Search Results (374)

Background/Objectives: Romania remains a tuberculosis (TB) hotspot in the European Union, yet host-derived factors of poor outcomes are poorly characterised. We quantified circulating pro-inflammatory cytokines and examined their interplay with behavioural risk factors, the nutritional status, and the clinical course in adults hospitalised with pulmonary TB. We analysed 80 adults with microbiologically confirmed pulmonary TB and 40 respiratory symptom controls; four TB patients (5%) died during hospitalisation, all within 10 days of admission. Methods: A retrospective analytical case–control study was conducted at the Constanța regional TB referral centre (October 2020—October 2023). Patients with smear- or culture-confirmed TB were frequency-matched by sex, 10-year age band, and BMI class to culture-negative respiratory controls at a 2:1 ratio. The patients’ serum interferon-γ (IFN-γ), interleukin-1α (IL-1α), interleukin-1β (IL-1β), and tumour-necrosis-factor-α (TNF-α) were quantified within 24 h of admission; the neutrophil/lymphocyte ratio (NLR) was extracted from full blood counts. Independent predictors of in-hospital mortality were identified by multivariable logistic regression; factors associated with the length of stay (LOS) were modelled with quasi-Poisson regression. Results: The median TNF-α (24.1 pg mL⁻¹ vs. 16.2 pg mL⁻¹; p = 0.009) and IL-1β (5.34 pg mL⁻¹ vs. 3.67 pg mL⁻¹; p = 0.008) were significantly higher in the TB cases than in controls. TNF-α was strongly correlated with IL-1β (ρ = 0.80; p < 0.001), while NLR showed weak concordance with multiplex cytokine patterns. Among the patients with TB, four early deaths (5%) exhibited a tripling of TNF-α (71.4 pg mL⁻¹) and a doubling of NLR (7.8) compared with the survivors. Each 10 pg mL⁻¹ rise in TNF-α independently increased the odds of in-hospital death by 1.8-fold (95% CI 1.1–3.0; p = 0.02). The LOS (median 29 days) was unrelated to the smoking, alcohol, or comorbidity load, but varied across BMI strata: underweight, 27 days; normal weight, 30 days; overweight, 23 days (Kruskal–Wallis p = 0.03). In a multivariable analysis, under-nutrition (BMI < 18.5 kg m⁻²) prolonged the LOS by 19% (IRR 1.19; 95% CI 1.05–1.34; p = 0.004) independently of the disease severity. Conclusions: A hyper-TNF-α/IL-1β systemic signature correlates with early mortality in Romanian pulmonary TB, while under-nutrition is the dominant modifiable determinant of prolonged hospitalisation. Admission algorithms that pair rapid TNF-α testing with systematic nutritional assessment could enable targeted host-directed therapy trials and optimise bed utilisation in high-burden settings. Full article

Tuberculosis (TB) is a global public health issue requiring early and accurate diagnosis. The loop-mediated isothermal amplification (LAMP) assay is a promising alternative recommended by the WHO for the initial diagnosis of pulmonary TB, particularly in resource-limited settings. This study evaluated the sensitivity and specificity of a commercial LAMP assay for TB detection using 198 samples from different countries including Mexico. The LAMP assay results were compared to the results of standard tests: AFB smear microscopy, cell culture, and Xpert PCR. Across all samples, LAMP showed a sensitivity of 96.20% and a specificity of 84.61%. When compared specifically to “true positives” and “true negatives” (defined by the consistency across the standard tests), LAMP demonstrated 100% sensitivity and 92.30% specificity. For context, the sensitivity of AFB smear microscopy against the culture and Xpert tests was 79.04%. A significant finding was that the LAMP test detected a high percentage (92.5%) of samples found positive by the culture and Xpert tests but negative by the AFB smear, highlighting its ability to identify cases missed by traditional microscopy. This study concluded that the LAMP assay is a sensitive and specific tool for TB diagnosis with potential for rapid and accurate diagnosis, especially in resource-limited areas. Full article

Tuberculosis (TB) and undernutrition are intricately linked, significantly impacting health outcomes. However, nutritional support for TB patients is not systematically implemented in Lao People’s Democratic Republic (Lao PDR). This study evaluated the effects of nutritional counselling and support on nutritional recovery and TB treatment outcomes. A longitudinal study involved 297 individuals with drug-susceptible TB, 39.4% of whom had a body mass index (BMI) below 18.5 kg/m². Participants were divided into an observation group and an intervention group, the latter receiving nutritional support. Nutritional support included ready-to-use therapeutic food and therapeutic milk products, tailored to patients’ nutritional status. Data collection was conducted at four intervals during treatment. By the end of treatment, 84.3% of participants improved their nutritional status to a BMI of 18.5 kg/m² or higher. The intervention group showed early nutritional recovery, particularly during the intensive phase of TB treatment, although the p-value (p = 0.067) should be interpreted with caution. The overall treatment success rate was high at 90.6%, with no significant difference between groups. Factors associated with treatment success included age under 45, HIV-negative status, a BMI of 18.5 kg/m² or higher, and clinically diagnosed pulmonary TB. Further assessment is required for the operational feasibility to provide systematic nutritional assessment and counselling for people with TB in Lao PDR. Full article

Background and Objectives: Blood-borne inflammatory ratios have been proposed as inexpensive prognostic tools across a range of diseases, but their role in pulmonary tuberculosis (TB) remains uncertain. In this retrospective case–control analysis, we explored whether composite indices derived from routine haematology—namely the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), the systemic immune–inflammation index (SII) and a novel CRP–Fibrinogen Index (CFI)—could enhance risk stratification beyond established cytokine measurements among Romanian adults with culture-confirmed pulmonary T. Materials and Methods: Data were drawn from 80 consecutive TB in-patients and 50 community controls. Full blood counts, C-reactive protein, fibrinogen, and four multiplex cytokines were extracted from electronic records, and composite indices were calculated according to standard formulas. The primary outcomes were in-hospital mortality within 90 days and length of stay (LOS). Results: Among TB patients, the median NLR was 3.70 (IQR 2.54–6.14), PLR was 200 (140–277) and SII was 1.36 × 10⁶ µL⁻¹ (0.74–2.34 × 10⁶), compared with 1.8 (1.4–2.3), 117 (95–140) and 0.46 × 10⁶ µL⁻¹ (0.30–0.60 × 10⁶) in controls. Those with SII above the cohort median exhibited more pronounced acute-phase responses (median CRP 96 vs. 12 mg L⁻¹; fibrinogen 578 vs. 458 mg dL⁻¹), yet median LOS remained virtually identical (29 vs. 28 days) and early mortality was low in both groups (8% vs. 2%). The CFI showed no clear gradient in hospital stay across its quartiles, and composite ratios—while tightly inter-correlated—demonstrated only minimal association with cytokine levels and LOS. Conclusions: Composite cell-count indices were markedly elevated but did not predict early death or prolonged admission. In low-event European cohorts, their chief value may lie in serving as cost-free gatekeepers, flagging those who should proceed to more advanced cytokine or genomic testing. Although routine reporting of NLR and SII may support low-cost surveillance, validation in larger, multicentre cohorts with serial sampling is needed before these indices can be integrated into clinical decision-making. Full article

The pivotal component in the protection against TB is the tissue macrophages (Mф). These cells have been demonstrated to play a crucial role in the elimination of pathogens and mycobacterial killing. Elucidation of the molecular and phenotypic events that determine the outcome of infection in Mф is fundamental to understanding the key features of these cells that are so important in fighting infection. Mф activation is driven by cytokines and other inflammatory mediators secreted by T lymphocytes. The interaction between Mycobacterium tuberculosis (Mtb) and host Мф has been the subject of extensive in vitro research. This dynamic interplay represents a pivotal step in the progression of mycobacterial infection because pulmonary macrophages constitute the primary line of defense against the pathogen, thereby serving as the initial immune cells to which Mtb must adapt to establish a replicative foothold within the host. Our studies have demonstrated that highly differentiated Th1 effectors with the CD27^low phenotype exhibit superior efficacy in activating both peritoneal (Mф: T cell ratio ranging from 125:1 to 625:1) and pulmonary macrophages (Mф: T cell ratio = 5:1) compared to cells with the CD27^high phenotype. Furthermore, our findings indicate that this activation mechanism is not contingent upon the production of reactive nitrogen species. To effectively activate the bacteriostatic function of macrophages, CD27^high T lymphocytes must differentiate into effectors with the CD27^low phenotype. Full article

High-altitude pulmonary edema (HAPE) is a severe condition associated with high-altitude environments, and its molecular mechanism has not been fully elucidated. This study systematically analyzed the DNA methylation status of HAPE patients and healthy controls using reduced-representation bisulfite sequencing (RRBS) and 850K DNA methylation chips, identifying key differentially methylated regions (DMRs). Targeted bisulfite sequencing (TBS) revealed significant abnormalities in DMRs of five genes, azurocidin 1 (AZU1), growth factor receptor bound protein 7 (GRB7), mannose receptor C-type 2 (MRC2), RUNX family transcription factor 3 (RUNX3), and septin 9 (SEPT9). The abnormal expression of AZU1 was validated using peripheral blood leukocytes from HAPE patients and normal controls, as well as rat lung tissue, indicating its potential importance in the pathogenesis of HAPE. To further validate the function of AZU1, we conducted experimental studies using a hypobaric hypoxia injury model in Human Umbilical Vein Endothelial Cells (HUVEC). The results showed that AZU1 was significantly upregulated under hypobaric hypoxia. Knocking down AZU1 mitigates the reduction in HUVEC proliferation, angiogenesis, and oxidative stress damage induced by acute hypobaric hypoxia. AZU1 induces cellular oxidative stress via the p38/mitogen-activated protein kinase (p38/MAPK) signaling pathway. This study is the first to elucidate the mechanism of AZU1 in HAPE via the p38/MAPK pathway, offering novel insights into the molecular pathology of HAPE and laying a foundation for future diagnostic and therapeutic strategies. Full article

Background: Acute respiratory distress syndrome (ARDS) secondary to tuberculosis (TB) is rare and associated with high mortality. Management is further complicated by comorbidities and ICU-related complications. Methods: We report a 43-year-old woman with post-polio sequelae and uncontrolled diabetes who developed ARDS due to pulmonary TB, complicated by recurrent nosocomial infections and gastrointestinal bleeding. Early bronchoscopy and GeneXpert MTB/RIF PCR were performed on ICU Day 2, enabling anti-TB therapy initiation by ICU Day 3. The patient received lung-protective ventilation, prone positioning, tailored antibiotics, and multidisciplinary care. Results: The patient’s clinical course was complicated by two episodes of ventilator-associated pneumonia and gastrointestinal bleeding, but with individualized management, she achieved ventilator weaning and functional recovery. Conclusions: Early TB recognition in ARDS is crucial. Multidisciplinary ICU management, including prudent steroid use, improves outcomes. Full article

Tuberculosis (TB) is a major global health threat, with the current Bacillus Calmette–Guérin (BCG) vaccine having limited efficacy against adult pulmonary disease. Trained immunity (TI) is a form of innate immune memory that enhances antimicrobial defense. It is characterized by the epigenetic and metabolic reprogramming of innate immune cells and holds promise as a promising approach to prevent TB. In this study, we investigated the capacity of heparin-binding hemagglutinin (HBHA), a methylated antigen of Mycobacterium tuberculosis, to induce TI in murine RAW264.7 macrophages, human-derived THP-1 macrophages, and human peripheral blood mononuclear cells (hPBMCs). HBHA-trained macrophages exhibited the enhanced expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) following secondary lipopolysaccharide stimulation. The epigenetic profiling indicated elevated levels of H3K4me1 and H3K4me3 histone marks at cytokine gene loci. Further, metabolic analysis revealed heightened lactate production and the increased expression of glycolytic enzymes. Functionally, HBHA-trained macrophages exhibited improved control of intracellular mycobacteria, as evidenced by a significant reduction in colony-forming units following BCG infection. These findings elucidate that HBHA induces a functional TI phenotype via coordinated epigenetic and metabolic changes, and suggest HBHA may serve as a valuable tool for studying TI and its relevance to host defense against mycobacterial infections, pending further in vivo and clinical validation. Full article

Tuberculosis (TB), primarily caused by Mycobacterium tuberculosis complex (MTBC), remains a global health challenge and can lead to severe pulmonary and extrapulmonary complications. Multidrug-resistant TB (MDR-TB) poses additional challenges, requiring advanced diagnostic and treatment strategies. This study evaluates the BD MAX MDR-TB molecular test for a rapid diagnosis of MDR-TB, detecting resistance to rifampicin (RIF) and isoniazid (INH). The BD MAX MDR-TB test, utilizing real-time PCR, was used to analyze specimens collected from TB-suspected patients, identifying MTB DNA and mutations associated with rifampicin and isoniazid resistance. Results were compared with traditional drug susceptibility testing, and 79 out of 638 samples tested were positive for MTB DNA, with 65 showing a sufficient amount of genetic material for resistance gene identification. The BD MAX test showed a 100% correlation with phenotypic rifampicin resistance, though discrepancies were noted for isoniazid resistance, with a 93% concordance. The BD MAX MDR-TB test is an effective tool for a rapid diagnosis of MDR-TB, especially for rifampicin resistance. However, it may not detect certain mutations related to isoniazid resistance. Complementary tests like Xpert MTB/XDR or whole-genome sequencing could improve diagnostic accuracy and support more effective TB control strategies. Full article

Background and Objectives: The role of adenosine deaminase (ADA) in pulmonary tuberculosis (PTB) remains insufficiently defined in advanced forms of disease. Likewise, the systemic immune inflammatory index (SII) has not been validated in severe PTB. This 6-year prospective observational study aims to evaluate biomarker signatures of serum ADA and SII. Materials and Methods: According to the PTB case definition, 232 adult patients were divided into group 1, with a positive bacteriologic exam (n = 168), and group 2, without bacteriological confirmation (n = 64). ADA serum levels were compared by age, gender, nutritional status, morphologic and bacteriological pattern of PTB lesions, survival status, along with serum levels of other inflammatory biomarkers. All patients with comorbidities, interfering with the level of ADA, were excluded to avoid bias. Results: A total cohort of 208 PTB adults, aged 54.37 ± 14.365 years, included 156 males. The overall mortality was 11.53%. Death occurred after a mean interval of 1.63 ± 3.228 months after PTB diagnosis. ADA serum mean levels were 32.94 ± 9.146 IU/L, significantly higher in G1 (p = 0.002), in patients with delayed diagnosis of PTB (p = 0.000), with lung cavitation (p = 0.003), and death as a poor outcome (p ˂ 0.02). SII had a mean value of 1752.226 ± 2704.150, significantly increased in bacteriologically confirmed PTB cases (p = 0.018), delayed diagnosis (p = 0.002), cavitary advanced pulmonary tuberculosis (APT) (p = 0.002), and deceased (p = 0.003). Both an ADA cut-off elevated risk value of over 30 IU/L and SII of over 902 were fulfilled by 73 patients, with 2.10 higher risk of advanced PTB (p = 0.006) and 4.49 higher risk of mortality (p = 0.000). Conclusions: Serum ADA and SII are recommended as predictors of advanced and severe pulmonary TB. These findings indicate that ADA and SII, when elevated together, delineate a high-risk PTB phenotype with greater disease severity and early mortality. The combination offers a pragmatic, biomarker-based approach to risk stratification in PTB. Full article

Mycobacterium bovis is the causative pathogen of bovine tuberculosis (bTB), a disease that affects cattle and other mammals, including humans. Currently, there is no efficient vaccine against bTB, underscoring the need for novel immunization strategies. The M72 fusion protein, composed of three polypeptides derived from Mycobacterium tuberculosis and M. bovis, has demonstrated protective efficacy against M. tuberculosis in clinical trials when combined with the AS01E adjuvant. Given the established efficacy of nanocapsule formulations as vaccine delivery systems, this study evaluated a novel immunization strategy combining BCG with either full-length M72 or a truncated M72 fused to a streptococcal albumin-binding domain (ABDsM72). Both antigens were encapsulated in chitosan/alginate nanocapsules and assessed in a murine M. bovis challenge model. Priming with BCG followed by an M72 boost significantly improved splenic protection compared to BCG alone, but it did not enhance pulmonary protection. Notably, boosting with ABDsM72 further increased the proportion of CD4+KLRG1-CXCR3+ T cells in the lungs of M. bovis-challenged mice, a key correlate of protective immunity. These findings demonstrate that chitosan/alginate-encapsulated antigens enhance BCG-induced immunity, supporting their potential as next-generation vaccine candidates for bTB control. Full article

Worldwide, several million people are infected with mycobacteria such as Mycobacterium tuberculosis (M. tb) or non-tuberculous mycobacteria (NTM). In 2023, 10.8 million cases and 1.25 million deaths due to M. tb were recorded. In Europe and North America, the emergence of NTM is tending to outstrip that of M. tb. Among pulmonary NTM, Mycobacterium avium complex (MAC) is the most common, accounting for 80% of NTM infections. First-line treatment requires the combination of at least three antibiotics over a long period and with different mechanisms of action to limit cross-resistance. The challenge is to discover more effective new anti-MAC molecules to reduce the duration of treatment and to overcome resistant strains. The aim of this review is to present an overview of the challenges posed by MAC infection such as side effects, reinfections and resistance mechanisms. The latest therapeutic options such as the optimized combination therapy, drug repurposing and the development of new formulations, as well as new anti-MAC compounds currently in (pre)clinical trials will also be discussed. Full article

Background/Objectives: The emergence of multidrug-resistant Acinetobacter baumannii (MDR A. baumannii) as a leading cause of fatal hospital-acquired infections underscores the urgent need for effective vaccines. While oral vaccines using live Bacillus subtilis spores expressing A. baumannii TonB-dependent receptor (TBDR) show promise, biosafety concerns regarding recombinant spore persistence necessitate alternative strategies. Here, we evaluated chemically inactivated B. subtilis spores displaying TBDR as a safer yet immunogenic vaccine candidate. Methods: Recombinant spores were inactivated using iron-ethanol sporicidal solution and administered to BALB/c mice (8–12 weeks old) to assess safety and immunogenicity. Toxicity was evaluated through clinical monitoring, serum biochemistry, and histopathology. Immune responses were characterized by T/B cell activation, IgG/IgA titers, and mucosal sIgA levels. Protective efficacy was determined by challenging immunized mice with MDR A. baumannii Ab35 and quantifying bacterial loads and examining tissue pathology. Results: The inactivated spores exhibited an excellent safety profile, with no adverse effects on clinical parameters, organ function, or tissue integrity. Immunization induced robust systemic and mucosal immunity, evidenced by elevated CD4+/CD8+ T cells, B cells, and antigen-specific IgG/IgA in serum and mucosal secretions. Following the challenge, vaccinated mice showed significantly reduced pulmonary bacterial burdens (>90% reduction), and preserved lung and spleen architecture compared to controls, which developed severe inflammation and tissue damage. Conclusions: These findings demonstrate that inactivated B. subtilis spores expressing TBDR are a safe, orally administrable vaccine platform that elicits protective immunity against MDR A. baumannii. By addressing biosafety concerns associated with live spores while maintaining efficacy, this approach represents a critical advance toward preventing high-risk nosocomial infections. Full article

Tuberculosis is an infectious condition caused by Mycobacterium tuberculosis, primarily targeting the pulmonary system, with the potential to disseminate to various other organs via the haematogenous pathway, ranking among the top ten causes of global mortality. Tuberculosis remains a serious public health problem worldwide. This narrative review aims to emphasise the clinical importance of the inter-relationships between nutrition, pharmacotherapy, and the most common drug–nutrient interactions in the context of tuberculosis and multi-drug-resistant tuberculosis management. Nowadays, pharmacologic approaches utilise polytherapeutic regimens that, although showing increased efficacy, prominently affect the nutritional status of patients and modify multiple metabolic pathways, thus influencing both the effectiveness of therapy and the patient outcomes. There is much evidence that antituberculosis drugs are associated with deficiencies in essential vitamins and various micronutrients, leading to serious adverse consequences. Moreover, poor nutrition exacerbates TB outcomes, and TB further exacerbates nutritional status, a vicious cycle that is particularly prevalent in low-resource environments. Nutritional support is necessary, and clinicians ought to evaluate it on a patient-by-patient basis, as empirical evidence has shown that it can improve immune recovery, decrease tuberculosis-associated morbidity, and increase adherence to therapy. However, drug–food interactions are increasingly prevalent, and patients with tuberculosis require personalised dietary and pharmacological regimens. In this context, antituberculosis treatment requires a holistic approach, based on the collaboration of the prescribing physician, pharmacist, and nutritionist, to assess the patient’s needs from a nutritional and pharmacological perspective, with the ultimate goal of decreasing mortality and improving the prognosis of patients through personalised therapies. Full article

Background/Objectives: Peripheral pulmonary lesions (PPLs) are the current challenge in bronchoscopy. Novel endoscopic approaches allow us to reach PPLs better than a few years ago. In patients with resectable non-small cell lung cancer (NSCLC), perioperative chemotherapy is associated with significantly greater event-free survival; this means that histological assessment before the resectable surgery of PPLs is becoming mandatory. Our objective was to evaluate the diagnostic yield (DY) of a thin bronchoscope (TB) for PPLs suspected for lung cancer that are not reachable with conventional bronchoscopy. Methods: A total of 176 patients with PPLs were evaluated from January 2022 to July 2023. Of the patients, 26 presented with not reachable PPLs with conventional bronchoscopy, and underwent the procedure again with a TB. When possible, R-EBUS was used. PPLs’ dimensions were recorded via chest computed tomography (CT) scan. DY was evaluated. Results: Mean lesion size was 29 mm, and overall DY for TB was 65% (17/26). When the lesion was bigger than 20 mm, DY was 76.5% (13/17), whereas in lesions smaller than 20 mm, DY was 55% (5/9). When PPLs presented a bronchus sign in the CT scan, diagnostic performance of TB was significantly better (76.5% vs. 40%, p = 0.04) compared to PPLs without a bronchus sign, independent from PPL dimensions. R-EBUS did not change DY. Conclusions: TB easily allows us to reach and sample PPLs with a high DY if a bronchus sign is positive, independently from PPL dimensions. Further studies are needed to evaluate if more flexible and penetrating bronchial wall biopsy tools can augment DY for PPLs with TB. Full article