Post-TB bronchiectasis: from pathogenesis to rehabilitation.

The destruction of lung parenchyma caused by TB can result in pulmonary sequelae that are classified as bronchiectasis due to traction (radiological sequelae), and bronchiectasis persisting with an inflammatory bronchial component and opportunistic bronchial infection. There is a lack of studies that comprehensively analyse whether post-TB bronchiectasis differs in clinical, prognostic or therapeutic aspects from bronchiectasis arising from other aetiologies. However, it has been noted that post-TB bronchiectasis tends to appear more frequently in the upper lung lobes. In many countries, TB is the most frequent known cause of bronchiectasis, but there is currently no targeted management of bronchiectasis due to TB as opposed to other aetiologies. It is imperative to first prevent TB, and when that fails to provide early diagnosis and adequate treatment for TB disease. In addition, efforts should be made to limit additional lung insults such as tobacco use and provide management of post TB bronchiectasis to minimise further pulmonary sequelae. The objective of this minireview was to provide an update on post-TB bronchiectasis, its definition, epidemiological data, pathophysiology, and clinical, diagnosis and therapeutic aspects.

Diagnostic value of ultrasound-guided transbronchial lung biopsy in peripheral tuberculous pulmonary lesions.

BACKGROUND: To investigate the diagnostic value of bronchial ultrasound-guided transbronchial lung biopsy (EBUS-TBLB) in tuberculous peripheral pulmonary lesions. METHODS: A total of 770 patients who completed CT imaging and ultrasound bronchoscopy were retrospectively analyzed. All patients underwent biopsy sampling as well as alveolar lavage under the guidance of ultrasound. Pathological analysis and molecular biological detection of pulmonary tuberculosis were performed in both pathological tissues and bronchoalveolar lavage fluid (BALF), and the diagnostic positive rate and diagnostic sensitivity were statistically analyzed. RESULTS: Of the 44 patients who were found to have lesions by EBUS-TBLB, 26 patients were able to achieve a definite diagnosis of PPLs, with an overall diagnostic yield of 59.1%. Of the 33 patients with all diagnosed benign lesions, 22 were diagnosed with active pulmonary tuberculosis with the diagnostic yield of 66.7%. Among above 22 cases, the overall positive rate of BALF diagnosis was as high as 95.6%, and the highest diagnostic rate of a single test was BALF XpertMTB/RIF, 59.1%. Compared with pathological tissues, the diagnostic positive rate of BALF as a diagnostic specimen was higher (p < .05). In addition, the diagnostic yield of EBUS-TBLB in pulmonary tuberculosis was not affected by patient's age, lesion extent size, EBUS probe position, presence or tracheal grade, or characteristics of lesions (all p > .05). CONCLUSION: Transbronchial radial ultrasound-guided lung biopsy of tuberculous PPLs possesses higher diagnostic rate, fewer complications and less interference, exerts potential application value in the diagnosis of tuberculous peripheral pulmonary lesions.

Heme oxygenase-1 modulates ferroptosis by fine-tuning levels of intracellular iron and reactive oxygen species of macrophages in response to Bacillus Calmette-Guerin infection.

Macrophages are the host cells and the frontline defense against Mycobacterium tuberculosis (Mtb) infection, and the form of death of infected macrophages plays a pivotal role in the outcome of Mtb infections. Ferroptosis, a programmed necrotic cell death induced by overwhelming lipid peroxidation, was confirmed as one of the mechanisms of Mtb spread following infection and the pathogenesis of tuberculosis (TB). However, the mechanism underlying the macrophage ferroptosis induced by Mtb infection has not yet been fully understood. In the present study, transcriptome analysis revealed the upregulation of heme oxygenase-1 (HMOX1) and pro-ferroptosis cytokines, but downregulation of glutathione peroxidase 4 (GPX4) and other key anti-lipid peroxidation factors in the peripheral blood of both patients with extra-pulmonary tuberculosis (EPTB) and pulmonary tuberculosis (PTB). This finding was further corroborated in mice and RAW264.7 murine macrophage-like cells infected with Bacillus Calmette-Guerin (BCG). A mechanistic study further demonstrated that heme oxygenase-1 protein (HO-1) regulated the production of reactive oxygen species (ROS) and iron metabolism, and ferroptosis in BCG-infected murine macrophages. The knockdown of Hmox1 by siRNA resulted in a significant increase of intracellular ROS, Fe2+, and iron autophagy-mediated factor Ncoa4, along with the reduction of antioxidant factors Gpx4 and Fsp1 in macrophages infected with BCG. The siRNA-mediated knockdown of Hmox1 also reduced cell survival rate and increased the release of intracellular bacteria in BCG-infected macrophages. By contrast, scavenging ROS by N-acetyl cysteine led to the reduction of intracellular ROS, Fe2+, and Hmox1 concentrations, and subsequently inhibited ferroptosis and the release of intracellular BCG in RAW264.7 cells infected with BCG. These findings suggest that HO-1 is an essential regulator of Mtb-induced ferroptosis, which regulates ROS production and iron accretion to alter macrophage death against Mtb infections.

Image-guided fine-needle aspiration cytology or core biopsy - A key to definitive diagnosis of tuberculous mastitis.

Despite advances in the treatment, tuberculosis (TB) is still a global health problem. The diagnosis of extrapulmonary TB in their primary form is very challenging. Breast TB is very uncommon and accounts for < 0.1% of all breast lesions. Due to rarity of the disease and difficulty in diagnosis, we report a case of a 40-year-old female who had a hard lump in the right breast. Full-field digital mammography suggested the lesion as American College of Radiology Breast Imaging Reporting and Data System-5 (ACR BIRADS-5) (highly suggestive of carcinoma). Histopathological examination of multiple cores of the breast tissue showed lymphocytic inflammatory infiltrates confined to breast lobules. Fungal stains and Ziehl-Neelsen (ZN) stain were negative. A diagnosis of chronic mastitis with the possibility of autoimmune lobular mastitis was suggested. Subsequent image-guided fine needle aspiration smears showed epithelioid granulomas mixed with lymphocytes. Areas of amorphous-to-granular eosinophilic material (caseous necrosis) were seen at places. ZN stain showed acid-fast bacilli. A diagnosis of tuberculous mastitis was given.

Gene Silencing of Toll-like Receptor 2 Gene Expression as a Tactic to Control Mycobacterium Tuberculosis and Granuloma Formation.

Mycobacterium tuberculosis (MT) is the causative agent of tuberculosis (TB) in humans. Tuberculosis is one of the top 10 causes of mortality worldwide, resulting in 1.8 million deaths and 10.4 million new cases in 2016. Understanding the fundamental features of MT biology is critical to the eradication of MT in the future. Due to the increasing frequency of antimicrobial treatment resistance and problems in vaccine development, the pathogenesis of TB for its survival and growth is highly dependent on host lipids and stimulated-lipid droplets formation. Toll-like receptor 2 (TLR2) forms heterophilic dimers with TLR1 and TLR6, therefore, recognizing many MT components. Both of these receptors identify the invading antigen and activate downstream protein kinases. Some studies demonstrated that the cyclooxygenase-2 (COX-2) promoter-driven gene expression includes connecting sites for transcription factors, such as nuclear factor-kappa B, CREB, NFAT, and c/EBPß. The current study aimed to investigate the role of the TLR2 receptor in positively regulating prostaglandin E2 production in M. bovis (BCG) infected macrophages in vivo using a human monocytic cell line THP-1. Our results revealed that MT infection triggers a time-dependent increase in COX-2 expression via pathways involving TLR2 receptor activation and enhances COX-2 expression, leading to an increase in lipid droplet formation and suppression of macrophage activation.

Cytology as a rapid tool in diagnosing tuberculosis of the parotid gland: A case series with a review of the literature.

Tubercular infection of the parotid gland often confuses clinicians, it being a rare entity even in an endemic area. Its similarity in presentation with that of parotid neoplasms, nonspecific symptoms, low incidence and non-contributory radiological findings often leads to its misdiagnosis as parotid neoplasm, which in the due course results in parotidectomy. Therefore, FNAC of parotid swelling is helpful to avoid unnecessary surgery and patient discomfort. We report four cases of FNAC of parotid swelling with suspicion of neoplasm/inflammatory lesion and were diagnosed as tuberculosis of the parotid gland. They were advised antitubercular drugs for 6 months and followed up. These case are reported not just to highlight that parotid is a rare site for tuberculosis, but also to ascertain that FNAC can be an easy and fast diagnostic modality for confirmation of tubercular parotitis rather than going through the long way of resection and confirmation on histopathology.

Diagnostic Challenges of Metacarpal Tuberculosis in Paediatrics: A Case Report.

Metacarpal tuberculosis is rare even in endemic areas. This is a report of a 12-year-old girl with gradual, painless swelling of the dorsal aspect of the right hand over a 2-year period. She developed a discharging sinus over the mass after a traumatic incident. The radiographs showed a well-defined, expansile osteolytic lesion. Blood test, fine needle aspiration biopsy and smears were not diagnostic. A second histologic examination with phenotypic test was required for diagnosis and to begin appropriate chemotherapy. Establishing the diagnosis was not straightforward, even though we suspected tuberculosis. Level of Evidence: Level V (Therapeutic).

Tuberculosis of the middle ear: A systematic review.

OBJECTIVE: Tuberculous otitis media (TOM) is a rare extrapulmonary manifestation of tuberculosis (TB) and remains challenging to diagnose due to non-specific symptoms. This systematic review identifies clinical characteristics, diagnostic evaluation, and outcomes in cases of TOM. METHODS: A comprehensive literature search utilizing the PubMed, CINAHL, Scopus, and Cochrane Library databases was conducted for relevant articles published between 2000 and 2021. Cases involving adult patients with TOM were included. Non-English studies, animal studies, and reviews were excluded. RESULTS: 41 case reports and 7 case series were included, comprising data from 67 patients. The mean age was 40 years (range, 19-87 years) and the majority were female (n = 46, 68.7 %). The mean symptom duration was 12.8 months (range, 0.25-120 months). Common symptoms included otorrhea (n = 60, 89.6 %), HL (n = 58, 86.6 %), otalgia (n = 19, 28.4 %), and FP (n = 18, 26.9 %). Otoscopy revealed tympanic membrane (TM) perforation in 45 patients (67.2 %). Most patients were diagnosed with tissue biopsy (n = 53, 79.1 %). Surgical interventions were performed in 48 patients (71.6 %) and 63 patients (94.0 %) were prescribed anti-TB chemotherapy. Long-term sequelae (e.g., HL, FP, and TM perforation) were noted in 39 patients (58.2 %) at a mean follow-up of 18.8 months (range, 1-120 months). CONCLUSION: TOM should be included in the differential diagnosis of chronic suppurative otitis media. Histopathological examination is a reliable diagnostic method. Early detection and management are recommended for optimizing outcomes. LEVEL OF EVIDENCE: 3b.

Rapid GPR183-mediated recruitment of eosinophils to the lung after Mycobacterium tuberculosis infection.

Influx of eosinophils into the lungs is typically associated with type II responses during allergy and fungal and parasitic infections. However, we previously reported that eosinophils accumulate in lung lesions during type I inflammatory responses to Mycobacterium tuberculosis (Mtb) in humans, macaques, and mice, in which they support host resistance. Here we show eosinophils migrate into the lungs of macaques and mice as early as one week after Mtb exposure. In mice this influx is CCR3 independent and instead requires cell-intrinsic expression of the oxysterol receptor GPR183, which is highly expressed on human and macaque eosinophils. Murine eosinophils interact directly with bacilli-laden alveolar macrophages, which upregulate the oxysterol-synthesizing enzyme Ch25h, and eosinophil recruitment is impaired in Ch25h-deficient mice. Our findings show that eosinophils are among the earliest cells from circulation to sense and respond to Mtb infection of alveolar macrophages and reveal a role for GPR183 in the migration of eosinophils into lung tissue.

Two-stage TKA for tuberculosis septic arthritis of the knee masquerading as pigmented villonodular synovitis: A case report.

A 25-year-old female presented with left knee pain following arthroscopic synovectomy for presumed pigmented villonodular synovitis (PVNS). Radiographs and magnetic resonance imaging demonstrated tricompartmental arthritic changes. She underwent a two-stage procedure first involving antibiotic spacer implantation, followed 1 week later by spacer removal and definitive total knee arthroplasty (TKA) once initial intraoperative culture results were negative. Subsequent cultures confirmed tuberculosis septic arthritis. Repeat evaluation 1 year postoperatively showed no complications and patient satisfaction with left knee function. This is a unique case report in the United States describing 1-year outcomes following staged TKA for tuberculosis septic arthritis masquerading as PVNS.

CD4 T cells are rapidly depleted from tuberculosis granulomas following acute SIV co-infection.

HIV/Mycobacterium tuberculosis (Mtb) co-infected individuals have an increased risk of tuberculosis prior to loss of peripheral CD4 T cells, raising the possibility that HIV co-infection leads to CD4 T cell depletion in lung tissue before it is evident in blood. Here, we use rhesus macaques to study the early effects of simian immunodeficiency virus (SIV) co-infection on pulmonary granulomas. Two weeks after SIV inoculation of Mtb-infected macaques, Mtb-specific CD4 T cells are dramatically depleted from granulomas, before CD4 T cell loss in blood, airways, and lymph nodes, or increases in bacterial loads or radiographic evidence of disease. Spatially, CD4 T cells are preferentially depleted from the granuloma core and cuff relative to B cell-rich regions. Moreover, live imaging of granuloma explants show that intralesional CD4 T cell motility is reduced after SIV co-infection. Thus, granuloma CD4 T cells may be decimated before many co-infected individuals experience the first symptoms of acute HIV infection.

Evaluation of the clinical impact of bone marrow cultures in current medical practice.

The clinical yield and benefit of performing bone marrow cultures for various clinical indications has been challenged and their clinical necessity remains debatable. We sought to assess the clinical yield and benefit of performing routine bone marrow cultures and determine whether various clinical, laboratory, and imaging parameters were predictive of a diagnostic bone marrow culture. This was a single center retrospective analysis of all patients who underwent a bone marrow study comprising bone marrow cultures from January 1, 2012, through March 1, 2018. Baseline clinical data were extracted from the institution's electronic medical records system. The analyzed cohort consisted of 139 patients with a median age of 46 years (range 4 months to 85 years). The most common indication for a bone marrow study was workup of a fever of unknown origin (105 patients, 76%) while investigation for infection in immunocompromised patients accounted for 22 cases (16%) and suspected tuberculosis was the reason for acquisition of bone marrow cultures in 6 patients (4%). Only 3 patients had positive bone marrow cultures, yielding in 2 patients a diagnosis of Mycobacterium avium and in one patient a microbiologically unclassifiable fungal infection. A univariate analysis revealed that mean age, hemoglobin level, platelet count, c-reactive protein levels, gender, indication for bone marrow study, yield of blood cultures, and contribution of imaging studies and bone marrow pathology results were not significantly different between patients with diagnostic and non-diagnostic bone marrow cultures. Mean white blood cell count was found to be significantly lower in patients with diagnostic bone marrow cultures (2.4 × 103/µL versus 8.7 × 103/µL; P = 0.038). We conclude that for most patients, performance of bone marrow cultures holds limited clinical value.

Tumor necrosis factor induces pathogenic mitochondrial ROS in tuberculosis through reverse electron transport.

Tumor necrosis factor (TNF) is a critical host resistance factor against tuberculosis. However, excess TNF produces susceptibility by increasing mitochondrial reactive oxygen species (mROS), which initiate a signaling cascade to cause pathogenic necrosis of mycobacterium-infected macrophages. In zebrafish, we identified the mechanism of TNF-induced mROS in tuberculosis. Excess TNF in mycobacterium-infected macrophages elevates mROS production by reverse electron transport (RET) through complex I. TNF-activated cellular glutamine uptake leads to an increased concentration of succinate, a Krebs cycle intermediate. Oxidation of this elevated succinate by complex II drives RET, thereby generating the mROS superoxide at complex I. The complex I inhibitor metformin, a widely used antidiabetic drug, prevents TNF-induced mROS and necrosis of Mycobacterium tuberculosis-infected zebrafish and human macrophages; metformin may therefore be useful in tuberculosis therapy.

Clival Tuberculosis: A Case Report.

A 39-year-old female presented with complaints of occipital headaches, diplopia, numbness over left half of face and deviation of face to the right. On examination she had hypoesthesia over left half of face, associated with bilateral abductor and left facial palsy. Neuroradiology showed a well-defined lytic lesion involving the clivus and adjacent sphenoid sinus and sella. The patient underwent an endoscopic transnasal decompression of the clival lesion. Intraoperative squash preparation was reported to show tuberculous granulation, which was confirmed on postoperative histology. The patient was advised anti-tubercular therapy. At 12 months follow up neuroradiology showed a near total resolution of the clival lesion. The patient had completely recovered from her cranial nerve deficits. Tuberculous involvement of spheno-clival region is rare and the authors' literature search has yielded only three previous similar case reports. A surgical decompression followed by anti-tubercular therapy is the recommended approach for management of clival tuberculosis. The relevant literature on the subject is presented.

Significance of lymph node fine needle aspiration for the diagnosis of HIV-associated lymphoma in a low-resource setting.

OBJECTIVE: Fine needle aspiration (FNA) is an early step in the work-up of lymphadenopathy in people with HIV (PWH). We set out to characterize the FNA cytology in PWH and report on the time to lymphoma diagnosis through the FNA clinics in the public healthcare system in Johannesburg, South Africa. DESIGN: Retrospective review of laboratory database. METHODS: A retrospective chart review of patients undergoing FNA through the department of cytopathology at the National Health Laboratory Service (NHLS) was undertaken. Results of FNAs performed between March and May 2018 were reviewed. Medical record chart abstraction included general demographics, HIV status, site and results of FNA, prior history of malignancy and other laboratory data. RESULTS: Five hundred and thirty-nine lymph node FNAs were performed on PWH. Pathological findings included tuberculosis 47% (252), inadequate sampling 14% (75), reactive adenopathy 13% (71), benign disease 12% (63), suspicious for lymphoproliferative neoplasm 8% (45), other malignancy 4% (21) and inflammation 2% ( n  = 12). Only 53% (24) of lymphomas were confirmed by biopsy. Those not confirmed had a high mortality (57%) and loss to follow-up rate (29%) over the following year. The median diagnostic interval exceeded 8 weeks from time of FNA to lymphoma diagnosis. CONCLUSION: FNA is an important screening modality in this high HIV and tuberculosis (TB) burden region. Patients with cytology suggestive for lymphoma, but without biopsy confirmation, have a high mortality rate suggesting undiagnosed lymphoma. A better understanding of the barriers to appropriate diagnostic triage for lymphoma is needed.

Clinical profile, diagnosis, treatment, and outcome of patients with tubercular versus nontubercular causes of spine involvement: A retrospective cohort study from India.

Background: In tuberculosis (TB) endemic areas, other pyogenic causes of spine involvement may be missed. The study aimed to describe TB and non-TB causes of spine involvement and identify features that can help in differentiating them. Methods: A retrospective cohort study was conducted to screen the clinical records of all admitted patients (Kasturba Hospital, Manipal) in 2018-20 for a diagnosis of spondylitis and/or sacroiliitis. The clinical features, radiological findings, laboratory parameters, treatment details, and outcomes were compared among those diagnosed with confirmed TB, confirmed brucellosis, or confirmed pyogenic infection. A scoring system was also developed to differentiate spondylodiscitis due to tuberculous and pyogenic causes. The qualitative variables were compared using the Chi-square test, while quantitative variables were compared using the one-way analysis of variance test. Results: Of 120 patients with spine infections, a total of 85 patients were confirmed with the microbiological diagnosis of interest. Involvement of the thoracic spine, longer duration of illness, and caseous granulomatous reaction on histopathology was more common in TB patients. Male gender, involvement of lumbar vertebra, and neutrophilic infiltrate on histopathology were more common in brucellosis patients. Male gender, diabetes mellitus, involvement of lumbar vertebra, neutrophilic infiltrate on histopathology, leukocytosis, and increased C-reactive protein were more commonly seen in patients with pyogenic infection. The scoring system had a sensitivity and specificity of 75% and 91%, respectively, when used to differentiate TB from pyogenic infection. Conclusions: In resource-limited settings, suggestive findings can be used to decide empiric therapy.

Primary tuberculous granuloma in the falciform ligament of liver.

Isolated tuberculous granuloma in the falciform ligament of the liver has never been reported. Here, we report a case of tuberculous granuloma in the falciform ligament of the liver of a 45-year-old woman who complained only of persistent right upper abdominal pain. On abdominal contrast-enhanced CT and MRI, it is difficult to distinguish benign from malignant masses. Imaging on 18 F-FDG PET/CT showed high uptake of 18 F-FDG in the lesion, which was thus considered more likely to be malignant. However, postoperative pathological examination showed granulomatous inflammation with caseous necrosis, which was diagnosed as tuberculosis.

Primary mesenteric gastrointestinal stromal tumour with concomitant mesenteric tuberculosis: Careful histopathology is essential.

Gastro-inestinal stromal tumours (GISTs) comprise 1-2% of all gastrointestinal (GI) tumours. The mesentery, retroperitoneum and omentum are common sites of extra-gastrointestinal stromal tumours (E-GISTs). Isolated involvement of the mesentery by tuberculosis (TB) without any evidence of pulmonary disease is quite unusual. Here we report a case of an E-GIST arising from the small bowel mesentery in a 60-year old female where an incidental concurrent mesenteric tuberculosis was diagnosed following surgical resection.

Utility of Esophageal Ultrasound-guided Biopsy of Mediastinal Lymph Nodes in Diagnosis of Childhood Tuberculosis.

A 6-year-old boy with autistic spectrum disorder was diagnosed with tuberculosis infection following contact tracing of his mother who had isoniazid-resistant pulmonary tuberculosis. He progressed to develop mediastinal lymphadenopathy causing a persistent cough. He was too small to undergo endobronchial ultrasound-guided biopsy. As an alternative, he underwent esophageal endoscopic ultrasound-guided biopsy, leading to confirmation of the diagnosis. We believe this approach to diagnostic biopsy is underrecognized in pediatric practice, and highlight its utility with this case and a brief literature review.

Prevalence and associated risk factors for tuberculosis among people living with HIV in Nepal.

BACKGROUND: Worldwide tuberculosis (TB) takes more lives than any other infectious diseases. WHO estimates around 68,000 incident TB cases in Nepal. However, in 2018 only around 27,232 new TB cases were reported in the national system, resulting around 40,768 incident TB cases missing every year in Nepal. National Tuberculosis Control Center carried out this study in anti-retroviral therapy (ART) sites to estimate the prevalence of TB and identify the associated risk factors for TB among the people living with Human Immunodeficiency Virus (PLHIVs) in Nepal. METHODS: It was a cross-sectional institution-based study conducted between March and August 2018. Six ART sites with high caseloads of PLHIVs were selected. PLHIVs who were equal or above 18 years of age and were in ART program at the selected study sites were considered eligible for the study. Diagnosis of tuberculosis among PLHIVs who agreed to participate in the study was carried out as per the National Tuberculosis Management Guideline of National Tuberculosis Program of Nepal. RESULTS: Among 403 PLHIVs, tuberculosis was diagnosed in 40 (9.9%) individuals. Median age of the participants was 36 (30-43) years. Prevalence of TB was significantly higher among male PLHIVs than female PLHIVs (13.6% Vs 5.8%; P = 0.02) and Dalit ethnic group compared to Brahmin/Chettri (22.0%Vs5.9%, P = 0.01). The risk of developing TB was found significant among those with HIV stage progressed to WHO stage 3 and 4 (OR = 4.85, P<0.001) and with the family history of TB (OR = 4.50, P = 0.002). CONCLUSIONS: Prevalence of TB among PLHIVs in Nepal was found 9.9%. Risk of developing TB was higher among PLHIVs who were male, Dalit, with HIV stage progressed to WHO stage 3 and 4 and with family history of TB. Hence, targeted interventions are needed to prevent the risk of developing TB among PLHIVs. Similarly, integrated, and comprehensive TB and HIV diagnosis and treatment services are needed for the management of TB/HIV co-infection in Nepal.