Effectiveness and Safety of Varying Doses of Linezolid With Bedaquiline and Pretomanid in Treatment of Drug-Resistant Pulmonary Tuberculosis: Open-Label, Randomized Clinical Trial.

BACKGROUND: Treatment of drug-resistant tuberculosis with bedaquiline-pretomanid-linezolid regimen has demonstrated good treatment efficacy. Given linezolid's toxicity profile, prudence suggests reconsidering its dose and duration. We determined the effectiveness and safety of structured dose reduction of linezolid with bedaquiline and pretomanid in adults with pre-extensively drug-resistant (pre-XDR) or treatment-intolerant/nonresponsive multidrug-resistant (MDRTI/NR) pulmonary tuberculosis. METHOD: Adults with pre-XDR or MDRTI/NR pulmonary tuberculosis were enrolled in a multicenter, parallel-group, randomized clinical trial in India. Patients were randomized to 26 weeks of bedaquiline, pretomanid, and daily linezolid, at 600 mg for 26 weeks (arm 1); 600 mg for 9 weeks followed by 300 mg for 17 weeks (arm 2); or 600 mg for 13 weeks followed by 300 mg for 13 weeks (arm 3). Study end points included sustained cure, bacteriological failure, toxicity, and death. RESULTS: Of 403 patients enrolled, 255 (63%) were <30 years old, 273 (68%) had prior tuberculosis episodes, and 238 (59%) were malnourished. At the end of treatment, after excluding those with negative baseline cultures, cure was seen in 120 (93%), 117 (94%), and 115 (93%) in arms 1, 2, and 3 respectively. Myelosuppression seen in 85 patients each in arms 1 and 2 and 77 patients in arm 3, not significantly different. Peripheral neuropathy was noticed in 66 patients (30, 17, and 19 in arms 1, 2, and 3) at 10-26 weeks (P = .02). The linezolid dose was reduced because of toxicity in 13, 2, and 4 patients in arms 1, 2, and 3, respectively. CONCLUSIONS: In adults with pre-XDR or MDRTI/NR pulmonary tuberculosis, structured linezolid dose reduction to 300 mg/d is as effective as the standard 600-mg dose but with fewer cases of peripheral neuropathy when given with bedaquiline and pretomanid. CLINICAL TRIALS REGISTRATION: Clinical Trial Registry of India (CTRI/2021/03/032189).

Thoracic follicular dendritic cell sarcoma - an outlandish presentation of a rare tumour with review of literature.

Follicular dendritic cell sarcoma is a rare low grade malignant neoplasm that arises from follicular dendritic cells in lymphoid tissue germinal centres and accounts for 0.4% of all soft tissue sarcomas. It is extremely rare to have pulmonary follicular dendritic cell sarcoma with endobronchial extension and as an anterior mediastinal mass with mediastinal lymph node involvement. We present the case of a 34-year-old male non-smoker who had been experiencing chest pain for three months. A lobulated left peri-hilar mass with endobronchial spread into the left main bronchus and mediastinal lymphadenopathy was identified on a chest CT. The bronchoscope-guided cryobiopsy of the endobronchial mass was inconclusive. After a thorough multidisciplinary discussion, the patient underwent left sided pneumonectomy, mediastinal mass resection, and systematic lymph node dissection. Histologic examination using immunohistochemistry revealed follicular dendritic cell sarcoma.

Metastatic thymic carcinoid: does surgeon have a primary role?

Thymic carcinoids are rare mediastinal tumours. These are aggressive tumours that often present late and have poor prognosis. Primary surgical treatment is recommended even in metastatic tumours since the role of adjuvant therapy is not well established. We present a case of metastatic thymic carcinoid managed with surgical excision.

Evaluation of AAICare®-TB sequence analysis tool for accurate diagnosis of drug-resistant tuberculosis: A comparative study with TB-Profiler and Mykrobe.

A rapid and comprehensive drug susceptibility test is essential for eliminating drug resistant tuberculosis. Next generation sequencing (NGS) based susceptibility testing is being explored as a potential substitute for the conventional phenotypic and genotypic testing methods. However, the adoption of NGS based genotypic susceptibility testing depends on the availability of simple, accurate and efficient analysis tools. This preliminary study aimed to evaluate the performance of a Mycobacterium tuberculosis (Mtb) genome analysis pipeline, AAICare®-TB, for susceptibility prediction, in comparison to two widely used gDST prediction tools, TB-Profiler and Mykrobe. This study was performed in a National Reference Laboratory in India on presumptive drug-resistant tuberculosis (DR-TB) isolates. Whole genome sequences of the 120 cultured isolates were obtained through Illumina sequencing on a MiSeq platform. Raw sequences were simultaneously analysed using the three tools. Susceptibility prediction reports thus generated, were compared to estimate the total concordance and discordance. WHO mutation catalogue (1st edition, 2021) was used as the reference standard for categorizing the mutations. In this study, AAICare®-TB was able to predict drug resistance status for First Line (Streptomycin, Isoniazid, Rifampicin, Ethambutol and Pyrazinamide) and Second Line drugs (Fluoroquinolones, Second Line Injectables and Ethionamide) in 93 samples along with lineage and hetero-resistance as per the WHO guidelines.

Recovery rates of mycobacterium from suspected extra-pulmonary tuberculosis patients using liquid culture at a tertiary referral centre of India.

Tuberculosis still remains a serious public health problem in developing countries. Rapid isolation of mycobacteria is critical for accurate diagnosis and management of tuberculosis. In the present study BACTEC MGIT 960 system was evaluated against Lowenstein Jensen (LJ) medium for isolation of mycobacteria from different extra-pulmonary specimens (N = 371). The samples were processed using NaOH-NALC method and inoculated in BACTEC MGIT and on LJ medium. The BACTEC MGIT 960 system detected 93 (25.06%) samples positive for acid fast bacilli and by LJ only 38 samples (10.24%) was positive. Furthermore, total 99 (26.68%) samples were detected positive by both the culture methods. The mean turnaround time to detection of mycobacteria by MGIT 960 were significantly less (12.4 days) as compared with LJ (22.76 days). In conclusion, BACTEC MGIT 960 system is more sensitive and rapid culture system for isolation of mycobacteria. However LJ culture method also suggested to further increase the detection rate of EPTB cases.

Surgical outcomes and the factors affecting lung expansion following open window thoracostomy in chronic tuberculous empyema with destroyed lung.

BACKGROUND: Patients with chronic tuberculous empyema and destroyed lung on a prolonged intercostal tube with failed lung expansion considered unsuitable for single-lung ventilation have poor outcomes. The study's objective was to analyze the surgical outcomes and lung expansion factors in these patients following the open window thoracostomy (OWT) procedure. METHODS: In a prospective study, patients (males = 63, females = 12) diagnosed with tuberculosis who underwent OWT were analyzed between 2017 and 2018. Factors including age, sex, side, comorbidities, body mass index (BMI), bacteriological culture, and patency of OWT site were evaluated for lung expansion. RESULTS: Mean preoperative weight 40.96 ± 5.70 kg increased significantly postoperatively. Pseudomonas aeruginosa (30.66%) was the most typical organism isolated and smoking (21.3%) was the common risk factor. At 6-month follow-up, complete lung expansion was noted in 60% of patients, while partial and no expansion is seen in 17.3% and 22.3% patients. Similarly 82.4% patients with pre-operative BMI>18.5 kg/m2 had complete lung expansion, while with BMI < 18.5 kg/m2, 41.7% and 45.8% had partial and no-expansion. Complete lung expansion was seen in 97.1%, 18.2%, and 23.1% of patients with obliterated OWT, sputum, and pleural pus positive for acid-fast bacilli (active disease), while in 57.9% of patients with comorbidities, complete lung expansion was absent. CONCLUSION: The analysis of various factors concludes that lung expansion is not affected by age, sex, side of the disease, and co-morbid conditions; however, extensively diseased lungs with low BMI and positive bacteriological culture, especially P. aeruginosa, active disease, smoking, and patent OWT, interfered with the expansion of the lung.

Multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis strains in geriatrics: An analysis and its implications in tuberculosis control.

Objective: This study aimed to analyze the trends of tuberculosis (TB) disease, drugs susceptibility patterns in geriatric TB over a period of three years (from 2010 to 2012). Materials & methods: In this study, laboratory data on diagnosis of geriatric tuberculosis suspected patients (age ≥60 years) was analyzed retrospectively at National Reference Laboratory (NRL). Results: Among 12,140 geriatric TB suspects, 1621 (13%) were acid-fast bacillus (AFB) smear-positive and 10,519 (87%) were smear-negative. Analysis of 915 culture results showed 470 (51%) as positive for Mycobacterium tuberculosis complex (MTBC), 63 (7%) contaminated and 36 (4%) identified as mycobacteria other than tuberculosis (MOTT). A total 210/470 (45%) were multidrug-resistant TB (MDR-TB) strains. Among the mono-resistant strains, isoniazid mono-resistant was found more frequently (134/470, 28%) whereas, it was least among rifampicin mono-resistant 5/470 (1%). The second-line drug susceptibility testing (DST) results showed 7% (17/240) extensively drug-resistant TB (XDR-TB) strains. Most common second line mono-resistant strain was observed with ofloxacin, 16% (38/240). Conclusion: This study shows high number of MDR/XDR geriatric TB patients at tertiary care TB hospital. The study highlighted the need of separate line of early identification, diagnosis and treatment of geriatric TB patients. However, further study with improved sample size may needed to confirm the findings.

Preparedness for establishing COVID-19 services during acute emergency of COVID-19 pandemic: Experience of a tertiary care TB and respiratory diseases hospital.

BACKGROUND: The ongoing coronavirus disease 2019 (COVID-19) calls for setting up of well-equipped and dedicated health facilities to manage sick patients while protecting healthcare workers and the environment. An ideal high-level isolation unit requires a high level of administrative commitment, availability of space, human resource and logistics. METHOD: The experience of setting up COVID-19 care facilities on a noticeably short period in a tertiary TB and respiratory diseases institute in wake of the COVID-19 pandemic is being shared here. RESULT: All the essential COVID-19 services were set up in record time of 8 days. A total of 115 COVID-19 patients were admitted. Out of these 89 patients were discharged in a satisfactory condition. There were 19 deaths, and 4 patients became critical and had to be referred to level 3 facility for ICU care. CONCLUSION: This experience will help other hospitals in planning out the strategies and solve the difficulties they may face while opening a COVID-19 care facility under limited resources on an urgent basis.

Diagnostic utility of GenoType MTBDRsl assay for the detection of moxifloxacin-resistant mycobacterium tuberculosis, as compared to phenotypic method and whole-genome sequencing.

Background: Recently, moxifloxacin (MFX)-resistant results of Mycobacterium tuberculosis (Mtb) obtained by GenoType MTBDRsl (second-line line probe assay [SL-LPA]) have been stratified to determine their resistance level; however, its accuracy has not been well studied. Therefore, the study aimed to evaluate the diagnostic accuracy of SL-LPA, with phenotypic drug susceptibility testing (pDST) and whole-genome sequencing (WGS) for the detection of MFX-resistant Mtb and their resistance level. Methods: A total of 111 sputum samples were subjected to SL-LPA according to the diagnostic algorithm of the National Tuberculosis Elimination Program. Results were compared with pDST of MFX (at critical concentration [CC, 0.25 µg/ml] and clinical breakpoint [CB, 1.0 µg/ml] using BACTEC mycobacterial growth indicator tube-960), and WGS. Results: At CC, SL-LPA and pDST yielded concordant results of MFX for 104 of 111 (94%). However, at CB, 23 of 30 (77%) isolates carrying gyrA mutation known to confer low-level resistance to MFX were scored as susceptible by pDST. Among 46 Mtb isolates carrying gyrA mutations known to confer high-level resistance to MFX, 36 (78%) isolates yielded concordant results, while 10 (22%) isolates were scored as susceptible at CB by pDST. WGS identified gyrA mutations in all isolates suggested by SL-LPA. Conclusion: It is concluded that the stratification of MFX-resistant results by SL-LPA/genotypic method is not very well correlated with pDST (at CB), and hence, pDST may not be completely replaced by SL-LPA. gyrA D94G and gyrAA90V are the most prevalent mutations in MFX-resistant Mtb.

Thoracic surgical interventions for DR-TB and their results.

BACKGROUND: Surgery in DR-TB is a highly contested intervention. However, in suitable selected cases, it has a great role in improving outcomes of treatment as well as symptomatic improvement in the quality of life of the patient. Indications of surgery in this setting will be localized disease with high likelihood of persistent progression or sputum positivity despite adequate therapy. Recurrent hemoptysis, intolerance to drugs or absence of radiological and bacteriological improvement during initial 3-4months of therapy becomes additional indications for surgical intervention. A review of 11 studies published in a period from 1993 to 2013 provides enough justification for the role of surgical intervention in pulmonary tuberculosis. INTERVENTIONS: At the NITRD, in the last 20years a total of 107 cases have been operated upon for DR-TB. Procedures done were 70 pneumonectomies, 20 lobectomies, 5 bilobectomies, 4 nonanatomical resections and 7 thoracoplasties. RESULTS: Sputum negativity was achieved in 93 cases after surgery and 62 were declared cured after 4years of follow up. 6 cases of DR TB were also operated upon in March 2013 in one MSF TB surgery mission and all of them are sputum negative till March 2015. CONCLUSIONS: In conclusion, surgical intervention should be offered and made available for greater number of DR-TB patients.

Surgical aspects of pulmonary tuberculosis: an update.

Tuberculosis remains a major global medical challenge and concern. In the world's population of over 7.4 billion people, 8.6 million are estimated to be infected with Mycobacterium tuberculosis; another 2.2 billion have latent tuberculosis. There is an annual incidence of 16,000 new cases in the USA and 7-8 million new cases worldwide, of which 440,000 are multidrug-resistant or extensively multidrug-resistant, mainly in developing countries or emerging economies. According to the World Health Organization, the incidence of tuberculosis is 133 cases per 100,000 of the population; 3.3% new cases are drug resistant and 20% are already treated cases. Of the drug-resistant cases, 9.7% are extensively drug-resistant. The annual global mortality attributable to tuberculosis is over 1.3 million people. The association with HIV/AIDS in 430,000 people has compounded the global concern and challenge. This review presents the historical indications for surgical treatment of tuberculosis, reviews the current literature and clinical experience, and collates this into increased awareness and contemporary understanding of the indications and need for surgery in primary active tuberculosis, adjuvant surgical therapy for multidrug-resistant tuberculosis, and the complications of chronic tuberculosis sequelae or previous tuberculosis surgery.

Incidental intraoperative diagnosis of retained foreign body lung misdiagnosed as pulmonary tuberculosis.

Tracheobronchial foreign body aspiration (FBA) is a very common and lethal problem among children. It can easily be diagnosed with a typical history of choking crisis. Clinical examination and radiology play a secondary role in diagnosis. Acute choking episode may lead to death or else to serious sequels such as bronchiectasis, atelectasis, and recurrent pneumonia. Here, we report an interesting case of bronchiectasis in a young female initially thought to be a consequence of pulmonary tuberculosis, who was subsequently found to have retained foreign body in the left lower lobe lung which was the actual cause of her symptoms.

Mediastinal Teratoma with Coexisting Adenocarcinoma and Carcinoid Tumor (Somatic-Type Malignancy): A Case Report with a Review of the Literature.

Germ cell tumors constitute 10% to 15% of anterior mediastinal neoplasms. Of these, mature teratoma is the most common. Somatic malignant transformation in mature teratoma is a very rare phenomenon. In the anterior mediastinum, few cases of malignant transformation in the form of carcinoma, sarcoma, or neuroendocrine tumors have been described. We present the case of a mature mediastinal teratoma in a 24-year-old female, diagnosed on computed tomography, where both carcinoid tumor and adenocarcinoma were seen. To the best of our knowledge, this is the first report of such a case. Malignant transformation in a mature teratoma confers a significantly worse prognosis and is difficult to diagnose only on clinical and radiological evaluation. As these lesions are so rare, the treatment options for these lesions are also not clearly defined. Extensive sampling and careful microscopic examination are needed when teratomas are submitted for pathological evaluation.

Proteomic analysis of HEK293 cells expressing non small cell lung carcinoma associated epidermal growth factor receptor variants reveals induction of heat shock response.

In view of the fact that certain non small cell lung carcinoma associated epidermal growth factor receptor mutations keep the receptor constitutively active, the downstream effectors of altered activity of mutant receptors are largely unknown. By 2D gel electrophoresis and MALDI-TOF/MS analysis, we showed that increased activity of EGFR mutants, L858R, L861Q and A871G induce heat shock proteins such as Hsp70, Hsp60, Hsp90B1, Hsp5a, Hsp71 and few transcriptional factors. Of which, Hsp70 was observed to be regulated more selectively to L861Q mutant. Our results suggest the possible role of heat shock proteins in lung tumor progression considering EGFR mutations.

Resurgence of therapeutically destitute tuberculosis: amalgamation of old and newer techniques.

Most of thoracic surgery developed as a result of efforts to treat tuberculosis (TB). The role of surgical therapy has declined but the role of surgery in TB still remains in situations like diagnostic difficulties, persistent sputum positive state despite therapy and complications and sequel like haemoptysis, destroyed or bronchiectatic lungs or empyema with or without broncho-pleural fistula (BPF). Various procedures have a role according to the indication. Some of the procedures have become obsolete but lobectomy, pneumonectomy, thoracoplasty, decortication and open window thoracostomy continue to be relevant. Recent published series have demonstrated mortality ranging from 0% to 3.1%. Surgery for complications and sequel of pulmonary TB still remain an important intervention for alleviation of human misery.

Spontaneous resolution of an inflammatory pseudotumour of the lung subsequent to wedge biopsy.

Spontaneous, complete resolution of inflammatory pseudotumour (IPT) of lungs is exceptionally rare. A 44-year-old male was referred for evaluation for «non resolving pneumonitis¼. He had cough and minimal expectoration for 5 months, chest pain, haemoptysis and fever for a fortnight. Computed tomography of thorax (CT-thorax) confirmed the presence of a homogenous mass with irregular borders in right middle lobe with areas of breakdown and air bronchogram. Transbronchial lung biopsy was suggestive of «plasma cell granuloma¼. Thoracotomy disclosed a hard mass in right middle lobe adherent to lower lobe, chest wall and mediastinum which could not be removed. A wedge biopsy confirmed IPT. Chest radiograph after 4 weeks revealed significant resolution. CT-thorax a year later showed fibrotic scar. Till date, there are only five reports documenting 6 patients with spontaneous resolution of IPT of lungs and in 4 this occurred within 3 months of an invasive diagnostic intervention.

Surgical treatment for tracheobronchial carcinoid tumors: a 16-year experience.

We conducted a 16-year retrospective review of 31 cases of tracheobronchial carcinoid tumors treated in our institution between 1995 and 2011, to determine their characteristic features and outcome of management. There were 12 men and 19 women. The most common presenting symptoms were cough and hemoptysis (71%) with a mean duration of 4 years. Preoperative bronchoscopy confirmed the diagnosis in 80% of patients. Right-sided tumors accounted for 60% of cases. Most tumors arose from the mainstem bronchi. Histologic analysis revealed typical carcinoids in 28 cases and atypical carcinoids in 3. Surgical treatment was mainly radical resection (pneumonectomy in 19 patients). A parenchymal-preserving surgery (sleeve resection of left main bronchus and end-to-end anastomosis) was only possible in 2 cases. Mediastinal lymph nodes were involved in 30% of cases. Most patients had widespread extraluminal extension. Follow-up revealed recurrence in one patient. No deaths were recorded, and complications were mainly atelectasis and air leak. Radical resection remains the mainstay of surgical management of bronchial carcinoids in cases of late presentation with destroyed and bronchiectatic distal pulmonary parenchyma. Parenchymal-preserving surgery should only be carried out when indicated.

Surgery for pulmonary tuberculosis - a 15-year experience.

BACKGROUND: Surgery for pulmonary tuberculosis (TB) has become rather limited. However, it is still required for some sequelae and complications. This is a 15-year retrospective study of cases operated upon for pulmonary TB at a centre. PATIENTS AND METHODS: A total of 2878 cases underwent surgical procedures for various complications of pulmonary TB over a 15-year-long period. After excluding those managed by tube thoracostomy, rib resection and open-window thoracostomy, 1297 cases out of this series were taken up for major thoracic surgical procedures. A total of 98 were operated for persistent sputum-positive status, 740 for recurrent massive haemoptysis or chest infections, 2024 for empyema and 18 for diagnostic reasons. Procedures were 830 lung resections, 12 primary thoracoplasties, 295 space-reducing thoracoplasties, 158 decortications, 744 open-window thoracoplasties and 837 tube thoracotomies alone. RESULTS: There were 18 early deaths and 37 late deaths. The cause of death was haemorrhage in seven cases and respiratory failure in nine cases and septicaemia in two cases. Late deaths were mostly because of progressive tubercular disease. There was significant morbidity in terms of broncho-pleural fistula (BPF) in 95 cases and persistent sinus in 37 cases. Milder complications such as pneumonia, fever and wound sepsis were noticed in some cases but definite records were not available. BPF was managed by tube drainage followed by either window thoracostomy or thoracoplasty. In multi-drug-resistant (MDR) cases, persistent documented sputum negativity was achieved in 64 out of 86 cases. Results were better in haemoptysis and chest infection group where the desired result was achieved in 699 cases. CONCLUSIONS: Surgery in pulmonary TB is still relevant in many cases and yields a very gratifying result. It is a challenging surgery and this series is a very large one.

Benign cystic teratoma of mediastinum.

Benign mediastinal teratoma accounts for 60% of all mediastinal germ cell tumors, which in turn account for 15-20% of all anterior mediastinal masses. It is frequently associated with compressive effects of surrounding structures. Total surgical excision is curative and life saving also. We are presenting a case of giant benign cystic mediastinal teratoma which underwent surgical excision but long term compressive effect on lungs resulted them to be small in size compared to thoracic cavity even six months postoperatively.