Search Results (18)

Tuberculosis (TB) continues to be the world’s deadliest infectious disease, with an estimated 10.8 million new cases reported in 2023, of which India alone accounted for 28% of the global burden. This study aims to evaluate the impact of tuberculosis on pulmonary function and exercise tolerance, and to examine how these impairments affect health-related quality of life (HRQoL). In a cross-sectional design, 96 bacteriologically confirmed TB patients and 96 age- and sex-matched community controls underwent spirometry, six-minute-walk test (6 MWT), and HRQoL evaluation. DR-TB was detected in 27 patients (28.1%): Isoniazid monoresistance 59.3%, rifampicin monoresistance 11.1%, and XDR-TB 29.6%. Dyspnoea (70.8%) and cough (37.5%) were the most commonly reported symptoms among TB patients. Mean values of FEV₁, FVC, and FEV₁/FVC were significantly lower in TB patients compared to controls (62.8%, 65.97%, and 70.08% vs. 82.55%, 80.09%, and 78.08%, respectively; p < 0.001). Recurrent or DR-TB was associated with reduced spirometric indices and 6 MWT distances (241 m vs. 358 m in drug-sensitive TB). St. George’s respiratory questionnaire (SGRQ) scores indicated significantly poorer health-related quality of life (HRQoL) in patients compared to controls across all domains—symptoms (23.7 vs. 10.7), activity (33.3 vs. 14.2), and impact (20.6 vs. 9.4; p < 0.05). SGRQ scores were inversely correlated with lung function parameters (r = −0.42 to −0.56). These findings underscore the persistent health burden TB poses post-therapy, highlighting the need for routine post-TB functional screening and robust DR-TB control to achieve End-TB goals. Full article

Background: Pulmonary tuberculosis (TB) frequently leads to long-term lung complications that contribute to increased mortality. Understanding the pathogenesis of post-TB lung impairments is crucial for improving long-term outcomes in TB patients; yet this area remains poorly researched. Methods: Our study assessed circulatory inflammatory markers in patients who completed TB treatment more than one year before enrolment (population 1) and patients receiving in-hospital treatment for active drug-sensitive TB (population 2). Results: IL-6 was seven times higher in both populations compared to the normal range. IL-8 was below the limit of detection (LOD) in population 1, while it was approximately 2.5 times higher in population 2 compared to the normal range. TNF-α was 21 times higher in population 1 and 19 times higher in population 2 compared to the normal range. CRP was almost 49 times higher in both populations, and IL-1Ra was below the LOD in population 1, while it was ~1.5 times higher in population 2 compared to the normal range. Conclusions: These inflammatory biomarkers correlated well with lung function in the post-TB state, and their high levels suggest a persistent pro-inflammatory state post-TB, which may contribute to post-TB lung disease. More research is warranted to better understand this phenomenon, but these findings may highlight a need to consider anti-inflammatory therapy for patients with post-TB lung disease, especially since these high levels of cytokines can directly contribute to lung damage. Full article

Despite the availability of antibiotic therapy, tuberculosis (TB) is prevailing as a leading killer among human infectious diseases, which highlights the need for better intervention strategies to control TB. Several animal model systems, including mice, guinea pigs, rabbits, and non-human primates have been developed and explored to understand TB pathogenesis. Although each of these models contributes to our current understanding of host-Mycobacterium tuberculosis (Mtb) interactions, none of these models fully recapitulate the pathological spectrum of clinical TB seen in human patients. Recently, humanized mouse models are being developed to improvise the limitations associated with the standard mouse model of TB, including lack of necrotic caseation of granulomas, a pathological hallmark of TB in humans. However, the spatial immunopathology of pulmonary TB in humanized mice is not fully understood. In this study, using a novel humanized mouse model, we evaluated the spatial immunopathology of pulmonary Mtb infection with a low-dose inoculum. Humanized NOD/LtSscidIL2Rγ null mice containing human fetal liver, thymus, and hematopoietic CD34+ cells and treated with human cytokines were aerosol challenged to implant <50 pathogenic Mtb (low dose) in the lungs. At 2 and 4 weeks post infection, the tissue bacterial load, disease pathology, and spatial immunohistology were determined in the lungs, liver, spleen, and adipose tissue using bacteriological, histopathological, and immunohistochemical techniques. The results indicate that implantation of <50 bacteria can establish a progressive disease in the lungs that transmits to other tissues over time. The disease pathology in organs correspondingly increased with the bacterial load. A distinct spatial distribution of T cells, macrophages, and natural killer cells were noted in the lung granulomas. The kinetics of spatial immune cell distribution were consistent with the disease pathology in the lungs. Thus, the novel humanized model recapitulates several key features of human pulmonary TB granulomatous response and can be a useful preclinical tool to evaluate potential anti-TB drugs and vaccines. Full article

New control measures are urgently required to control tuberculosis (TB), as the current vaccine, Bacille Calmette–Guérin (BCG), has had a limited impact on disease spread. The identification of virulence mechanisms of Mycobacterium tuberculosis is an important strategy in vaccine design, as it permits the development of strains attenuated for growth that may have vaccine potential. In this report, we determined the role of the PdtaS response regulator in M. tuberculosis virulence and defined the vaccine potential of a pdtaS-deficient strain. Deletion of pdtaS (Mtb^ΔpdtaS) resulted in reduced persistence of M. tuberculosis within mouse organs, which was equivalent to the persistence of the BCG vaccine in the lung and liver of infected mice. However, the generation of effector CD4⁺ and CD8⁺ T cells (CD44⁺CD62L^loKLRG1⁺) was similar between wild-type M. tuberculosis and Mtb^ΔpdtaS and greater than that elicited by BCG. Heightened immunity induced by Mtb^ΔpdtaS compared to BCG was also observed by analysis of antigen-specific IFN-γ-secreting T cell responses induced by vaccination. Mtb^ΔpdtaS displayed improved protection against aerosol M. tuberculosis compared to BCG, which was most apparent in the lung at 20 weeks post-infection. These results suggest that the deletion of the PdtaS response regulator warrants further appraisal as a tool to combat TB in humans. Full article

Objectives: Primary and post-primary tuberculosis (TB) are distinct entities. The aim of this study was to study the histopathology of primary and post-primary TB by using the unique human autopsy material from the pre-antibiotic era, 1931–1947. Material and Methods: Autopsy data were collected from the autopsy journals, and the human tissue was collected from the pathology archives at the Department of Pathology, the Gades Institute. Results: Histological presentations of TB lesions showed great diversity within a single lung. Post-primary TB starts as a pneumonia forming early lesions, characterized by the infiltration of foamy macrophages containing mycobacterial antigens within alveoli, and progressing to necrotic pneumonias with an increasing density of mycobacterial antigens in the lesions. These necrotic pneumonic lesions appeared to either resolve as fibrocaseous lesions or lead to cavitation. The typical granulomatous inflammation, the hallmark of TB lesions, appeared later in the post-primary TB and surrounded the pneumonic lesions. These post-primary granulomas contained lesser mycobacterial antigens as compared to necrotic pneumonia. Conclusions: Immunopathogenesis of post-primary TB is different from primary TB and starts as pneumonia. The early lesions of post-primary TB may progress or regress, holding the key to understanding how a host can develop the disease despite an effective TB immunity. Full article

Currently, tuberculosis (TB) is a bacterial infection caused by Mycobacterium tuberculosis (Mtb) that primarily affects the lungs. The severity of active pulmonary TB (APTB) is an important determinant of transmission, morbidity, mortality, disease experience, and treatment outcomes. Several publications have shown a high prevalence of disabling complications in individuals who have had severe APTB. Furthermore, certain strains of Mtb were associated with more severe disease outcomes. The use of biomarkers to predict severe APTB patients who are candidates for host-directed therapies, due to the high risk of developing post-tuberculous lung disease (PTLD), has not yet been implemented in the management of TB patients. We followed 108 individuals with APTB for 6 months using clinical tools, flow cytometry, and whole-genome sequencing (WGS). The median age of the study population was 26.5 years, and the frequency of women was 53.7%. In this study, we aimed to identify biomarkers that could help us to recognize individuals with APTB and improve our understanding of the immunopathology in these individuals. In this study, we conducted a follow-up on the treatment progress of 121 cases of APTB. The follow-up process commenced at the time of diagnosis (T0), continued with a control visit at 2 months (T2), and culminated in an exit appointment at 6 months following the completion of medical treatment (T6). People classified with severe APTB showed significantly higher levels of IL-6 (14.7 pg/mL; p < 0.05) compared to those with mild APTB (7.7 pg/mL) at T0. The AUCs for the ROC curves and the Matthews correlation coefficient values (MCC) demonstrate correlations ranging from moderate to very strong. We conducted WGS on 88 clinical isolates of Mtb, and our analysis revealed a total of 325 genes with insertions and deletions (Indels) within their coding regions when compared to the Mtb H37Rv reference genome. The pattern of association was found between serum levels of CHIT1 and the presence of Indels in Mtb isolates from patients with severe APTB. A key finding in our study was the high levels of CHIT1 in severe APTB patients. We identified a biomarker profile (IL-6, IFN-γ, IL-33, and CHIT1) that allows us to identify individuals with severe APTB, as well as the identification of a panel of polymorphisms (125) in clinical isolates of Mtb from individuals with severe APTB. Integrating these findings into a predictive model of severity would show promise for the management of APTB patients in the future, to guide host-directed therapy and reduce the prevalence of PTLD. Full article

Surgery has played an important role in managing complicated tuberculosis in former Soviet Union countries, including the Kyrgyz Republic. However, published information is limited. This study aimed to document the trend, characteristics and outcomes of tuberculosis patients who underwent thoracic surgery, using routinely collected data. Between 2017 and 2021, 4–7% of tuberculosis patients in the Kyrgyz Republic underwent thoracic surgery in two centres in Bishkek and Osh. In 2021, case records were retrieved in 264 (78%) of 340 patients undergoing thoracic surgery in the country. The most common indications for surgery were pleural exudate/empyema in 127 (44%) and tuberculoma in 83 (32%). Most patients (73%) underwent surgery within 30 days of starting TB treatment. Two-thirds of patients underwent radical surgery, and surgical outcomes were excellent in 99% of patients with one death. Post-operatively, 63 (23%) patients had no TB detected by the histology, with the two most common specified conditions being lung cancer and pulmonary hydatid disease. TB treatment was stopped in these patients. Of the 201 patients with confirmed TB after surgery, TB-treatment success was documented in 163 (81%), died/failure/lost to follow-up in 10 (5%) and not evaluated in 28 (14%). This study shows that thoracic surgery is feasible, safe and effective in the routine programme setting. Recommendations are made to strengthen referral and monitoring systems. Full article

Background: During the first two years after lung transplantation (LTx), the incidence of fragility fractures (FX) is estimated to be 15–50% and it is lower in patients with cystic fibrosis (CF) as compared with other end-stage lung diseases (nCF). The aim of our study is to compare the skeletal outcomes, after the first 2 years post-LTx, in long-term survivors with CF and nCF. Materials and Methods: We evaluated the FX rate, the changes in bone mineral density (BMD) and trabecular bone score (TBS) in 68 patients (38 CF and 30 nCF) who underwent LTx in our center and with a follow-up after LTx longer than 5 years (7.3 ± 2.0 years). Results: After the second year post-LTx: (i) the FX rate was lower than during the first two years post-LTx (4.4 vs. 20.6%, p = 0.004), with no difference between CF and nCF patients (5.3 vs. 3.3%, p = 0.589); (ii) BMD at lumbar spine, femoral neck and total hip remained stable (−1.6 ± 1.0 vs. −1.4 ± 1.1, p = 0.431, −1.8 ± 0.9 vs. −1.9 ± 0.9, p = 0.683, −1.5 ± 0.9 vs. −1.4 ± 0.9, p = 0.678, respectively) as well as TBS (1.200 ± 0.124 vs. 1.199 ± 0.205, p = 0.166). Conclusions: After the second year post-LTx, the skeletal complications become less frequent and have similar incidence in patients with CF and nCF. Full article

HIV infection causes systemic immune activation, impacts TB disease progression and hence may influence the diagnostic usability of Mycobacterium tuberculosis-specific T cell profiling. We investigated changes of activation and maturation markers on MTB-specific CD4+ T-cells after anti-tuberculosis treatment initiation in relation to HIV status and the severity of lung impairment. Thawed peripheral blood mononuclear cells from TB patients with (n = 27) and without HIV (n = 17) were analyzed using an intracellular IFN-γ assay and flow cytometry 2 and 6 months post-TB treatment initiation. H37Rv antigen was superior to the profile MTB-specific CD4+ T-cells phenotype when compared to PPD and ESAT6/CFP10. Regardless of HIV status and the severity of lung impairment, activation markers (CD38, HLA-DR and Ki67) on MTB-specific CD4+ T-cells declined after TB treatment initiation (p < 0.01), but the expression of the maturation marker CD27 did not change over the course of TB treatment. The MTB-specific T cell phenotype before, during and after treatment completion was similar between people living with and without HIV, as well as between subjects with severe and mild lung impairment. These data suggest that the assessment of activation and maturation markers on MTB-specific CD4+ T-cells can be useful for TB treatment monitoring, regardless of HIV status and the severity of lung disease. Full article

Coronavirus disease 2019 (COVID-19) and tuberculosis (TB) are currently the two leading causes of death among infectious diseases. As we progress towards a “new normal”, more information is required regarding post-COVID-19 syndromes. We present a case of latent tuberculosis reactivation 3 months after a successful inpatient treatment of COVID-19. A 74-year-old female from the Philippines presented with a new left mid-lung infiltrate with worsening shortness of breath and lethargy for one week prior to admission. The clinical course of the patient deteriorated despite broad-spectrum antibiotics, diuretics, and high-dose steroid therapy requiring intubation and mechanical ventilation. Her sputum culture yielded the microbiological diagnosis of TB. Anti-tubercular medications were started and the patient had a favorable clinical outcome. Our case demonstrates that immunosuppression secondary to COVID-19 and its treatments may promote the development of an active TB infection from a latent infection. It is important to be aware of this potential increase in risk during and after a COVID-19 treatment. This is especially important in high-risk populations to ensure an early diagnosis and prompt management as well as to reduce transmission. Full article

Tuberculosis (TB), caused by the human pathogen Mycobacterium tuberculosis (Mtb), is an infectious disease that presents a major threat to human health. Bacillus Calmette-Guérin (BCG), the only licensed TB vaccine, is ineffective against latent TB infection, necessitating the development of further TB drugs or therapeutic vaccines. Herein, we evaluated the therapeutic effect of a novel subunit vaccine AEC/BC02 after chemotherapy in a spontaneous Mtb relapse model. Immunotherapy followed 4 weeks of treatment with isoniazid and rifapentine, and bacterial loads in organs, pathological changes, and adaptive immune characteristics were investigated. The results showed slowly increased bacterial loads in the spleen and lungs of mice inoculated with AEC/BC02 with significantly lower loads than those of the control groups. Pathological scores for the liver, spleen, and lungs decreased accordingly. Moreover, AEC/BC02 induced antigen-specific IFN-γ-secreting or IL-2-secreting cellular immune responses, which decreased with the number of immunizations and times. Obvious Ag85b- and EC-specific IgG were observed in mice following the treatment with AEC/BC02, indicating a significant Th1-biased response. Taken together, these data suggest that AEC/BC02 immunotherapy post-chemotherapy may shorten future TB treatment. Full article

Mast cells (MCs) have relevant participation in inflammatory and vascular hyperpermeability events, responsible for the action of the kallikrein–kinin system (KKS), that affect patients inflicted by the severe form of COVID-19. Given a higher number of activated MCs present in COVID-19 patients and their association with vascular hyperpermeability events, we investigated the factors that lead to the activation and degranulation of these cells and their harmful effects on the alveolar septum environment provided by the action of its mediators. Therefore, the pyroptotic processes throughout caspase-1 (CASP-1) and alarmin interleukin-33 (IL-33) secretion were investigated, along with the immunoexpression of angiotensin-converting enzyme 2 (ACE2), bradykinin receptor B1 (B1R) and bradykinin receptor B2 (B2R) on post-mortem lung samples from 24 patients affected by COVID-19. The results were compared to 10 patients affected by H1N1pdm09 and 11 control patients. As a result of the inflammatory processes induced by SARS-CoV-2, the activation by immunoglobulin E (IgE) and degranulation of tryptase, as well as Toluidine Blue metachromatic (TB)-stained MCs of the interstitial and perivascular regions of the same groups were also counted. An increased immunoexpression of the tissue biomarkers CASP-1, IL-33, ACE2, B1R and B2R was observed in the alveolar septum of the COVID-19 patients, associated with a higher density of IgE⁺ MCs, tryptase⁺ MCs and TB-stained MCs, in addition to the presence of intra-alveolar edema. These findings suggest the direct correlation of MCs with vascular hyperpermeability, edema and diffuse alveolar damage (DAD) events that affect patients with a severe form of this disease. The role of KKS activation in events involving the exacerbated increase in vascular permeability and its direct link with the conditions that precede intra-alveolar edema, and the consequent DAD, is evidenced. Therapy with drugs that inhibit the activation/degranulation of MCs can prevent the worsening of the prognosis and provide a better outcome for the patient. Full article

Voles are maintenance hosts of Mycobacterium microti. In line with the goal to eradicate tuberculosis (TB) in livestock, the role of this mycobacteria needs to be assessed since it might interfere with current M. bovis/M. caprae surveillance strategies. To better understand the pathogenesis of TB in voles, an experimental infection model was set up to reproduce M. microti infection in laboratory Bank voles (Myodes glareolus). Two infection routes (intragastric and intraperitoneal) and doses (10⁵ and 10⁶ CFU/0.1 mL) were assessed. Voles were culled at different post-infection time points. Serology, histopathology, acid-fast bacilli staining, qPCR, and mycobacterial culture from tissues were performed. In addition, qPCR from feces and oral swabs were conducted to assess bacterial shedding. The model allowed us to faithfully reproduce the disease phenotype described in free-ranging voles and characterize the pathogenesis of the infection. Most animals showed multifocal and diffuse granulomatous lesions in the liver and spleen, respectively. Less frequently, granulomas were observed in lungs, lymph nodes, muscles, and salivary gland. Mycobacterial DNA was detected in feces from a few animals but not in oral swabs. However, one contact uninfected vole seroconverted and showed incipient TB compatible lesions, suggesting horizontal transmission between voles. Full article

Children and adolescents living with HIV continue to be impacted disproportionately by tuberculosis as compared to peers without HIV. HIV can impact TB screening and diagnosis by altering screening and diagnostic test performance and can complicate prevention and treatment strategies due to drug–drug interactions. Post-tuberculosis lung disease is an underappreciated phenomenon in children and adolescents, but is more commonly observed in children and adolescents with HIV-associated tuberculosis. This review presents new data related to HIV-associated TB in children and adolescents. Data on the epidemiology of HIV-associated TB suggests that an elevated risk of TB in children and adolescents with HIV persists even with broad implementation of ART. Recent guidance also indicates the need for new screening strategies for HIV-associated TB. There have been major advances in the availability of new antiretroviral medications and also TB prevention options for children, but these advances have come with additional questions surrounding drug–drug interactions and dosing in younger age groups. Finally, we review new approaches to manage post-TB lung disease in children living with HIV. Collectively, we present data on the rapidly evolving field of HIV-associated child tuberculosis. This evolution offers new management opportunities for children and adolescents living with HIV while also generating new questions for additional research. Full article

The clinical characteristics of patients with post-tuberculosis (TB) bronchiectasis have not been well evaluated. We enrolled 598 patients with bronchiectasis who participated in the Korean prospective bronchiectasis registry and compared the characteristics of post-TB bronchiectasis (19.7%) with post-infectious (19.6%), idiopathic (40.8%), and other (19.9%) bronchiectasis. The patients with post-TB bronchiectasis had a lower body mass index, higher rate of chronic obstructive pulmonary disease, and lower rate of asthma than those in the other groups. The patients with post-TB bronchiectasis had more upper lobe involvement, more severe radiological extent, and worse lung function than those in the other groups. Long-acting muscarinic antagonist/long-acting ß agonist use and mucolytics were more commonly used in the patients with post-TB bronchiectasis than those in the other groups, while inhaled corticosteroid/long-acting ß agonist was less commonly used. There were no significant intergroup differences in bronchiectasis severity scores except for FACED, the number of exacerbations, and quality of life. Post-TB bronchiectasis is characterised by reduced lung function and higher rates of mucolytic use when compared with other bronchiectasis; thus, adequate bronchodilator use and airway clearance techniques may alleviate symptom burden in this population. Full article