, LV function remained impaired in CMV+ patients (LVEF: 47.8% vs 49.7%; p=0.035). This was mirrored by CMV+ patients displaying higher NT-pro BNP levels at 2-7 days (1381 vs 1172pg/mL, p=0.097) and 3 months (575 vs 338pg/mL, p=0.021). Finally, impaired LV function appeared to affect quality of life. Over 3 months, in contrast to CMV-negative patients, those with the highest CMV IgG experienced almost no improvement in quality of life, measured by change in the EQ-5D VAS (negative: +9.93; high-positive: +0.70; p=0.0002). Conclusion CMV+ patients with STEMI experience worse outcomes, with impaired reperfusion, persistently reduced LV function and less improvement in health-related quality of life over 3 months. We hypothesise that the effect of CMV is mediated through immune activation. Future research should explore the mechanisms by which CMV-specific lymphocytes interact with myocardial reperfusion and repair post-STEMI.

Expression of Immunodominant gI Protein of Duck Enteritis Virus and its Evaluation for ELISA

Background: Duck plague (DP), also known as duck viral enteritis (DVE) caused by Anatid alpha herpesvirus-1, is the major infectious viral disease reported in India very often with significant economic losses due to high morbidity and mortality. The genome is approximately 158,091 bp with a genomic arrangement pattern (UL-IRS-US-TRS) that corresponds to type-D herpesvirus. The incubation period of the disease in domestic ducks ranges from 3 to 7 days and the mortality varies from 5-100%. It has been reported that the strategies to monitor and control DVE were often frustrating because the disease tends to establish a latent infection in waterfowl and vaccination failure. The present study was taken as an attempt to develop indirect ELISA using developed recombinant gI protein to diagnose DEV in field condition. Methods: In this study, we selected a membrane glycoprotein protein I (US7) gene, that plays an important role in virion sorting, cell-cell spread and binding of IgG Fc receptor. The gI protein was cloned with pET-32a (+) and expressed in a prokaryotic (E. coli) expression system. Further, recombinant protein was purified by nickel column affinity chromatography and refolded by dialysis. The obtained concentrated protein was then evaluated for its antigenicity and reliability in an Indirect-Enzyme-linked immunosorbent assay (ELISA) for DEV antibody detection in duck sera. Result: A panel of positive, negative and vaccinal serum was evaluated which indicated the potential use of the protein in the development of a serological assay for sero- surveillance of duck plague infection.

A LANA peptide inhibits tumor growth by inducing CHD4 protein cleavage and triggers cell death.

Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a latent infection, and viral genes are poised to be transcribed in the latent chromatin. In the poised chromatins, KSHV latency-associated nuclear antigen (LANA) interacts with cellular chromodomain-helicase-DNA-binding protein 4 (CHD4) and inhibits viral promoter activation. CHD4 is known to regulate cell differentiation by preventing enhancers from activating promoters. Here, we identified a putative CHD4 inhibitor peptide (VGN73) from the LANA sequence corresponding to the LANA-CHD4 interaction surface. The VGN73 interacts with CHD4 at its PHD domain with a dissociation constant (KD) of 14nM. Pre-treatment with VGN73 enhanced monocyte differentiation into macrophages and globally altered the repertoire of activated genes in U937 cells. Furthermore, the introduction of the peptide into the cancer cells induced caspase-mediated CHD4 cleavage, triggered cell death, and inhibited tumor growth in a xenograft mouse model. The VGN73 may facilitate cell differentiation therapy.