Beneficial or detrimental activity of regulatory T cells, indoleamine 2,3-dioxygenase, and heme oxygenase-1 in the lungs is influenced by the level of virulence of Mycobacterium tuberculosis strain infection.

Tuberculosis (TB) caused by the complex Mycobacterium tuberculosis (Mtb) is the main cause of death by a single bacterial agent. Last year, TB was the second leading infectious killer after SARS-CoV-2. Nevertheless, many biological and immunological aspects of TB are not completely elucidated, such as the complex process of immunoregulation mediated by regulatory T cells (Treg cells) and the enzymes indoleamine 2,3-dioxygenase (IDO) and heme oxygenase 1 (HO-1). In this study, the contribution of these immunoregulatory factors was compared in mice infected with Mtb strains with different levels of virulence. First Balb/c mice were infected by intratracheal route, with a high dose of mild virulence reference strain H37Rv or with a highly virulent clinical isolate (strain 5186). In the lungs of infected mice, the kinetics of Treg cells during the infection were determined by cytofluorometry and the expression of IDO and HO-1 by RT-PCR and immunohistochemistry. Then, the contribution of immune-regulation mediated by Treg cells, IDO and HO-1, was evaluated by treating infected animals with specific cytotoxic monoclonal antibodies for Treg cells depletion anti-CD25 (PC61 clone) or by blocking IDO and HO-1 activity using specific inhibitors (1-methyl-D,L-tryptophan or zinc protoporphyrin-IX, respectively). Mice infected with the mild virulent strain showed a progressive increment of Treg cells, showing this highest number at the beginning of the late phase of the infection (28 days), the same trend was observed in the expression of both enzymes being macrophages the cells that showed the highest immunostaining. Animals infected with the highly virulent strain showed lower survival (34 days) and higher amounts of Treg cells, as well as higher expression of IDO and HO-1 one week before. In comparison with non-treated animals, mice infected with strain H37Rv with depletion of Treg cells or treated with the enzymes blockers during late infection showed a significant decrease of bacilli loads, higher expression of IFN-g and lower IL-4 but with a similar extension of inflammatory lung consolidation determined by automated morphometry. In contrast, the depletion of Treg cells in infected mice with the highly virulent strain 5186 produced diffuse alveolar damage that was similar to severe acute viral pneumonia, lesser survival and increase of bacillary loads, while blocking of both IDO and HO-1 produced high bacillary loads and extensive pneumonia with necrosis. Thus, it seems that Treg cells, IDO and HO-1 activities are detrimental during late pulmonary TB induced by mild virulence Mtb, probably because these factors decrease immune protection mediated by the Th1 response. In contrast, Treg cells, IDO and HO-1 are beneficial when the infection is produced by a highly virulent strain, by regulation of excessive inflammation that produced alveolar damage, pulmonary necrosis, acute respiratory insufficiency, and rapid death.

Pediatric COVID-TB: A Clinical Perspective Based on the Analysis of Three Cases.

Coronavirus disease 2019 (COVID-19) and tuberculosis (TB) are currently two major causes of death among infectious diseases. Active tuberculosis and a history of tuberculosis appear to be associated with an increased risk of COVID-19. This coinfection, named COVID-TB, was never described in previously healthy children. We report three cases of pediatric COVID-TB. We describe three girls affected by tuberculosis, who tested positive for SARS-CoV-2. The first patient is a 5-year-old girl who was hospitalized for recurrent TB lymphadenopathy. As she never had any complications related to the concomitant infection with SARS-CoV-2, she received TB treatment. The second case is a 13-year-old patient with a history of pulmonary and splenic tuberculosis. She was admitted to the hospital due to deteriorating respiratory dynamics. She was already undergoing treatment for TB, but in the absence of improvement, she also required treatment for COVID-19. Slowly, the general condition improved until discharge. The last patient, a 10-year-old girl, was hospitalized for supraclavicular swelling. The investigations showed disseminated TB characterized by lung and bone involvement without COVID-19-related complications. She was treated with antitubercular and supportive therapy. Based on the data obtained from the adult population and our small experience, a pediatric patient with COVID-TB infection should be considered potentially at risk of worse clinical outcomes; for this reason, we suggest close observation, careful clinical management, and consideration of targeted anti-SARS-CoV-2 therapies.

[Dynamics of the structure of renal tuberculosis over 20 years].

BACKGROUND: Tuberculosis is a serious medical and social problem that does not lose its importance, despite all the advances in pharmacology and surgery. Diagnosis of urogenital tuberculosis (UGTB), as a rule, is delayed due to low index of suspicion to tuberculosis and the absence of pathognomonic symptoms. AIM: Determining the change in the ratio of clinical forms of renal tuberculosis from 1999 to 2020. MATERIALS AND METHODS: A retrospective cohort comparative non-interventional study on the spectrum of the incidence of extrapulmonary tuberculosis (EPTB) was carried out. Among all 13852 extrapulmonary tuberculosis patients which were diagnosed from 1999 to 2020, patients with renal tuberculosis were selected, and the spectrum of their clinical forms in three periods was analyzed: 1st period 1999-2004 (1155 patients), second period 2005-2014 (2657 patients), and the third period 2015-2020 (671 patients). The clinical features of nephrotuberculosis in 88 patients was also estimated. RESULTS: Over the 20 years of the analyzed period, the number of patients with UGTB decreased by 80.6%; for the year of the COVID-19 pandemic, this figure fell by another third. In the first period, destructive complicated forms of nephrotuberculosis prevailed (922 patients - 79.8%), while the so-called "minor forms" were diagnosed in 233 patients (20.2%). In the second period, the situation was statistically significantly more favorable: the proportion of destructive and complicated forms of renal tuberculosis decreased to 43.8% (1124 patients), "small forms" were diagnosed in 1443 patients (56.2%). In the third period, destructive and complicated forms of nephrotuberculosis were diagnosed in 531 patients (77.6%), and the proportion of "small forms" in comparison with the previous period decreased by half, to 22.4%. Analysis of the clinical features of renal tuberculosis, depending on the prevalence of the destruction, showed that an asymptomatic course is possible, and pain, dysuria, intoxication and renal colic are present with different frequencies, and the clinical picture of tuberculosis of the renal parenchyma differs significantly from the clinical picture of tuberculous papillitis, cavernous nephrotuberculosis and symptoms of renal tuberculosis as whole. CONCLUSION: Currently, there is no screening on urogenital tuberculosis at all. Patients are diagnosed by referral, with a long history, after receiving multiple courses of antibacterial treatment; mainly through the pathomorphological examination of the operating material. Thus, a sharp decrease in the proportion of UGTB patients does not mean the disappearance of tuberculosis of this localization, but only states the tragic defects in timely diagnosis and low index of suspicion of medical doctors in relation to UGTB.

Tuberculosis in Poland in 2020.

AIM OF THE STUDY: To evaluate the main features of epidemiology of tuberculosis (TB) in 2020 in Poland and to compare with the situation in the European Union and European Economic Area (EU/EEA) countries. MATERIAL AND METHODS: Analysis of case-based data on TB patients from National TB Register, data on anti-TB drug susceptibility in cases notified in 2020, data from Statistics Poland on deaths from tuberculosis in 2019, data from National Institute of Public Health NIH - National Research Institute (NIPH NIH - NRI) on HIV-positive subjects for whom TB was an AIDS-defining disease, data from the report "European Centre for Disease Prevention and Control, WHO Regional Office for Europe. Tuberculosis surveillance and monitoring in Europe 2022 - 2020 data. Copenhagen: WHO Regional Office for Europe and Stockholm: European Centre for Disease Prevention and Control; 2022." RESULTS: In 2020, 3,388 TB cases were reported in Poland. The incidence rate was 8.8 cases per 100,000 with large variability between voivodeships from 5.5 to 13.3 per 100,000. A decrease in the incidence was found in 15 voivodeships, the most significant in Slaskie voivodship (63.9%). The number of all pulmonary tuberculosis cases was 3,237 i.e. 8.4 per 100,000. Pulmonary cases represented 95.5% of all TB cases. In 2020, 151 extrapulmonary TB cases were notified (4.5% of all TB cases). Pulmonary tuberculosis was bacteriologically confirmed in 2,573 cases (79.5% of all pulmonary TB cases, the incidence rate 6.7 per 100,000). The number of smear-positive pulmonary TB cases was 1,771 i.e. 4.6 per 100,000 (54.7% of all pulmonary TB cases). In 2020, there were 38 cases (15 of foreign origin) with multidrug resistant TB (MDR-TB) representing 1.6% of cases with known drug sensitivity. The incidence rates of tuberculosis were growing along with increasing age from 0.7 per 100,000 among children (0-14 years) to 15.0 per 100,000 among subjects in the age group 45-64 years, the incidence rate in the age group ≥65 years was 12.1 per 100,000. There were 39 cases in children up to 14 years of age (1.2% of the total) and 49 cases in adolescents between 15 and 19 years of age - rates 0.7 and 2.7 per 100,000 respectively. In 2020, there were 2,506 cases of tuberculosis in men and 882 in women. The TB incidence in men - 13.5 per 100,000 was 3.0 times higher than among women - 4.5. The biggest difference in the TB incidence between the two sex groups occurred in persons aged 50-54 years - 26.8 vs. 4.1 and in age group 55 to 59 years - 28.7 vs. 4.8. In 2020, there were 116 patients of foreign origin among all cases of tuberculosis in Poland (3.4%). In 2019, TB was the cause of death for 456 people (mortality rate - 1.2 per 100,000). CONCLUSIONS: TB incidence in Poland in 2020 was 36.7% lower than in 2019. Such significant declines in the incidence have not been observed in the last two decades. As in previous years, there were differences in incidence rates between voivodeships with an unexpectedly sharp decrease in incidence in Silesia (Slaskie voivodeship). The percentage of tuberculosis cases with bacteriological confirmation exceeded 78%, more than in EU/EEA countries (67.3%). The percentage of MDR-TB cases was still lower than the average in EU/EEA countries (1.6% vs. 3.8%). The highest incidence rates were found in Poland in the older age groups (EU/EEAaged 25 to 44). The percentage of children up to 14 years of age among the total number of TB patients was 1.2%, less than the average in EU/EEA countries (3.8%). The incidence of tuberculosis in men was three times higher than in women in Poland, and six times higher in patients aged 50 to 59. The impact of migration on the TB pattern in Poland has not yet become significant in 2020. The percentage of foreigners among TB patients was 3.4% (33% in EU/EEA countries).

Drug Reaction With Eosinophilia and Systemic Symptoms-Associated Perimyocarditis After Initiation of Anti-tuberculosis Therapy: A Case Report.

A 34-year-old female who was recently placed on anti-tuberculosis medication with rifampin, isoniazid, pyrazinamide, and levofloxacin therapy for suspected tuberculosis reinfection presented with subjective fevers, rash, and generalized fatigue. Labs showed signs of end-organ damage with eosinophilia and leukocytosis. One day later, the patient became hypotensive with a worsening fever, and an electrocardiogram showed new diffuse ST segment elevations with an elevated troponin. An echocardiogram revealed a reduction in ejection fraction with diffuse hypokinesis, and cardiac magnetic resonance imaging (MRI) showed circumferential myocardial edema with subepicardial and pericardial inflammation. Prompt diagnosis of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome using the European Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria and discontinuation of therapy was initiated. Due to the hemodynamic instability of the patient, the patient was started on systemic corticosteroids and cyclosporine, with the improvement of her symptoms and rash. A skin biopsy was performed, which revealed perivascular lymphocytic dermatitis, consistent with DRESS syndrome. As the patient's ejection fraction improved spontaneously with corticosteroids, the patient was discharged with oral corticosteroids, and a repeat echocardiogram showed full recovery of ejection fraction. Perimyocarditis is a rare complication of DRESS syndrome that is associated with degranulation and the release of cytotoxic agents into myocardial cells. Early discontinuation of offending agents and initiation of corticosteroids are essential to rapid recovery of ejection fraction and improved clinical outcomes. Multimodality imaging, including MRI, should be used to confirm perimyocardial involvement and guide the necessity for mechanical support or transplant. Further research should be on the mortality of DRESS syndrome with and without myocardial involvement, with an increased emphasis on cardiac evaluation in DRESS syndrome.

Massive pulmonary embolism led to cardiac arrest two days after thoracoscopy in a young male with pleural tuberculosis.

TB itself is considered an independent risk factor for VTE; however, developing pulmonary embolism after medical thoracoscopy is extremely rare. Herein, we describe a 30-year-old previously healthy male with pleural tuberculosis developed a massive pulmonary embolism with subsequent cardiac arrest after a diagnostic medical thoracoscopy. Computed tomography pulmonary angiogram (CTPA) showed major right pulmonary embolism (PE). Unfortunately, the patient passed away despite resuscitation and extensive organ support in the intensive care unit (ICU). This case highlights the thrombotic risk in this population group in order to avoid such devastating complications.

A CRISPR-Cas12a-based platform for ultrasensitive rapid highly specific detection of Mycobacterium tuberculosis in clinical application.

Tuberculosis, caused by Mycobacterium tuberculosis (MTB), is the second leading cause of death after COVID-19 pandemic. Here, we coupled multiple cross displacement amplification (MCDA) technique with CRISPR-Cas12a-based biosensing system to design a novel detection platform for tuberculosis diagnosis, termed MTB-MCDA-CRISPR. MTB-MCDA-CRISPR pre-amplified the specific sdaA gene of MTB by MCDA, and the MCDA results were then decoded by CRISPR-Cas12a-based detection, resulting in simple visual fluorescent signal readouts. A set of standard MCDA primers, an engineered CP1 primer, a quenched fluorescent ssDNA reporter, and a gRNA were designed targeting the sdaA gene of MTB. The optimal temperature for MCDA pre-amplification is 67°C. The whole experiment process can be completed within one hour, including sputum rapid genomic DNA extraction (15 minutes), MCDA reaction (40 minutes), and CRISPR-Cas12a-gRNA biosensing process (5 minutes). The limit of detection (LoD) of the MTB-MCDA-CRISPR assay is 40 fg per reaction. The MTB-MCDA-CRISPR assay does not cross reaction with non-tuberculosis mycobacterium (NTM) strains and other species, validating its specificity. The clinical performance of MTB-MCDA-CRISPR assay was higher than that of the sputum smear microscopy test and comparable to that of Xpert method. In summary, the MTB-MCDA-CRISPR assay is a promising and effective tool for tuberculosis infection diagnosis, surveillance and prevention, especially for point-of-care (POC) test and field deployment in source-limited regions.

Impact of aging on immunity in the context of COVID-19, HIV, and tuberculosis.

Knowledge of aging biology needs to be expanded due to the continuously growing number of elderly people worldwide. Aging induces changes that affect all systems of the body. The risk of cardiovascular disease and cancer increases with age. In particular, the age-induced adaptation of the immune system causes a greater susceptibility to infections and contributes to the inability to control pathogen growth and immune-mediated tissue damage. Since the impact of aging on immune function, is still to be fully elucidated, this review addresses some of the recent understanding of age-related changes affecting key components of immunity. The emphasis is on immunosenescence and inflammaging that are impacted by common infectious diseases that are characterized by a high mortality, and includes COVID-19, HIV and tuberculosis.

Infections and the Kidney

Global infections are very frequent cause of AKI. Often this is due to the non-specific systemic effects of sepsis and volume depletion and therefore can occur with many infectious agents perhaps most searingly brought to our attention with the SARS-CoV-2 pandemic. The kidney can also be damaged by infections directly involving the renal parenchyma, because of persistent infection elsewhere in the body, as a post-infectious response and secondary diseases causing obstruction. Identifying, first, that kidney injury is due to infection and the particular infection causing the patient's presentation is critical to management. Some infections discussed in this chapter are confined to specific areas of the world, but with increasing global travel and migration, patients may present to healthcare facilities anywhere;thus, a thorough travel history is invaluable. © Springer Nature Switzerland AG 2014, 2022.

Stratification of Risks of Tuberculosis Relapses during the Pandemic of the Novel Coronavirus Infection

The objective: to assess risk factors for tuberculosis relapse during the COVID-19 pandemic. Results. During the retrospective study, medical documents of patients treated for tuberculosis in 2020-2022 were analyzed. 140 patients above 18 years old with confirmed tuberculosis were included: newly diagnosed tuberculosis – 50 patients, early relapses – 50 patients, and late relapses – 40 patients. At the first stage, significant factors for relapse development were identified (ANOVA): diabetes (F=19402,8;p=0,000000), substances abuse (F=547,6;p=0,000000), alcohol abuse (F=149,7;p=0,000000), MDR MTB (F=107,8;p=0,000000), HIV infection (F=72,4;p=0,000000), imprisonment (F=49,5;p=0,000000), chronic respiratory diseases (F=47,1;p=0,000000), smoking (F=29,0;p=0,000000), and social status (F=28,9;p= 0,000000). At the second stage (cluster analysis), factors implementing the risks of development of early or late relapses were identified. As well as before the COVID-19 pandemic, social, medical and biological risk factors play a significant role in the development of tuberculosis relapses;history of COVID-19 was not one of the risk factors;and stratification of the risk factors made it possible to identify factors that contribute to development of both early and late relapses and to determine preventive measures. © 2023 New Terra Publishing House. All rights reserved.

Kenneth Peter Goldman

Ken's first registrar job was at Paddington Green, then he had a fruitful experience at Sully Hospital in south Wales between 1960 and 1963, which at the time was the Welsh Regional Centre for Thoracic and Cardiac Surgery. When 92 years old, he, his wife and one of their sons developed covid-19 symptoms, Ken was admitted to hospital, and later died from covid-19 pneumonia. Consultant physician, general and chest disease, Dartford and Gravesham (b 1928;q Cambridge/St Mary's Hospital Medical School 1957;MD, FRCP), died from covid-19 pneumonia on 14 April 2020

An Analysis of The Trend of Incidences and Fatality of Pulmonary Tuberculosis in East Java from 2015-2020: A Lesson From COVID-19

Background: Pulmonary tuberculosis is still a public health problem, and surveillance data analysis has not been done much. Recently a global pandemic of COVID-19 has the potential in disturbing TB elimination programs and treatment. This study aims to comprehensively analyse the incidence rate (IR) and Case Fatality Rate (CFR) of pulmonary tuberculosis in East Java from 2015–2020 and during COVID-19 and the strategies for optimizing tuberculosis disease control. Methodology: The study analyzed annual surveillance data using an analytical descriptive design. The Variables were analyzed with Spearman correlation with a level of evidence of 95% (p<0.05). Results: The prevalence of pulmonary tuberculosis in East Java fluctuated from 2015–2020. In 2020 and during the COVID-19 pandemic, the number of cases and morbidity rates increased. Statistic results confirm the presence of a significant correlation between the values of Incidence rate (IR) and Case Fatality rate (CFR) (p = 0.032), IR and Treatment Success Rate (TSR) (p = 0.020), and CFR and TSR (p = 0.002). Population density is not correlated with the number of new cases (p = 0.667). Treatment rates have increased to 51%;cure and treatment rates have decreased to 76% and 89%, respectively, and there was a 4% increase in mortality during COVID-19. Conclusions: COVID-19 has tremendously affected the treatment of pulmonary TB cases in East Java, Indonesia by increasing the incidence rate and decreasing the fatality rate. The pandemic promotes fear in the community to check their medical status and improve the quality of their health in East Java. © The Authors retain the copyrights of this article, with first publication rights granted to Medsci Publications.

Heterologous Production of the D-Cycloserine Intermediate O-acetyl-L-serine in Human Lung Cancer Cells

According to the World Health Organization, Tuberculosis (TB) is the second leading cause of death by a single infectious disease behind COVID-19. Despite a century of effort, the current TB vaccine does not effectively prevent pulmonary TB, promote herd immunity, or prevent transmission. Therefore, we seek to develop a genetic prophylaxis for TB. We have determined D-cycloserine to be the optimal target for this approach due to its relatively short six-enzyme biosynthetic pathway. D-CS is a second-line antibiotic for TB that inhibits bacterial cell wall synthesis. The first committed step towards D-CS synthesis is catalyzed by the L-serine-O-acetyltransferase (DcsE) which converts L-serine and acetyl-CoA to O-acetyl-L-serine (L-OAS). To test if the D-CS pathway could be an effective prophylaxis for TB in human cells, we endeavored to express DcsE in human cells and test its functionality. We overexpressed DcsE tagged with FLAG and GFP in A549 lung cancer cells as determined using fluorescence microscopy. We observed that purified DcsE catalyzed the synthesis of L-OAS as observed by HPLC-MS. Therefore, DcsE synthesized in human cells is a functional enzyme capable of converting L-serine and acetyl-CoA to L-OAS demonstrating the first step towards DCS production in human cells.Copyright © 2023 The American Society for Biochemistry and Molecular Biology, Inc.

A Hybrid Deep Fused Learning Approach to Segregate Infectious Diseases

Humankind is facing another deadliest pandemic of all times in history, caused by COVID-19. Apart from this challenging pandemic, World Health Organization (WHO) considers tuberculosis (TB) as a preeminent infectious disease due to its high infection rate. Generally, both TB and COVID-19 severely affect the lungs, thus hardening the job of medical practitioners who can often misidentify these diseases in the current situation. Therefore, the time of need calls for an immediate and meticulous automatic diagnostic tool that can accurately discriminate both diseases. As one of the preliminary smart health systems that examine three clinical states (COVID-19, TB, and normal cases), this study proposes an amalgam of image filtering, data-augmentation technique, transfer learning-based approach, and advanced deep-learning classifiers to effectively segregate these diseases. It first employed a generative adversarial network (GAN) and Crimmins speckle removal filter on X-ray images to overcome the issue of limited data and noise. Each pre-processed image is then converted into red, green, and blue (RGB) and Commission Internationale de l'Elcairage (CIE) color spaces from which deep fused features are formed by extracting relevant features using DenseNet121 and ResNet50. Each feature extractor extracts 1000 most useful features which are then fused and finally fed to two variants of recurrent neural network (RNN) classifiers for precise discrimination of three-clinical states. Comparative analysis showed that the proposed Bi-directional long-short-term-memory (Bi-LSTM) model dominated the long-short-term-memory (LSTM) network by attaining an overall accuracy of 98.22% for the three-class classification task, whereas LSTM hardly achieved 94.22% accuracy on the test dataset.

Chest X-ray Imaging System for Early Detection of Tuberculosis

Today it is observed that few people respect the biosecurity measures announced by the WHO, which aimed to reduce the amount of COVID-19 infection among people, even knowing that this virus has not disappeared from our environment, being an unprecedented infection in the world. It should be noted that before this pandemic, tuberculosis affected millions of people, having a great role because it is highly contagious and directly affects the lungs, although it has a cure, if it is not treated in time it can be fatal for the person, although there are many methods of detection of tuberculosis, one that is most often used is the diagnosis by chest x-ray, although it has low specificity, when the image processing technique is applied, tuberculosis would be accurately detected. In view of this problem, in this article a chest X-ray image processing system was conducted for the early detection of tuberculosis, helping doctors to detect tuberculosis accurately and quickly by having a second opinion by the system in the analysis of the chest x-ray, prevents fatal infections in patients. Through the development of the tuberculosis early detection system, it was possible to observe the correct functioning of the system with an efficiency of 97.84% in the detection of tuberculosis, detailing the characteristics presented by normal or abnormal images so that the doctor detects tuberculosis in the patient early. © 2023 IEEE.

Oesophageal and oral ulcer tuberculous associated with human T-cell lymphotropic virus type 1 (HTLV-1) and SARS-CoV-2 infection

Oesophageal involvement due to tuberculosis (TB) and coinfection with HTLV-1 is rare and can be complicated by the presence of other infections that affect the mucosa of the upper respiratory tract, such as COVID-19. We present the case of a 27-year-old male patient, with 3 months of illness, weight loss, dysphagia, and ulcers in the oral cavity. Tomography showed oesophageal perforation and after oesophageal ulcer biopsy, TB was diagnosed, in addition to infection by HTLV-1 and severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). The patient responded satisfactorily to antituberculous treatment and corticosteroids. Considering the association between rare extrapulmonary tuberculosis and other immunosuppressive pathologies, it is crucial to identify these pathologies in such patients.