Tuberculosis (TB) is a leading cause of mortality due to infectious disease, but the factors determining disease progression are unclear. Transcriptional signatures associated with type I IFN ...signalling and neutrophilic inflammation were shown to correlate with disease severity in mouse models of TB. Here we show that similar transcriptional signatures correlate with increased bacterial loads and exacerbate pathology during Mycobacterium tuberculosis infection upon GM-CSF blockade. Loss of GM-CSF signalling or genetic susceptibility to TB (C3HeB/FeJ mice) result in type I IFN-induced neutrophil extracellular trap (NET) formation that promotes bacterial growth and promotes disease severity. Consistently, NETs are present in necrotic lung lesions of TB patients responding poorly to antibiotic therapy, supporting the role of NETs in a late stage of TB pathogenesis. Our findings reveal an important cytokine-based innate immune effector network with a central role in determining the outcome of M. tuberculosis infection.
Polyclonal infections occur when at least two unrelated strains of the same pathogen are detected in an individual. This has been linked to worse clinical outcomes in tuberculosis, as undetected ...strains with different antibiotic resistance profiles can lead to treatment failure. Here, we examine the amount of polyclonal infections in sputum and surgical resections from patients with tuberculosis in the country of Georgia. For this purpose, we sequence and analyse the genomes of Mycobacterium tuberculosis isolated from the samples, acquired through an observational clinical study (NCT02715271). Access to the lung enhanced the detection of multiple strains (40% of surgery cases) as opposed to just using a sputum sample (0-5% in the general population). We show that polyclonal infections often involve genetically distant strains and can be associated with reversion of the patient's drug susceptibility profile over time. In addition, we find different patterns of genetic diversity within lesions and across patients, including mutational signatures known to be associated with oxidative damage; this suggests that reactive oxygen species may be acting as a selective pressure in the granuloma environment. Our results support the idea that the magnitude of polyclonal infections in high-burden tuberculosis settings is underestimated when only testing sputum samples.
Mycobacterium tuberculosis (Mtb) has been found to persist within cavities in patients who have completed their anti-tuberculosis therapy. The clinical implications of Mtb persistence after therapy ...include recurrence of disease and destructive changes within the lungs. Data on residual changes in patients who completed anti-tuberculosis therapy are scarce. This case highlights the radiological and pathological changes that persist after anti-tuberculosis therapy completion and the importance of achieving sterilization of cavities in order to prevent these changes.
This is a case report of a 33 year old female with drug-sensitive pulmonary tuberculosis who despite successfully completing standard 6-month treatment had persistent changes in her lungs on radiological imaging. The patient underwent multiple adjunctive surgeries to resect cavitary lesions, which were culture positive for Mtb. After surgical treatment, the patient's chest radiographies improved, symptoms subsided, and she was given a definition of cure.
Medical therapy alone, in the presence of severe cavitary lung lesions may not be able to achieve sterilizing cure in all cases. Cavities can not only cause reactivation but also drive inflammatory changes and subsequent lung damage leading to airflow obstruction, bronchiectasis, and fibrosis. Surgical removal of these foci of bacilli can be an effective adjunctive treatment necessary for a sterilizing cure and improved long term lung health.
In 2021, the World Health Organization recommended new extensively drug-resistant (XDR) and pre-XDR tuberculosis (TB) definitions. In a recent cohort of TB patients in Eastern Europe, we show that ...XDR TB as currently defined is associated with exceptionally poor treatment outcomes, considerably worse than for the former definition (31% vs. 54% treatment success).
•After the successful treatment, strong lung damage may occur in multi/extensively drug-resistant tuberculosis (M/XDR-TB) patients.•Chest X-ray may be a useful aid in determining high risk for ...post-treatment lung damage.•Subjects undergoing adjunctive surgery had less respiratory symptoms at follow-up.•Close correlation of the St. George Respiratory Questionnaire and spirometry results was observed among the TB subjects.•M/XDR-TB patients need more adequate medical care and pulmonary rehabilitation.
Post-treatment morbidity among subjects with drug-resistant tuberculosis (DR-TB) is unclear.
This was a cross-sectional study of patients from Tbilisi, Georgia with cavitary DR-TB and an outcome of cure. Participants had a chest X-ray (CXR), St. George Respiratory Quality (SGRQ) survey, and pulmonary function tests (PFTs) performed. Correlations between SGRQ and PFT results and factors associated with pulmonary impairment were examined.
Among 58 subjects (median age 31 years), 40% used tobacco, 59% had prior TB, and 47% underwent adjunctive surgical resection. The median follow-up time was 41 months. Follow-up CXR revealed fibrosis in 30 subjects (52%) and bronchiectasis in seven (12%). The median forced expiratory volume (FEV1)/forced vital capacity (FVC) ratio was 0.72, with 24 subjects (41%) having a ratio of ≤0.70. Significant correlations existed between PFT measures and overall and component SGRQ scores. In linear regression, age, prior TB, and CXR fibrosis or bronchiectasis were significantly associated with decreased pulmonary function. Adjunctive surgery was significantly associated with a higher percent predicted FEV1 and FVC.
A high proportion of DR-TB subjects had residual pulmonary impairment, particularly with recurrent TB and severe radiological disease. The association of surgical resection with improved lung function deserves further study. PFTs and SGRQ may both be useful to evaluate lung health.
Summary The global emergence and spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis has led to the re-examination of surgery as a possible adjunctive treatment. We ...present the case of a 26-year-old HIV-seronegative patient with XDR pulmonary tuberculosis refractory to medical therapy. Surgical resection of the patient's solitary cavitary lesion was done as adjunctive treatment, and a successful outcome with a combination of surgery and drug therapy was achieved. We review the history of surgical therapy for tuberculosis and reports of its role in treatment of MDR and XDR tuberculosis. 26 case series and cohort studies were included, and together showed that surgical resection is beneficial in the treatment of drug-resistant tuberculosis. However, the results might not be applicable in all settings because investigations were observational and typically included patients with less severe disease, and all surgeries were done at specialised thoracic-surgery centres. Well designed studies are needed to establish the efficacy of surgery in treatment of drug-resistant tuberculosis.
Abstract
OBJECTIVES
Surgical resection is recommended as adjunctive treatment for multidrug-resistant (MDR) tuberculosis (TB) in certain scenarios; however, data are limited. We sought to evaluate ...the impact of surgery by comparing TB outcomes among patients with cavitary disease who received medical versus combined medical and surgical treatment.
METHODS
A cohort of all patients with cavitary MDR or extensively drug-resistant (XDR) TB treated in Tbilisi, Georgia, between 2008 and 2012. Patients meeting indications for surgery underwent adjunctive resection in addition to medical treatment. We compared TB outcomes (proportions achieving cure/complete) among patients who received adjunctive surgery to those who received medical treatment alone using an adjusted robust Poisson regression.
RESULTS
Among 408 patients, 299 received medical treatment alone and 109 combined medical and surgical treatment. Patients in the non-surgical group were older and had higher rates of tobacco and alcohol use and bilateral disease compared to the surgical group. Patients in the surgical group had higher rates of XDR disease (28% vs 15%). Favourable outcomes were higher among the surgical versus non-surgical group cohort (76% vs 41%). After adjusting for multiple factors, the association between adjunctive resection and favourable outcome remained (adjusted risk ratio 1.6, 95% confidence interval 1.3–2.0); the relationship was also observed in secondary models that excluded patients with bilateral disease (contraindication for surgery) and patients receiving <6 months of treatment. Major postoperative complications occurred among 8 patients (7%) with no postoperative mortality.
CONCLUSIONS
Adjunctive surgery is safe and may improve the effectiveness of treatment among select patients with cavitary MDR- and XDR-TB.
The emergence and persistence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) is a major obstacle to achieving TB elimination goals 1.
The country of Georgia has a high prevalence of tuberculosis (TB) and hepatitis C virus (HCV) infection.
To determine whether HCV co-infection increases the risk of incident drug-induced hepatitis ...among patients on first-line anti-TB drug therapy.
Prospective cohort study; HCV serology was obtained on all study subjects at the time of TB diagnosis; hepatic enzyme tests (serum alanine aminotransferase ALT activity) were obtained at baseline and monthly during treatment.
Among 326 study patients with culture-confirmed TB, 68 (21%) were HCV co-infected, 14 (4.3%) had chronic hepatitis B virus (HBV) infection (hepatitis B virus surface antigen positive HBsAg+), and 6 (1.8%) were HIV co-infected. Overall, 19% of TB patients developed mild to moderate incident hepatotoxicity. In multi-variable analysis, HCV co-infection (adjusted Hazards Ratio aHR=3.2, 95% CI=1.6-6.5) was found to be an independent risk factor for incident anti-TB drug-induced hepatotoxicity. Survival analysis showed that HCV co-infected patients developed hepatitis more quickly compared to HCV seronegative patients with TB.
A high prevalence of HCV co-infection was found among patients with TB in Georgia. Drug-induced hepatotoxicity was significantly associated with HCV co-infection but severe drug-induced hepatotoxicity (WHO grade III or IV) was rare.
The duration and regimen of tuberculosis (TB) treatment is currently based predominantly on whether the M. tuberculosis (Mtb) strain is drug-sensitive (DS) or multidrug-resistant (MDR) with doses ...adjusted by patients' weight only. The systematic stratification of patients for personalized treatment does not exist for TB. As each TB case is different, individualized treatment regimens should be applied to obtain better outcomes. In this scenario, novel therapeutic approaches are urgently needed to (1) improve outcomes and (2) shorten treatment duration, and host-directed therapies (HDT) might be the best solution. Within HDT, repurposed drugs represent a shortcut in drug development and can be implemented at the short term. As hyperinflammation is associated with worse outcomes, HDT with an anti-inflammatory effect might improve outcomes by reducing tissue damage and thus the risk of permanent sequelae.
SMA-TB is a multicentre randomized, phase IIB, placebo-controlled, three-arm, double-blinded clinical trial (CT) that has been designed in the context of the EC-funded SMA-TB Project ( www.smatb.eu ) in which we propose to use 2 common non-steroidal anti-inflammatory drugs (NSAID), acetylsalicylic acid (ASA) and ibuprofen (Ibu), as an HDT for use as adjunct therapy added to, and compared with, the standard of care (SoC) World Health Organization (WHO)-recommended TB regimen in TB patients. A total of 354 South African and Georgian adults diagnosed with confirmed pulmonary TB will be randomized into SoC TB treatment + placebo, SoC + acetylsalicylic acid or SoC + ibuprofen.
SMA-TB will provide proof of concept of the HDT as a co-adjuvant treatment and identify the suitability of the intervention for different population groups (different epidemiological settings and drug susceptibility) in the reduction of tissue damage and risk of bad outcomes for TB patients. This regimen potentially will be more effective and targeted: organ saving, reducing tissue damage and thereby decreasing the length of treatment and sequelae, increasing cure rates and pathogen clearance and decreasing transmission rates. It will result in better clinical practice, care management and increased well-being of TB patients.
Clinicaltrials.gov NCT04575519. Registered on October 5, 2020.
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