Transmissibility of Mycobacterium pinnipedii in a murine model.

The causative agent of tuberculosis in pinnipeds is Mycobacterium pinnipedii, a member of the Mycobacterium tuberculosis complex (MTC). The natural hosts are pinnipeds; however, other non-marine mammals, including humans, can also be infected. The transmissibility of a pathogen is related to its virulence. The transmissibility of a M. pinnipedii strain (i.e., 1856) was investigated in a murine model and compared with that of two Mycobacterium bovis strains (i.e., 534 and 04-303) with different reported virulence. Non-inoculated mice (sentinels) were co-housed with intratracheally inoculated mice. Detailed inspection of mice to search for visible tuberculosis lesions in the lungs and spleen was performed, and bacillus viability at 30, 60, and 90 days post-inoculation (dpi) was assayed. A transmissibility of 100% was recorded at 30 dpi in sentinel mice co-housed with the inoculated mice from the M. pinnipedii and M. bovis 04-303 groups, as evidenced by the recovery of viable M. pinnipedii and M. bovis from the lungs of sentinel mice. Mice inoculated with M. pinnipedii (1856) and M. bovis (534) survived until euthanized, whereas five of the M. bovis 04-303-inoculated mice died at 17 dpi. This study constitutes the first report of the transmissibility of a M. pinnipedii strain in mice and confirms the utility of this experimental model to study virulence features such as the transmission of poorly characterized MTC species.

The challenges in diagnosing isolated epididymal tuberculosis (TB) in an adolescent male: a case report.

BACKGROUND: Genitourinary tuberculosis (GUTB) is a common form of extrapulmonary TB (EPTB) in children. An example of GUTB is epididymal TB, which usually presents unspecific chronic clinical manifestations. Definitive diagnosis can be conducted based on bacteriologic confirmation and histopathologic results, but this is challenging due to the paucibacillary nature of EPTB. Therefore, we reported the challenges in diagnosing isolated epididymal TB in an adolescent male. CASE PRESENTATION: A 16-year-old male presented to respirology clinic with painful swelling of the left scrotum for 3 months before visiting to the hospital. The symptoms were associated with persistent coughing for 2 months, and physical examination of the left scrotum showed swelling accompanied by cardinal signs. A palpable hard mass was found on the left scrotum, with firm borders, measuring 7 × 4 cm. Laboratory examination and tumor markers were within normal limits, although leukocyturia was found, and the urine culture was negative. Genital ultrasound (US) showed epididymitis sinistra with septal hydrocele, while magnetic resonance imaging (MRI) indicated inhomogeneous left epididymitis with bilateral inguinal lymph node enlargement. Although TB evaluation presented a negative purified protein derivative (PPD) test and bacteriologic examination, chest X-ray (CXR) showed perihilar lymphadenopathy. Based on the clinical and radiologic results suggesting TB, the patient was diagnosed with isolated epididymal TB and received quadruple antituberculosis therapy (ATT) for 6 months. After treatment, the left testicle size started to shrink and was equal to the right testicle, also, there were no signs of inflammation, the body weight increased by 5 kg, and cough disappeared. Sperm analysis at the end of treatment indicated teratozoospermia, which was subsequently treated by the urologic surgery department. CONCLUSIONS: Biopsy and bacteriologic confirmation for TB epididymitis were challenging to perform in the clinical setting. Epididymal TB should be considered in adolescent males with complaints of chronic scrotal swelling and pain. Clinical judgment based on history taking, physical examination, and radiologic features supporting TB features could be helpful in accurate and fast diagnosis for favorable outcome.

Mycobacterium tuberculosis SecA2-dependent activation of host Rig-I/MAVs signaling is not conserved in Mycobacterium marinum.

Retinoic acid inducible gene I (Rig-I) is a cytosolic pattern recognition receptor canonically described for its important role in sensing viral RNAs. Increasingly, bacterially-derived RNA from intracellular bacteria such as Mycobacterium tuberculosis, have been shown to activate the same host Rig-I/Mitochondrial antiviral sensing protein (MAVS) signaling pathway to drive a type-I interferon response that contributes to bacterial pathogenesis in vivo. In M. tuberculosis, this response is mediated by the protein secretion system SecA2, but little is known about whether this process is conserved in other pathogenic mycobacteria or the mechanism by which these nucleic acids gain access to the host cytoplasm. Because the M. tuberculosis and M. marinum SecA2 protein secretion systems share a high degree of genetic and functional conservation, we hypothesized that Rig-I/MAVS activation and subsequent induction of IFN-ß secretion by host macrophages will also be conserved between these two mycobacterial species. To test this, we generated a ΔsecA2 M. marinum strain along with complementation strains expressing either the M. marinum or M. tuberculosis secA2 genes. Our results suggest that the ΔsecA2 strain has a growth defect in vitro but not in host macrophages. These intracellular growth curves also suggested that the calculation applied to estimate the number of bacteria added to macrophage monolayers in infection assays underestimates bacterial inputs for the ΔsecA2 strain. Therefore, to better examine secreted IFN-ß levels when bacterial infection levels are equal across strains we plated bacterial CFUs at 2hpi alongside our ELISA based infections. This enabled us to normalize secreted levels of IFN-ß to a standard number of bacteria. Applying this approach to both WT and MAVS-/- bone marrow derived macrophages we observed equal or higher levels of secreted IFN-ß from macrophages infected with the ΔsecA2 M. marinum strain as compared to WT. Together our findings suggest that activation of host Rig-I/MAVS cytosolic sensors and subsequent induction of IFN-ß response in a SecA2-dependent manner is not conserved in M. marinum under the conditions tested.

Mathematical model of oxygen, nutrient, and drug transport in tuberculosis granulomas.

Physiological abnormalities in pulmonary granulomas-pathological hallmarks of tuberculosis (TB)-compromise the transport of oxygen, nutrients, and drugs. In prior studies, we demonstrated mathematically and experimentally that hypoxia and necrosis emerge in the granuloma microenvironment (GME) as a direct result of limited oxygen availability. Building on our initial model of avascular oxygen diffusion, here we explore additional aspects of oxygen transport, including the roles of granuloma vasculature, transcapillary transport, plasma dilution, and interstitial convection, followed by cellular metabolism. Approximate analytical solutions are provided for oxygen and glucose concentration, interstitial fluid velocity, interstitial fluid pressure, and the thickness of the convective zone. These predictions are in agreement with prior experimental results from rabbit TB granulomas and from rat carcinoma models, which share similar transport limitations. Additional drug delivery predictions for anti-TB-agents (rifampicin and clofazimine) strikingly match recent spatially-resolved experimental results from a mouse model of TB. Finally, an approach to improve molecular transport in granulomas by modulating interstitial hydraulic conductivity is tested in silico.

The etiological spectrum of multiple ring-enhancing lesions of the brain: a systematic review of published cases and case series.

OBJECTIVE: Multiple ring-enhancing lesions of the brain are enigmatic neuroimaging abnormality. In this systematic review, we evaluated the etiological spectrum of these lesions. METHODS: This systematic review adhered to the PRISMA guidelines. We searched PubMed, Embase, Scopus, and Google Scholar up until 15 June 2023. We included case reports and case series. Quality evaluation of each case was based on selection, ascertainment, causality, and reporting. The extracted information included demographic characteristics, clinical features, type and number of multiple enhancing brain lesions, diagnostic procedures, final diagnoses, treatments, and patient outcomes. PROTOCOL REGISTRATION: PROSPERO CRD42023437081. RESULTS: We analyzed 156 records representing 161 patients, 60 of whom were immunocompromised. The mean age was 42.6 years, and 67% of patients experienced symptoms for up to 1 month. A higher proportion of immunocompromised patients (42% vs. 30%) exhibited encephalopathy. Chest or CT thorax abnormalities were reported in 27.3% of patients, while CSF abnormalities were found in 31.7%, more frequently among the immunocompromised. Definitive diagnoses were established via brain biopsy, aspiration, or autopsy in 60% of cases, and through CSF examination or other ancillary tests in 40% of cases. Immunocompromised patients had a higher incidence of Toxoplasma gondii infection and CNS lymphoma, while immunocompetent patients had a higher incidence of Mycobacterium tuberculosis infection and immune-mediated and demyelinating disorders. The improvement rate was 74% in immunocompetent patients compared to 52% in the immunocompromised group. CONCLUSION: Multiple ring-enhancing lesions of the brain in immunocompromised patients are more frequently caused by Toxoplasma gondii infections and CNS lymphoma. Conversely, among immunocompetent patients, Mycobacterium tuberculosis infection and immune-related demyelinating conditions are common.

T cell-specific P2RX7 favors lung parenchymal CD4+ T cell accumulation in response to severe lung infections.

CD4+ T cells are key components of the immune response during lung infections and can mediate protection against tuberculosis (TB) or influenza. However, CD4+ T cells can also promote lung pathology during these infections, making it unclear how these cells control such discrepant effects. Using mouse models of hypervirulent TB and influenza, we observe that exaggerated accumulation of parenchymal CD4+ T cells promotes lung damage. Low numbers of lung CD4+ T cells, in contrast, are sufficient to protect against hypervirulent TB. In both situations, lung CD4+ T cell accumulation is mediated by CD4+ T cell-specific expression of the extracellular ATP (eATP) receptor P2RX7. P2RX7 upregulation in lung CD4+ T cells promotes expression of the chemokine receptor CXCR3, favoring parenchymal CD4+ T cell accumulation. Our findings suggest that direct sensing of lung eATP by CD4+ T cells is critical to induce tissue CD4+ T cell accumulation and pathology during lung infections.

Rare primary pulmonary mucosa-associated lymphoid tissue lymphoma misdiagnosed with tuberculosis: A case report.

RATIONALE: Primary pulmonary mucosa-associated lymphoid tissue lymphoma (MALToma) is a rare subtype of non-Hodgkin lymphoma with a relatively low incidence rate clinically. Atypical clinical symptoms and nonspecific chest computed tomography features of the disease make it difficult to determine and treatment is delayed. We discuss the diagnosis and treatment of a patient with primary pulmonary MALToma to raise clinicians' awareness of this condition. PATIENT CONCERNS: A 66-year-old male patient with a medical history of tuberculosis has been experiencing progressive exacerbation of respiratory symptoms and nonresponsive treatment without an unclear diagnosis for 5 years. He was transferred to our hospital because a nonspecific soft tissue mass in the right upper lobe of the lung was found on his chest computed tomography. Laboratory results with serum immunofixation electrophoresis showed polyclonal immunoglobulin (Ig) G, IgM, IgA, and λ-light chain on admission. DIAGNOSIS: Pathological examination and immunohistochemical staining of lung biopsy revealed a definitive diagnosis of pulmonary MALToma with stage IV. INTERVENTIONS AND OUTCOMES: The patient received immunotherapy with anti-CD20 monoclonal antibody (rituximab), and showed significant clinical improvement at the 6-month follow-up. CONCLUSIONS AND LESSONS: Diagnosis of primary pulmonary MALToma mainly relies on histopathological examination, and comprehensive laboratory examinations are also necessary. Clinicians should combine laboratory tests (such as immunofixation electrophoresis in our case) to assist in medical diagnosis in cases of atypical clinical manifestations and imaging characteristics. Immunotherapy appears to be the main treatment protocol for advanced patients.

Pulmonary sclerosing pneumocytoma - approaching a solitary pulmonary nodule and the limitations of risk prediction models.

Our case is an asymptomatic, non-smoking, East Asian woman in her 40s presenting with a solitary pulmonary nodule (SPN). On imaging, the 1.7 cm solid SPN located in the left upper lobe, was rounded in morphology and moderately fluorodeoxyglucose avid. The clinical pretest probability of malignancy assessed by risk prediction models such as Brock (19.1%), Mayo Clinic (56.2%) and Herder (51.4%) was discordant. She underwent a percutaneous CT-guided needle biopsy, establishing a diagnosis of pulmonary sclerosing pneumocytoma (PSP). PSP is a rare benign lung neoplasm with indolent growth characteristics that has been described predominantly in non-smoking women. Our case illustrates the limitations of applying existing risk prediction models in Asia where the epidemiology and biology of lung cancer differ significantly from the Caucasian derivation cohorts. Additionally, the risk models do not account for tuberculosis, which is endemic in Asia and can mimic malignancy. Non-surgical lung biopsy remains useful in minimising unnecessary thoracotomy.

Pathomorphological characteristics of tuberculous placenta and its clinical implication.

BACKGROUND: The study of pathologic diagnosis of placental TB is rare. The aim of this study is analyzing the pathomorphological characteristics of tuberculosis (TB) placenta during pregnancy and its clinical significance. METHODS: Nineteen cases of placental tissue specimens during pregnancy were collected from June 2015 to February 2022 at Shanghai Public Health Clinical Center, the only inpatient center for pregnant women with TB in Shanghai, China. Hematoxylin-eosin staining, acid-fast staining, and molecular testing were applied to analyze them comprehensively in combination with clinical information. RESULTS: Among the 19 cases, 7 cases caused intrauterine stillbirth, 3 cases received artificial abortion required by the pregnant woman, the other 9 cases received standard delivery and the infants survived, however, 3 of them were low-weight preterm infants, and another 1 case suffered mild intrauterine asphyxia. The 9 surviving infants were followed-up, of which 3 cases got congenital TB. For pathological characteristics of placental tissues under light microscopy, there were 3 cases of epithelioid granuloma formation, 13 cases of acute fetal membranitis, 4 cases of caseous necrosis, 7 cases of inflammatory necrosis, 10 cases of coagulative necrosis, and 6 cases with small focal calcifications. All placental tissues were positive for acid-fast staining and polymerase chain reaction (PCR). Molecular pathological diagnosis showed that 18 cases were positive for Mycobacterium tuberculosis, with 1 case not having received examination. CONCLUSIONS: Combining acid-fast staining and molecular pathological testing is helpful for accurately diagnosing placental TB.

[Breast tuberculosis. Report of two cases]. / Tuberculosis mamaria. Reporte de dos casos.

Two cases of mammary tuberculosis (TB) are presented, one of them with additional pleural and lymph node involvement. Both were HIV-negative, with no history of previous TB, with long-standing breast lesions. Both presented a successful outcome with antituberculosis treatment. Breast TB is a very rare pathology that is difficult to diagnose. The cases are presented to consider their differential diagnosis in patients with chronic mastitis and/or nodular or ulcerated lesions of the breast. Multidisciplinary management is recommended.

Se presentan los casos de dos pacientes con tuberculosis (TB) mamaria, una de ellas también con compromiso pleural y ganglionar. Ambas HIV negativas, sin antecedentes de TB previa, con lesiones mamarias de largo tiempo de evolución. Las dos presentaron buena evolución con tratamiento antifímico. La TB mamaria es una afección muy poco frecuente de difícil diagnóstico. Se presentan los casos con el fin de plantear su diagnóstico diferencial en pacientes con mastitis crónicas y/o lesiones nodulares o ulceradas de la mama. Se recomienda el manejo multidisciplinario.

Mechanopathology of biofilm-like Mycobacterium tuberculosis cords.

Mycobacterium tuberculosis (Mtb) cultured axenically without detergent forms biofilm-like cords, a clinical identifier of virulence. In lung-on-chip (LoC) and mouse models, cords in alveolar cells contribute to suppression of innate immune signaling via nuclear compression. Thereafter, extracellular cords cause contact-dependent phagocyte death but grow intercellularly between epithelial cells. The absence of these mechanopathological mechanisms explains the greater proportion of alveolar lesions with increased immune infiltration and dissemination defects in cording-deficient Mtb infections. Compression of Mtb lipid monolayers induces a phase transition that enables mechanical energy storage. Agent-based simulations demonstrate that the increased energy storage capacity is sufficient for the formation of cords that maintain structural integrity despite mechanical perturbation. Bacteria in cords remain translationally active despite antibiotic exposure and regrow rapidly upon cessation of treatment. This study provides a conceptual framework for the biophysics and function in tuberculosis infection and therapy of cord architectures independent of mechanisms ascribed to single bacteria.

Monitoring the immune response of macrophages in tuberculous granuloma through the expression of CD68, iNOS and HLA-DR in naturally infected beef cattle.

Bovine tuberculosis still represents a universal threat that creates a wider range of public and animal health impacts. One of the most important steps in the pathogenesis of this disease and granuloma formation is the phagocytosis of tuberculous bacilli by macrophages. Mycobacteria replicate in macrophages, which are crucial to the pathophysiology of mycobacterial infections; however, scarce information is available about the dynamics of the granuloma-stage immunological response. Therefore, immunohistochemistry was used in this work to evaluate the expression of CD68, iNOS, and HLA-DR in different stages of TB granulomas from naturally infected cattle with tuberculosis. Two thousand, one hundred and fifty slaughtered beef cattle were examined during the period from September 2020 to March 2022. Sixty of them showed gross tuberculous pulmonary lesions and samples were collected from all of them for histopathological examination, Ziehl-Neelsen (ZN) staining, and bacteriological culturing. Selected samples that yielded a positive result for ZN and mycobacterial culturing were subjected to an immunohistochemical study of CD68, iNOS, and HLA-DR expression by macrophages according to granuloma stages. Immunohistochemical analysis revealed that the immunolabeling of CD68+, iNOS+, and HLA-DR+ macrophages significantly reduced as the stage of granuloma increased from stage I to stage IV (P < 0.003, P < 0.002, and P < 0.002, respectively). The distribution of immunolabeled macrophages was similar for the three markers, with immunolabeled macrophages distributed throughout early-stage granulomas (I, II), and surrounding the necrotic core in late-stage granulomas (III, IV). Our results suggest a polarization to the pro-inflammatory environment and increased expression of CD68+, iNOS+, and HLA-DR+ macrophages in the early stages of granulomas (I, II), which may play a protective role in the immune response of naturally infected beef cattle with tuberculosis.

A Retrospective Analysis of the Clinicopathological Features of Patients with Tuberculous Mastitis: A Single Institution's Experience.

INTRODUCTION: Tuberculosis remains a global health burden, especially in low- and middle-income countries. Breast tuberculosis is a rare disease with minimal research available. This disease produces a diagnostic challenge as the clinical presentation is variable, and diagnosis often requires additional investigations. This study was undertaken to determine the efficacy of cytology and histology, together with ancillary studies, in diagnosing tuberculous mastitis. METHODS: This retrospective study was conducted in a Johannesburg Hospital over 5 years. Thirty-two patients with confirmed tuberculous mastitis were included. The patients were considered positive for tuberculous mastitis if histological or cytological findings were confirmed with either a positive tuberculosis culture, Ziehl-Neelsen stain, or polymerase chain reaction examination/GeneXpert. RESULTS: This case series comprises 3 males and 29 females with a mean age of 35.66. A breast mass was the most common presentation. Over these 5 years, more biopsies were performed on inflammatory breast lesions than fine needle aspirations. There was a higher confirmation rate for cytology diagnoses compared to histology diagnoses. CONCLUSION: This study supports using fine needle aspiration combined with GeneXpert as the primary diagnostic modality in diagnosing tuberculous mastitis. This test combination is advantageous in resource- and financially constrained environments as it is relatively simple to perform, cost-effective, and has a rapid turnaround time.

Isolated tubercular dacryoadenitis in a non-immunocompromised healthy adult.

A middle-aged woman presented with a slowly enlarging mass in the right superotemporal orbit and ptosis. The patient had an elevated erythrocyte sedimentation rate, and incisional biopsy showed granulomatous inflammation with Langhan's giant cells suggestive of a tubercular etiology. Tuberculin skin test was negative. The patient responded well to anti-tuberculous therapy. Tubercular dacryoadenitis is a rare presentation of a lacrimal gland mass.

Pancreatic tuberculosis mimicking as pancreatic malignancy: Surgeon's dilemma.

Pancreatic tuberculosis is a rare form of Tuberculosis (TB) which requires a high index of suspicion to diagnose. Here, we report a case of middle-aged gentleman presenting with abdominal pain and constitutional symptoms who was diagnosed with pancreatic tuberculosis on imaging, which was confirmed by Fine Needle Aspiration (FNA) from the lesion. The patient was given Anti-Tubercular Treatment (ATT) as per conventional protocol. Follow-up showed recovery from the entity. A review of patient presentation, patho-physiology, diagnosis, and management of pancreatic tuberculosis is mentioned in this article.

Isolated pancreatic tuberculosis masquerading pancreatic malignancy.

Pancreatic tuberculosis is the rarest form of abdominal and extrapulmonary tuberculosis. We present a patient in his 40s who presented with pain abdomen and a fever. On examination, the patient had mild jaundice and right hypochondriac tenderness. Blood investigation was suggestive of obstructive jaundice. Imaging studies were representative of pancreatic head lesion, causing mild intrahepatic biliary radical dilatation. Endoscopic ultrasound-guided fine-needle aspiration done from the pancreatic head lesion was diagnostic of tuberculosis. The patient was started on antitubercular medications and responded well.

[Risk factors for pulmonary atelectasis in adults with tracheobronchial tuberculosis].

Objective: To investigate the risk factors for pulmonary atelectasis in adults with tracheobronchial tuberculosis(TBTB). Methods: Clinical data of adult patients (≥18 years old) with TBTB from February 2018 to December 2021 in Public Health Clinical Center of Chengdu were retrospectively analyzed. A total of 258 patients were included, with a male to female ratio of 1∶1.43. The median age was 31(24, 48) years. Clinical data including clinical characteristics, previous misdiagnoses/missed diagnoses before admission, pulmonary atelectasis, the time from symptom onset to atelectasis and bronchoscopy, bronchoscopy and interventional treatment were collected according to the inclusion and exclusion criteria. Patients were divided into two groups according to whether they had pulmonary atelectasis. Differences between the two groups were compared. Binary logistic regression was used to analyze the risk factors for pulmonary atelectasis. Results: The prevalence of pulmonary atelectasis was 14.7%, which was most common in the left upper lobe (26.3%). The median time from symptom onset to atelectasis was 130.50(29.75,358.50)d, and the median time from atelectasis to bronchoscopy was 5(3,7)d. The median age, the proportion of misdiagnosis of TBTB before admission, and the time from symptom onset to bronchoscopy in the atelectasis group were higher than those without atelectasis, and the proportion of receiving bronchoscopy examination and interventional therapy previously, and the proportion of pulmonary cavities were lower than those without atelectasis (all P<0.05). The proportions of cicatrices stricture type and lumen occlusion type in the atelectasis group were higher than those without atelectasis, while the proportions of inflammatory infiltration type and ulceration necrosis type were lower than those without atelectasis (all P<0.05). Older age (OR=1.036, 95%CI: 1.012-1.061), previous misdiagnosis(OR=2.759, 95%CI: 1.100-6.922), longer time from symptom onset to bronchoscopy examination (OR=1.002, 95%CI: 1.000-1.005) and cicatrices stricture type (OR=2.989, 95%CI: 1.279-6.985) were independent risk factors for pulmonary atelectasis in adults with TBTB (all P<0.05). Of the patients with atelectasis who underwent bronchoscopy interventional therapy, 86.7% had lung reexpansion or partial reexpansion. Conclusions: The prevalence of pulmonary atelectasis is 14.7% in adult patients with TBTB. The most common site of atelectasis is left upper lobe. The TBTB type of lumen occlusion is complicated by pulmonary atelectasis in 100% of cases. Being older, misdiagnosed as other diseases, longer time from onset of symptoms to bronchoscopy examination, and being the cicatrices stricture type are factors for developing pulmonary atelectasis. Early diagnosis and treatment are needed to reduce the incidence of pulmonary atelectasis and increase the rate of pulmonary reexpansion.

[Primary tuberculosis of the cavum: An unusual diagnosis]. / Tuberculose primitive du cavum : un diagnostic peu commun.

Primary tuberculosis of the cavum is a rare entity. It can occur at any age, especially between the second and ninth decade. We report the case of a 17-years-old patient with nasal obstruction and left laterocervical adenomegaly. A cervico-facial CT scan showed a suspicious looking tumor process of the nasopharynx. Histological analysis of the biopsies taken showed chronic granulomatous inflammation with necrosis and the absence of tuberculosis lesions in the usual sites, especially the lungs, led to the diagnosis of primary tuberculosis of the cavum. There was a good evolution on antituberculosis drugs. This unusual location can be a source of difficulties and delay in diagnosis, especially because of the clinical presentation, which suggests a nasopharyngeal tumour. In developing countries, where this disease remains relatively endemic, cross-sectional imaging techniques and histopathological analysis are of great interest for the management of patients.