Chronic Tuberculosis Research Articles

Global prevalence of hepatitis B or hepatitis C infection among patients with tuberculosis disease: systematic review and meta-analysis

There is a substantial overlap in the epidemiology of chronic hepatitis B (HBV), hepatitis C (HCV) and tuberculosis (TB) due to overlapping risk factors. Testing for viral hepatitis is not widely recommended for patients with TB. The aim of this systematic review was to evaluate the global prevalence of chronic viral hepatitis infection among patients with TB. MEDLINE, EMBASE, Web of Science, Cochrane Library, African Journals Online, LILACS, and country TB reports were searched for studies published between January 1st, 2011 and June 17th 2021. Random-effects meta-analyses for proportions were conducted to obtain pooled prevalences. The prevalence of chronic HBV/HCV infection among patients with TB was also compared to that in the general population. The protocol was registered on PROSPERO (CRD42021276468). This analysis included 127 studies (83 for both HBV and HCV, 28 for HBV only, and 25 for HCV only) and data from 94,936 patients. The global pooled seroprevalence was 5.8% (95% CI 5.0-6.8) for HBs-antigen and 10.3% (95% CI 8.4-12.3) for HCV-antibodies. Pooled prevalence was highest in the WHO African Region for HBV at 7.8% (95% CI 5.2-10.9) and in the WHO European Region at 17.5% (95% CI 12.2-23.5) for HCV. In studies among TB patients who inject drugs, HCV prevalence was 92.5% (95% CI 80.8-99.0). Pooled HCV-antibody seroprevalence among patients with TB was higher than in the general population in all six WHO regions while HBs-antigen seroprevalence was higher in 3/6 regions. This review highlights the syndemicity of chronic viral hepatitis and TB and suggests that routine testing for hepatitis upon TB diagnosis may be justified. The prevalence of chronic HBV and HCV infections was higher among patients with TB than in the general population. This study was study was funded by the Global Tuberculosis Programme, World Health Organization.

Antibodies against Histoplasma capsulatum and Aspergillus fumigatus among chronic TB patients in Indonesia: a cross-sectional study.

Chronic pulmonary fungal infections may occur in patients with previous history of pulmonary tuberculosis (TB), and are often clinically misclassified as TB, especially when bacteriological confirmation for Mycobacterium tuberculosis is absent. In this study, we investigated the prevalence of antibody against Histoplasma capsulatum and Aspergillus fumigatus in patients with confirmed and clinically chronic TB. Antibodies against H. capsulatum and A. fumigatus were measured from serum samples using enzyme-linked immunosorbent assay (ELISA). The presence M. tuberculosis in sputum was confirmed using smear microscopy, GeneXpert MTB/RIF assay, or culture. Antibodies against H. capsulatum and A. fumigatus were elevated in 16.9% and 26.9% of bacteriologically confirmed chronic TB patients, and 12.1% and 18.2% in those without bacteriological confirmation, respectively. Approximately one-third of patients who had positive anti-Histoplasma antibody also had elevated levels of antibody against Aspergillus fumigatus (P<.001). Our study highlights the importance of chronic pulmonary fungal infection in post-TB patients with recurrent respiratory symptoms.

Identification of potential compounds for the management of multidrug-resistant tuberculosis using computational methods

Background: Tuberculosis is caused by Mycobacterium tuberculosis and is spread through the air. Multidrug-resistant tuberculosis (MDR TB) has become a global health concern. This study focuses on developing alternative compounds to Levofloxacin, Moxifloxacin, Bedaquiline, Kanamycin, Amikacin, Cycloserine, Ethambutol, Pyrazinamide, Linezolid and Streptomycin that can be used to treat patients with multidrug resistance TB. The virtual screening will aid in discovering other possible compounds for use in the management of MDR TB, thereby providing a superior alternative to currently existing medications and aid in eradicating TB. The objective of this study was to identify potential compounds that can be used in managing MDR TB in chronic tuberculosis patients using computational methods. Methods: The Swiss Similarity tool was used to identify similar compounds to the tuberculosis drugs in a ZINC database. Compounds more similar to the tuberculosis drugs were selected and used to test the molecular docking with their respective targets. The pharmacokinetics and toxicity profiles of the selected compounds were analyzed using Swiss ADME and Pro Tox Server, respectively. Results: Overall, 90 compounds had higher binding energies than the medications, 88 had lower binding energies, and 14 had binding energies that were equivalent to those of the drugs. Only 14 of the 200 compounds lacked CYP inhibition, were p-glycoprotein substrates, had superior docking scores to the compounds, and fell into toxicity classes V and VI. Conclusions: The 14 potential compounds should undergo further in vivo and in vitro studies to develop new compounds for managing multidrug-resistant tuberculosis.

B cells promote granulomatous inflammation during chronic Mycobacterium tuberculosis infection in mice.

The current study reveals that in chronic TB, the B cell-deficient μMT strain, relative to wild-type (WT) C57BL/6 mice, displays in the lungs lower levels of inflammation that are associated with decreased CD4+ T cell proliferation, diminished Th1 response, and enhanced levels of interleukin (IL)-10. The latter result raises the possibility that B cells may restrict lung expression of IL-10 in chronic TB. These observations are recapitulated in WT mice depleted for B cells using anti-CD20 antibodies. IL-10 receptor (IL-10R) blockade reverses the phenotypes of decreased inflammation and attenuated CD4+ T cell responses in B cell-depleted mice. Together, these results suggest that in chronic murine TB, B cells, by virtue of their capacity to restrict expression of the anti-inflammatory and immunosuppressive IL-10 in the lungs, promote the development of a robust protective Th1 response, thereby optimizing anti-TB immunity. This vigorous Th1 immunity and restricted IL-10 expression may, however, allow the development of inflammation to a level that can be detrimental to the host. Indeed, decreased lung inflammation observed in chronically infected B cell-deficient mice, which exhibit augmented lung IL-10 levels, is associated with a survival advantage relative to WT animals. Collectively, the results reveal that in chronic murine TB, B cells play a role in modulating the protective Th1 immunity and the anti-inflammatory IL-10 response, which results in augmentation of lung inflammation that can be host-detrimental. Intriguingly, in tuberculous human lungs, conspicuous B cell aggregates are present in close proximity to tissue-damaging lesions manifesting necrosis and cavitation, suggesting the possibility that in human TB, B cells may contribute to the development of exacerbated pathology that is known to promote transmission. Since transmission is a major hindrance to TB control, investigating into whether B cells can shape the development of severe pulmonic pathological responses in tuberculous individuals is warranted.

Joint modeling of longitudinal change in pulse rate and survival time of heart failure patients treated at Arbaminch General Hospital, Southern Ethiopia.

Heart failure is a chronic progressive disease in which the heart muscle is unable to pump enough blood to meet the body's need. It is a severe health problem around the world with high re-hospitalization and death rates. The main aim of this study was to identify the factors associated with longitudinal change of pulse rate and survival time to death of congestive heart failure patients treated at Arba Minch General Hospital. A retrospective study design was undertaken on congestive heart failure patients admitted to the Arba Minch General Hospital from January 2017 to December 2020. Data was collected from a total of 199 patients. After evaluating the longitudinal data with a linear mixed model and the survival time to death data with cox proportional model, Bayesian joint model of both sub models was fitted in R software using JMbayes2 package. Findings from Bayesian joint model revealed that the estimated value for the association parameter was positive and statistically significant. This indicates that there is significant evidence of an association between the mean longitudinal change of pulse rate and the risk of death. Weight of patients at baseline, gender, chronic kidney disease, left ventricular ejection fraction, New York Heart Association classification, diabetes, tuberculosis, pneumonia and family history were statistically significant factors associated with mean evolution of pulse rate of congestive heart failure patients. Left ventricular ejection fraction, etiology of congestive heart failure, type of congestive heart failure, chronic kidney disease, smoking, family history, alcohol and diabetes were found to be statistically significant factors associated with survival time to death. To reduce the risk level, health professionals should give attention to congestive heart failure patients with high pulse rate, co-morbidities of chronic kidney disease, tuberculosis, diabetic, smoking status, family history, and pneumonia in the study area.

Genome sequences of BCG Pasteur ATCC 35734 and its derivative, the vaccine candidate BCGΔBCG1419c

Background:Bacillus Calmette–Guérin (BCG) remains the only vaccine to prevent tuberculosis (TB) during childhood, with relatively low to no efficacy against pulmonary TB in adolescents and adults. BCG consists of close to 15 different substrains, where genetic variations among them might contribute to the variable protective efficacy afforded against pulmonary TB. We have shown that the vaccine candidate, BCGΔBCG1419c, which is based on BCG Pasteur, improved protection against chronic TB in murine models, as well as against pulmonary and extrapulmonary TB in guinea pigs. Here, to confirm deletion of the BCG1419c gene and to detect possible genetic variations occurring as a consequence of the spontaneous mutations that may arise during in vitro culture of mycobacteria, the genomes of BCG Pasteur ATCC 35734 and its isogenic derivative, BCGΔBCG1419c, were sequenced and subjected to a comparative analysis between them and against BCG Pasteur 1173P2.Results:The complete catalog of variants in genes relative to the reference genome BCG Pasteur 1173P2 (GenBank NC008769) showed that the parental strain BCG Pasteur ATCC 35734, from which the mutant BCGΔBCG1419c originated, showed five synonymous mutations, three missense mutations, and five codon insertions, whereas the BCGΔBCG1419c mutant reported the same changes. When BCG Pasteur ATCC 35734 and BCGΔBCG1419c were compared, we confirmed that the latter was devoid of the BCG1419c gene, with only one unanticipated SNP at position 2, 828, 791 which we consider has no role in vaccine properties reported thus far.Conclusion:We provide evidence that the mutagenesis performed to remove BCG1419c from BCG Pasteur ATCC 35734 solely deleted this gene, and that compared with the reference strain BCG Pasteur 1173P2, few changes were present confirming that they are BCG Pasteur strains, and that changes in immunogenicity or efficacy observed thus far in BCGΔBCG1419c are most likely derived solely from the elimination of the BCG1419c gene.

Hepatotoxicity and tuberculosis treatment outcomes in chronic liver disease.

The treatment of tuberculosis (TB) is known to cause liver injury, however, there is limited data to guide optimal treatment for patients with chronic liver disease. We undertook a retrospective case series of patients with chronic liver disease and TB disease. The primary objective was to determine if there was a difference in the incidence of drug-induced liver injury (DILI) in patients with cirrhosis versus those with chronic hepatitis. Additionally, we sought to compare TB treatment outcomes, type and duration of therapy, and incidence of adverse events. We included 56 patients (chronic hepatitis 40; cirrhosis 16). There were 33 patients (58.9%) who experienced DILI requiring treatment modification, with no significant difference between groups (65% versus 43.8%, p = 0.23). Patients with chronic hepatitis were more likely to receive treatment with standard first-line intensive phase therapy that included a combination of rifampin (RIF), isoniazid, and pyrazinamide (80.8% versus 19.2%, p = 0.03) and any regimen than included isoniazid (92.5% versus 68.8%, p = 0.04). The risk of DILI was higher when more hepatotoxic TB medications were used. Overall treatment success in this cohort was low (55.4%), with no significant difference between groups (62.5% versus 37.5%, p = 0.14). Most patients with treatment success (97%) were able to tolerate a rifamycin. The risk of DILI is high, especially with the use of isoniazid, in patients with TB and chronic liver disease. This risk can be effectively mitigated with no difference in treatment outcomes in the presence of cirrhosis.

Molecular mechanisms of inflammation in the pathogenesis of respiratory disorders in patients with pulmonary tuberculosis

Aim. To assess external respiration (ER) and its relationship with the activity of enzymes involved in purine metabolism in patients with acute and chronic forms of pulmonary tuberculosis (TB).Materials and methods. In patients with acute and chronic TB, we assessed the activity of adenosine deaminase (ADA)-1, 2 in the blood serum (eADA), mononuclear cells, and neutrophils, the concentration of ecto-5’-nucleotidase (eNT5E) in the blood serum, the level of CD26 (dipeptidyl peptidase-4, DPPIV) in the blood serum and mononuclear cells, production of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI) in mononuclear cells and neutrophils, as well as parameters of ER.Results. Patients with TB were found to have an increase in the concentration of eNT5E and eADA-2 activity in the blood serum, stimulated production of ROI in neutrophils, a decrease in the concentration of DPPIV (CD26) in mononuclear cells, and a fall in the production of RNI in mononuclear cells and neutrophils. In patients with chronic TB, a decrease in the activity of ADA-1 in mononuclear cells and a fall in the concentration of DPPIV (CD26) in the blood serum were noted. In patients with acute TB, a decrease in the activity of eADA-1 in the blood serum and ADA-1 in neutrophils, reduced production of ROI in mononuclear cells, and an increase in spontaneous production of ROI in neutrophils were revealed. Correlations were found between the parameters of ER and the concentration of eNT5E in the blood serum, spontaneous production of ROI in mononuclear cells and production of RNI in neutrophils in chronic TB, as well as between eADA-2 in the blood serum, ADA-1 in neutrophils, DPPIV (CD26) activity in mononuclear cells, and ROI and RNI production in mononuclear cells and neutrophils.Conclusion. The data obtained make it possible to associate regulation of external respiration with parameters of purine metabolism, in particular with the concentration and activity of enzymes responsible for generation and metabolism of adenosine, that determine its level outside cells and inside mononuclear cells and neutrophils, with expression of cofactor molecules, as well as with the duration of activation of cells in innate immunity, neutrophils, and monocytes/ macrophages, determined largely by the potential of adenosine regulation.

Diets Differently Regulate Pulmonary Pathogenesis and Immune Signaling in Mice during Acute and Chronic Mycobacterium tuberculosis Infection.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) infection persists as a leading cause of mortality and morbidity globally, especially in developing and underdeveloped countries. The prevalence of TB-DM (diabetes mellitus) is higher in low- and middle-income countries where TB and DM are most prevalent. Epidemiological data suggest that slight obesity reduces the risk of TB, whereas DM increases the risk of pulmonary TB. Diets can alter the levels of body fat mass and body mass index by regulating systemic adiposity. Earlier, using a transgenic Mtb-infected murine model, we demonstrated that loss of body fat increased the risk of pulmonary bacterial load and pathology. In the present study, we investigated whether increased adiposity alters pulmonary pathology and bacterial load using C57BL/6 mice infected with HN878 Mtb strain and fed a medium-fat diet (MFD). We analyzed the effects of MFD on the lung during acute and chronic infections by comparing the results to those obtained with infected mice fed a regular diet (RD). Histological and biochemical analyses demonstrated that MFD reduces bacterial burden by increasing the activation of immune cells in the lungs during acute infection and reduces necrosis in the lungs during chronic infection by decreasing lipid accumulation. Our data suggest that slight adiposity likely protects the host during active TB infection by regulating immune and metabolic conditions in the lungs.

Prolonged B-Lymphocyte-Mediated Immune and Inflammatory Responses to Tuberculosis Infection in the Lungs of TB-Resistant Mice.

During tuberculosis (TB) infection, B-lymphocytes migrate to the lungs and form B-cell follicles (BCFs) in the vicinity of TB granulomata. B-cell-lacking mice display enhanced susceptibility to TB infection, and early B-cell depletion in infected non-human primates alters T-lymphocyte cytokine responses and increases bacterial burdens in the lungs. However, the role of B cells during late TB stages remained unaddressed. Here, we demonstrate that B cells and BCFs persist up to weeks 25-45 post-challenge in the lungs of TB-resistant C57BL/6 (B6) mice. In hyper-susceptible I/St mice, B-cell content markedly drops between weeks 12-16 post-infection, paralleled by diffuse lung tissue inflammation and elevated gene expression levels for pro-inflammatory cytokines IL-1, IL-11, IL-17a, and TNF-α. To check whether B-cells/BCFs control TB infection at advanced stages, we specifically depleted B-cells from B6 mice by administrating anti-CD20 mAbs at week 16 post-infection. This resulted in more rapid cachexia, a shortened lifespan of the infected animals, an increase in (i) lung-infiltrating CD8+ T cells, (ii) IL-6 production by F4/80+ macrophages, (iii) expression levels of genes for neutrophil-attracting factors CXCL1 and IL-17, and tissue-damaging factors MMP8, MMP9, and S100A8. Taken together, our results suggest that lung B cells and BCFs are moderately protective against chronic TB infection.

Klinická prezentácia tuberkulózy na intenzívnej jednotke

Tuberculosis is a curable communicable infectious disease in majority caused by bacillus Mycobacterium tuberculosis. Tuberculosis patients requiring acute intensive care make up about 1-3% of all tuberculosis patients. Targeted therapy is often delayed due to the atypical progression of the tuberculosis disease and its forms. Patients with respiratory failure due to advanced destruction of the lung parenchyma in pulmonary tuberculosis are among the most common reasons for admission to the intensive care unit. Massive hemoptysis as a symptom of advanced chronic tuberculosis is a severe condition with a risk of suffocating the patient. Neurological symptoms in miliary tuberculosis are a common sign of advanced disease, leading the patient to the intensive care department. Tuberculosis patients, regardless of age, often present with serious hypoalbuminemia, which is a significant predictor of mortality and morbidity.

Harmful Alcohol Use Among Patients with Tuberculosis in Gedeo Zone, Southern Ethiopia.

Alcohol consumption among patients with tuberculosis is on the rise. There is evidence that alcohol consumption negatively affects treatment outcomes for these populations. Due to this, a substantial number of people relapse, withdraw from treatment, or even die as a result of their alcohol addiction. Despite this, little research has been conducted on the factors associated with the harmful use of alcohol by this group of people in Ethiopia. The purpose of this study was to determine the prevalence and associated factors of harmful alcohol use among patients with tuberculosis in the Gedeo Zone, southern Ethiopia. A cross-sectional study was conducted at healthcare facilities. Four hundred and fifteen participants aged 18 and older were recruited using a systematic random sampling method. Data on sociodemographic factors, clinical factors, social support, perceptions of the stigma associated with tuberculosis, and depression were collected using structured and validated instruments. Measurement of harmful alcohol consumption was conducted using the AUDIT. The prevalence of harmful alcohol use among tuberculosis patients was 20% (95% CI; 16.1-24.2%). There is a significant correlation between medical comorbidity (AOR = 2.44, 95% CI: 1.29-4.62), disease duration (≥12 months) (AOR = 2.88, 95% CI: 1.03-3.04), and being male (AOR = 2.10, 95% CI: 1.17-3.77) with harmful alcohol consumption. Our study revealed that alcohol consumption was high among tuberculosis patients. The presence of comorbidities, being male, and having a long-term illness were significant predictors of harmful alcohol consumption. It is imperative to screen patients who have suffered from chronic tuberculosis for an extended period of time. It is also pertinent to screen patients with comorbid medical conditions for alcohol abuse. Screening for alcohol abuse at an early stage can prevent poor treatment outcomes as well as the effects of comorbid medical conditions and harmful use of alcohol.

Dynamic analysis of tuberculosis specific mononuclear cells in peripheral blood of HIV patients with tuberculosis

Objective: To evaluate the response of peripheral blood mononuclear cells (PBMCs) in patients with human immunodeficiency virus (HIV) combined with active tuberculosis (TB) to TB-specific antigen stimulation. Methods: From January to December, 2018, individuals infected with both HIV and TB (HIV/TB group) were taken as the study subjects. Individuals infected with HIV alone (HIV group), individuals infected with TB alone (TB group) and healthy people (Health control group, HC group) were taken as the control groups. PBMCs were isolated and stimulated with purified protein derivative of bacillus calmette-guerin (BCG-PPD). The expression of surface molecules in T cells (CD3+, CD4+, CD8+) and monocytes (CD14+) and the percentages of Interferon (IFN)-γ and tumor necrosis factor (TNF)-α were detected by cell surface molecular staining, direct intracellular cytokine staining and flow cytometry (CD3- lymphocytes were mainly B lymphocytes and NK cells). Analysis of non-parametric data was used to compare the data between the two groups, and paired t-test was used to compare the data before and after PPD stimulation in each group. Results: Before PPD stimulation, the percentage of IFN-γ+ CD8+ cells in the peripheral blood of HIV/TB group(mean 0.52%) was significantly lower than that in TB group(mean 0.94%, P=0.010). The TNF-α+cell percentages in CD3+, CD4+, CD8+, or CD14+ cells in the HIV/TB group(mean 19.2%) were significantly lower than those in the HIV group(mean 31.9%, P=0.002). The percentage of TNF-α secreted by monocytes in the HIV group was significantly lower than that in the HC group. The percentages of IFN-γ+ CD8+ and IFN-γ+ CD3- cells in the peripheral blood of the TB group (mean 0.94%) were significantly higher than thoset in the HC group(mean 0.51%, P=0.020), while the percentages of TNF-α+ cells in each subsets of PBMCs were significantly lower than those in the HC group. After PPD stimulation, the percentage of IFN-γ+ CD8+ cells in the HIV/TB group was significantly lower than that in the TB group(P=0.008), and the change was more marked than that before stimulation. The percentage of IFN-γ+ CD8+ cells in the HIV group(mean 0.20%) was lower than that in the HC group (mean 0.52%, P=0.044). The percentage of IFN-γ+ CD3- in the TB group was significantly higher than in the HC group. There were no significant differences in TNF-α+ cell percentages in the 3 groups compared with the control group after PPD stimulation. The percentages of IFN-γ+ CD4+ cells in the HC and the TB groups were significantly increased after PPD stimulation in each group (P=0.002, P=0.001, respectively). However, there were no significant differences of IFN-γ+ CD4+ cell percentages in the HIV/TB group and the HIV group. The percentages of TNF-α production by monocytes were significantly increased after PPD stimulation in all groups. Conclusions: Chronic Mycobacterium tuberculosis (MTB) infection reduced the ability of PBMCs to produce TNF-α. For patients with TB infection, the production of TNF-α was reduced when combined with HIV infection. The capacity of CD8+ and CD3- lymphocytes to produce IFN-γ was increased in TB patients, while the capacity of CD8+ T cells to produce IFN-γ was decreased with co-infection of HIV. Infection of HIV weakened the immune response to MTB infection, which made the clinical diagnosis and treatment of TB more difficult.

Stromal structure remodeling by B lymphocytes limits T cell activation in lymph nodes of Mycobacterium tuberculosis-infected mice.

An effective adaptive immune response depends on the organized architecture of secondary lymphoid organs, including the lymph nodes (LNs). While the cellular composition and microanatomy of LNs under steady state are well defined, the impact of chronic tissue inflammation on the structure and function of draining LNs is incompletely understood. Here we showed that Mycobacterium tuberculosis infection remodeled LN architecture by increasing the number and paracortical translocation of B cells. The formation of paracortical B lymphocyte and CD35+ follicular dendritic cell clusters dispersed CCL21-producing fibroblastic reticular cells and segregated pathogen-containing myeloid cells from antigen-specific CD4+ T cells. Depletion of B cells restored the chemokine and lymphoid structure and reduced bacterial burdens in LNs of the chronically infected mice. Importantly, this remodeling process impaired activation of naive CD4+ T cells in response to mycobacterial and unrelated antigens during chronic tuberculosis infection. Our studies reveal a mechanism in the regulation of LN microanatomy during inflammation and identify B cells as a critical element limiting the T cell response to persistent intracellular infection in LNs.

Expert consensus on the treatment of chronic kidney disease with tuberculosis (2022 version)

China is a country with a high burden of chronic kidney disease(CKD) and tuberculosis. Patients with CKD are at increased risk of Mycobacterium tuberculosis infection, and the prevalence of CKD is also significantly higher in patients with tuberculosis. The coexistence of the two diseases brings great difficulties for clinical treatment. In this consensus, the general situation, clinical characteristics, metabolic characteristics of anti-tuberculous drugs, and the principles of protocol formulation of such patients were discussed and summarized. When making anti-tuberculosis regimen for patients with chronic renal failure, drugs that metabolized through liver, liver and kidney channels or metabolic pathways other than liver and kidney should be selected as far as possible. Drugs with significant renal toxicity and mainly metabolized by the kidney should be avoided. For CKD patients with mild decrease in GFR (60-89 ml·min-1·1.73 m-2), anti-tuberculosis regimen should be carried out according to the national standards and guidelines, without reducing the dose of anti-tuberculosis drugs. For CKD patients with significantly reduced GFR, mainly CKD3b, stages 4-5, and those receiving dialysis, the anti-tuberculosis regimen must be adjusted according to the GFR. For CKD patients with GFR less than 30 ml·min-1·1.73 m-2, this consensus also recommended anti-tuberculous regimen for initial, retreated and multi-drug-resistant tuberculosis patients. This consensus aimed to improve clinicians' understanding of CKD complicated with tuberculosis, standardize the clinical treatment, improve the curative effect, and reduce adverse reactions. Data from previous trials of CKD combined with TB treatment are still scarce. We look forward to further investigation and evidence-based medical research on CKD with tuberculosis in the future, and make positive efforts for the control of CKD and tuberculosis in China.

Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs

Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold.

BCGΔBCG1419c increased memory CD8+ T cell-associated immunogenicity and mitigated pulmonary inflammation compared with BCG in a model of chronic tuberculosis

Previously, we reported that a hygromycin resistant version of the BCGΔBCG1419c vaccine candidate reduced tuberculosis (TB) disease in BALB/c, C57BL/6, and B6D2F1 mice infected with Mycobacterium tuberculosis (Mtb) H37Rv. Here, the second-generation version of BCGΔBCG1419c (based on BCG Pasteur ATCC 35734, without antibiotic resistance markers, and a complete deletion of BCG1419c) was compared to its parental BCG for immunogenicity and protective efficacy against the Mtb clinical isolate M2 in C57BL/6 mice. Both BCG and BCGΔBCG1419c induced production of IFN-γ, TNF-α, and/or IL-2 by effector memory (CD44+CD62L−), PPD-specific, CD4+ T cells, and only BCGΔBCG1419c increased effector memory, PPD-specific CD8+ T cell responses in the lungs and spleens compared with unvaccinated mice before challenge. BCGΔBCG1419c increased levels of central memory (CD62L+CD44+) T CD4+ and CD8+ cells compared to those of BCG-vaccinated mice. Both BCG strains elicited Th1-biased antigen-specific polyfunctional effector memory CD4+/CD8+ T cell responses at 10 weeks post-infection, and both vaccines controlled Mtb M2 growth in the lung and spleen. Only BCGΔBCG1419c significantly ameliorated pulmonary inflammation and decreased neutrophil infiltration into the lung compared to BCG-vaccinated and unvaccinated mice. Both BCG strains reduced pulmonary TNF-α, IFN-γ, and IL-10 levels. Taken together, BCGΔBCG1419c increased memory CD8+T cell-associated immunogenicity and mitigated pulmonary inflammation compared with BCG.

An intranasal stringent response vaccine targeting dendritic cells as a novel adjunctive therapy against tuberculosis.

Lengthy tuberculosis (TB) treatment is required to overcome the ability of a subpopulation of persistent Mycobacterium tuberculosis (Mtb) to remain in a non-replicating, antibiotic-tolerant state characterized by metabolic remodeling, including induction of the RelMtb-mediated stringent response. We developed a novel therapeutic DNA vaccine containing a fusion of the relMtb gene with the gene encoding the immature dendritic cell-targeting chemokine, MIP-3α/CCL20. To augment mucosal immune responses, intranasal delivery was also evaluated. We found that intramuscular delivery of the MIP-3α/relMtb (fusion) vaccine or intranasal delivery of the relMtb (non-fusion) vaccine potentiate isoniazid activity more than intramuscular delivery of the DNA vaccine expressing relMtb alone in a chronic TB mouse model (absolute reduction of Mtb burden: 0.63 log10 and 0.5 log10 colony-forming units, respectively; P=0.0002 and P=0.0052), inducing pronounced Mtb-protective immune signatures. The combined approach involving intranasal delivery of the DNA MIP-3α/relMtb fusion vaccine demonstrated the greatest mycobactericidal activity together with isoniazid when compared to each approach alone (absolute reduction of Mtb burden: 1.13 log10, when compared to the intramuscular vaccine targeting relMtb alone; P<0.0001), as well as robust systemic and local Th1 and Th17 responses. This DNA vaccination strategy may be a promising adjunctive approach combined with standard therapy to shorten curative TB treatment, and also serves as proof of concept for treating other chronic bacterial infections.

Vaccination saves lives: a real-time study of patients with chronic diseases and severe COVID-19 infection.

ObjectivesThis study aims to describe the demographic and clinical profile and ascertain the determinants of outcome among hospitalised COVID-19 adult patients enrolled in the National Clinical Registry for COVID-19 (NCRC).MethodsNCRC is an on-going data collection platform operational in 42 hospitals across India. Data of hospitalized COVID-19 patients enrolled in NCRC between 1st September 2020 to 26th October 2021 were examined.ResultsAnalysis of 29,509 hospitalised, adult COVID-19 patients [mean (SD) age: 51.1 (16.2) year; male: 18752 (63.6%)] showed that 15678 (53.1%) had at least one comorbidity. Among 25715 (87.1%) symptomatic patients, fever was the commonest symptom (72.3%) followed by shortness of breath (48.9%) and dry cough (45.5%). In-hospital mortality was 14.5% (n = 3957). Adjusted odds of dying were significantly higher in age-group ≥60 years, males, with diabetes, chronic kidney diseases, chronic liver disease, malignancy, and tuberculosis, presenting with dyspnea and neurological symptoms. WHO ordinal scale 4 or above at admission carried the highest odds of dying [5.6 (95% CI: 4.6, 7.0)]. Patients receiving one [OR: 0.5 (95% CI: 0.4, 0.7)] or two doses of anti-SARS CoV-2 vaccine [OR: 0.4 (95% CI: 0.3, 0.7)] were protected from in-hospital mortality.ConclusionsWHO ordinal scale at admission is the most important independent predictor for in-hospital death in COVID-19 patients. Anti-SARS-CoV2 vaccination provides significant protection against mortality.

263 Minimally Invasive Non-Radical Nephrectomy for Benign Renal Disease: A Single Centre Experience Comparing Two Surgical Approaches

Abstract In our high-volume tertiary centre for renal disease, we perform in excess of 150 nephrectomies for benign or malignant disease per annum. In this study we compare outcomes between laparoscopic and retroperitoneoscopic minimally invasive (MI) approaches. We retrospectively reviewed our database of all patients who underwent MI non-radical nephrectomy over a 3-year period. Indication for surgery, conversion rate, operative time, blood loss, length of stay and post-operative complications were examined. A total of 61 MI nephrectomies were performed by three experienced minimal access surgeons. Indications for surgery included chronic infection, stone disease, tuberculosis, and obstruction associated with pain. Mean age was 51 years (range 22–89), 72% were female. The approach was laparoscopic in 62% and retroperitoneoscopic in 38%. Median operative time 137 minutes. The overall conversion rate was 3% (2 patients). Median blood loss 50ml's with 1.5% transfusion rate. Median length of stay was 2 days (1–69). There was no significant change in the renal function (P=0.32). Four patients developed Clavien-Dindo grade 3 complication. There was no recorded mortality in our series. We acknowledge this is a retrospective study that may be subject to selection bias, however our experience of this procedure in high volume centre with experienced operators shows that both laparoscopic and retroperitoneoscopic approaches are safe in performing MI non-radical nephrectomy with very low conversion rate.