Extrapulmonary Sites Research Articles

Mycobacterial Adhesion: From Hydrophobic to Receptor-Ligand Interactions.

Adhesion is crucial for the infective lifestyles of bacterial pathogens. Adhesion to non-living surfaces, other microbial cells, and components of the biofilm extracellular matrix are crucial for biofilm formation and integrity, plus adherence to host factors constitutes a first step leading to an infection. Adhesion is, therefore, at the core of pathogens’ ability to contaminate, transmit, establish residency within a host, and cause an infection. Several mycobacterial species cause diseases in humans and animals with diverse clinical manifestations. Mycobacterium tuberculosis, which enters through the respiratory tract, first adheres to alveolar macrophages and epithelial cells leading up to transmigration across the alveolar epithelium and containment within granulomas. Later, when dissemination occurs, the bacilli need to adhere to extracellular matrix components to infect extrapulmonary sites. Mycobacteria causing zoonotic infections and emerging nontuberculous mycobacterial pathogens follow divergent routes of infection that probably require adapted adhesion mechanisms. New evidence also points to the occurrence of mycobacterial biofilms during infection, emphasizing a need to better understand the adhesive factors required for their formation. Herein, we review the literature on tuberculous and nontuberculous mycobacterial adhesion to living and non-living surfaces, to themselves, to host cells, and to components of the extracellular matrix.

Abstract P3-19-20: Are traditional indications for radiation therapy appropriate for small cell carcinoma of the breast: An NCDB outcomes analysis and treatment utilization report

Abstract Background: Small-cell carcinomas (SCC) are poorly differentiated neuroendocrine tumors arising primarily in the lung. Extra-pulmonary SCC composes roughly 6% of all SCCs, with SCC arising in the breast (SCCB) accounting for roughly 4% of all extra-pulmonary sites. Due to its rarity, current practice is guided by traditional breast cancer studies and small-cell lung cancer experience. Prior database analyses of extra-pulmonary SCC’s have revealed mixed results regarding the effect of radiation therapy. The remaining literature regarding the treatment of SCCB is limited to case reports and small case series with no agreed upon “standard” radiation dose or regimen. Method: Using the NCDB, a retrospective observational cohort study was performed investigating survival outcomes and prognostic indicators for SCCB patients. Using cases from 2004-2017, females with primary SCCB and only one lifetime malignancy were included. Patients with in-situ or metastatic disease were excluded. Kaplan Meier method, log-rank test, and Cox proportional hazards regression were performed to determine characteristics associated with OS. Results: A total of 153 patients met criteria for descriptive analysis, with 142 patients having all outcomes information for survival analysis. Median age at diagnosis was 59 years. The majority of patients were white (79%), followed by Black (16%), with other reported races accounting for <1% each. The cohort was composed of 19% stage I, 57.5% stage II, and 23.5% stage III patients. Triple negative (ER, PR, and HER2 negative) malignancies composed the largest group (37%), followed by ER or PR positive, HER2 negative cancers (28%), with ER or PR positive, HER2 positive group making up only 2%, and 33% having an unreported molecular subtype. Regarding surgical intervention, 42% received breast conserving surgery, 42% received mastectomy, and 16% had no surgery. Chemotherapy was administered to 82% of patients. Radiation therapy was administered to 65% of the cohort with a median dose of 6000cGy and a median of 33 fractions. Hormone therapy was administered to 19%. With median follow-up of 32 months, median survival was not met for stage I (75th percentile was 101 months) and was 57 months (95% CI 23-91) and 17 months (95% CI 6-28) for stage II and III respectively. On multivariate analysis (MVA), Age greater than 60 years old had a hazard ratio (HR) of 1.97 (95% CI 1.2-3.4, p = 0.01). When compared to stage I, stage II had a HR of 5.4 (95% CI 1.6-18.3, p = 0.007) and stage III a HR 5.8 (95% CI 1.6-21.3, p = 0.008). Receipt of hormone therapy had a HR of 0.32 (95% CI 0.15-0.72, p = 0.006). When compared to no surgery, breast conserving surgery (BCS) had a HR of 0.17 (95% CI 0.08-0.39 p = 0.0001) and mastectomy had a HR of 0.43 (95% CI 0.23-0.81 p = 0.009). Neither receipt of radiation or chemotherapy reached statistical significance. However, when looking at patients with traditional indications for radiation therapy, i.e., BCS or mastectomy with positive lymph nodes on pathology, the receipt of radiation was associated with better overall survival (median OS was 16.7 months (95% CI 0-36) without radiation versus 114 months (95% CI 93-137) with a p-value of 0.003). Conclusion: In one of the largest cohorts reported to date for SCCB, median survival was not met for stage I (75th percentile of 101 months) and was 57 months (95% CI 23-91) and 17 months (95% CI 6-28) for stage II and III respectively. Age < 60, lower stage, use of hormone therapy, and receipt of surgery were positive prognostic factors on MVA. Receipt of radiation was associated with a significantly longer survival in patients possessing traditional indications for radiotherapy (BCS or mastectomy with positive lymph nodes). Median radiation dose was 6000cGy and median number of fractions was 33. Citation Format: James Nathan Cantrell, Patricia Pius, Pawan Acharya, Sara Vesely, Christina Henson, Ozer Algan. Are traditional indications for radiation therapy appropriate for small cell carcinoma of the breast: An NCDB outcomes analysis and treatment utilization report [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-19-20.

Protean Clinical Features and Diagnostic Dilemmas of Pancreatic Tuberculosis

Abstract Tuberculosis (TB) is a systemic disease with protean manifestations and an important health problem. Approximately 15% of cases involve extrapulmonary sites with pancreatic TB (PTB) being rare. Clinically and radiologically, it may mimic a pancreatic malignancy, thus posing a clinical dilemma. The vague symptomatology and lack of clinical findings make it trickier to diagnose. We present a case series of patients with PTB and their tricky diagnosis and management. Endoscopic ultrasound–guided fine needle aspiration cytology along with various ancillary tests were used for the correct diagnosis. Endoscopic ultrasound–guided fine needle aspiration cytology provided the diagnosis, especially with the help of an expert cytologist experienced in the diagnosis of TB, thereby avoiding unnecessary laparotomy. Response to antituberculous therapy for 6 to 12 months is predictable and complete in these patients. Endoscopic ultrasound–guided fine needle aspiration cytology is the modality of choice for diagnosing PTB. However, patients still need to be followed up carefully for subjective and objective response to therapy to rule out the rare possibility of TB coexisting with malignancy, especially in endemic areas.

Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: possible implications for viral mutagenesis.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of the respiratory system can progress to a multisystemic disease with aberrant inflammatory response. Cellular senescence promotes chronic inflammation, named senescence-associated secretory phenotype (SASP). We investigated whether coronavirus disease 2019 (COVID-19) is associated with cellular senescence and SASP.MethodsAutopsy lung tissue samples from 11 COVID-19 patients and 43 age-matched non-COVID-19 controls with similar comorbidities were analysed by immunohistochemistry for SARS-CoV-2, markers of senescence and key SASP cytokines. Virally induced senescence was functionally recapitulated in vitro, by infecting epithelial Vero-E6 cells and a three-dimensional alveosphere system of alveolar type 2 (AT2) cells with SARS-CoV-2 strains isolated from COVID-19 patients.ResultsSARS-CoV-2 was detected by immunocytochemistry and electron microscopy predominantly in AT2 cells. Infected AT2 cells expressed angiotensin-converting enzyme 2 and exhibited increased senescence (p16INK4A and SenTraGor positivity) and interleukin (IL)-1β and IL-6 expression. In vitro, infection of Vero-E6 cells with SARS-CoV-2 induced senescence (SenTraGor), DNA damage (γ-H2AX) and increased cytokine (IL-1β, IL-6, CXCL8) and apolipoprotein B mRNA-editing (APOBEC) enzyme expression. Next-generation sequencing analysis of progenies obtained from infected/senescent Vero-E6 cells demonstrated APOBEC-mediated SARS-CoV-2 mutations. Dissemination of the SARS-CoV-2-infection and senescence was confirmed in extrapulmonary sites (kidney and liver) of a COVID-19 patient.ConclusionsWe demonstrate that in severe COVID-19, AT2 cells infected by SARS-CoV-2 exhibit senescence and a proinflammatory phenotype. In vitro, SARS-CoV-2 infection induces senescence and inflammation. Importantly, infected senescent cells may act as a source of SARS-CoV-2 mutagenesis mediated by APOBEC enzymes. Therefore, SARS-CoV-2-induced senescence may be an important molecular mechanism of severe COVID-19, disease persistence and mutagenesis.

Diagnosis of Genital Tuberculosis by Cartrdige Based Nucleic Acid Amplification Test in Subfertile Women of Rural Hospital

Tuberculosis has serious extra-pulmonary manifestations that are sometimes difficult to diagnose and thus left untreated. One such manifestation is female - genital tuberculosis (FGTB). Any diagnostic test is not efficient enough to prove the evidence of female genital tuberculosis. High level of clinical examination, detailed history of the patient, systemic examination, a series of tests to document M. tuberculosis as well as imaging techniques for characteristic structural changes are essential for the diagnosis.
 There exists lot of diagnostic dilemmas for genital tuberculosis in the available literature.no single test is found confirmatory except for wet culture and histopathological positivity, which may become paucibacillary extrapulmonary sites and time consuming, which creates a need for an investigation which can provide quicker and accurate results. cartridge based nucleic acid amplification test [CBNAAT] being a molecular test may be rapid and promising to diagnose these lesions.
 The diagnostic value of CBNAAT in detection of female genital tuberculosis seems to be limited, although it has a high positive predictive value.

Clinical Profile of 327 patients with Sarcoidosis in India: An Ambispective Cohort Study in a Tuberculosis (TB) Endemic Population.

Introduction:Sarcoidosis is a multisystem granulomatous disease with a varied clinical presentation. We describe the clinical characteristics of patients with sarcoidosis from a tuberculosis (TB) endemic setting.Methods:We performed an analysis of the sarcoidosis database at a tertiary care facility in North India.Results:Of the 327 patients, 50.8% were male, with a mean age of 42.8 years (range: 16–70 years). Females were significantly older. 42.6% had comorbidities, of which diabetes (17.1%) was most common. More than half (57.1%) were obese. Serum angiotensin-converting enzyme levels were elevated in 186 (57.9%). Eleven (3.8%) had hypercalcemia, while hypercalciuria was present in 54 (31.7%). The majority (89.9%) were tuberculin skin test negative (<10 mm induration), while 71.9% were tuberculin anergic. 47.7% had normal spirometry, while a restrictive impairment was the most common abnormality (44.6%). Obstruction on spirometry was present in 8.3%. Nearly half (160, 49%) had involvement of an extrapulmonary site. Most patients were (96%) symptomatic. Cough, shortness of breath, fatigue, weight loss, and fever were the predominant symptoms. A majority had Stage 1 (47.7%) sarcoidosis. Two hundred and eighty-seven (87.8%) patients underwent bronchoscopy or endosonographic (endobronchial ultrasound-guided transbronchial needle aspiration [EBUS-TBNA] or transesophageal bronchoscopic ultrasound-guided fine-needle aspiration [EUS-B-FNA]) sampling. A histopathological diagnosis with the demonstration of granulomas was achieved in 90.8%. The diagnostic yield of EBUS-TBNA/EUS-B-FNA was 77.4%. In 13.5% of patients, necrotizing granulomas were present in tissue samples.Conclusion:The clinical profile of patients with sarcoidosis in TB endemic settings has certain differences from nonendemic populations. Bronchoscopy and endosonography allow a confident diagnosis in the majority of patients.

Association of Tumor Necrosis Factor α Inhibitor Use with Diagnostic Features and Mortality of Tuberculosis in the United States, 2010-2017.

BackgroundAn elevated risk of tuberculosis (TB) disease in persons who have received tumor necrosis factor alpha inhibitor medications (TNF-α inhibitors) has been reported for nearly two decades, but clinical diagnostic features and outcomes of TB in this population remain poorly described.MethodsWe analyzed national surveillance data for TB cases among persons aged 15 years and older reported in the United States during 2010–2017 and associated mortality data reported through 2019 to describe the clinical characteristics of those receiving TNF-α inhibitors.ResultsOf 70 129 TB cases analyzed, 504 (0.7%) of the patients had TNF-α inhibitor use reported at TB diagnosis. Patients with TNF-α inhibitor use at TB diagnosis were more likely than TB patients not receiving TNF-α inhibitors to have TB diagnosed in extrapulmonary sites in conjunction with pulmonary sites (28.8% vs 10.0%, P < .001). Patients receiving TNF-α inhibitors were less likely to have acid-fast bacilli noted on sputum smear microscopy (25.6% vs 39.1%, P = .04), and more likely to have drug-resistant disease (13.5% vs 10.0%, P < .001). TB-attributed deaths did not significantly differ between patients receiving and not receiving TNF-α inhibitors (adjusted odds ratio, 1.46 [95% confidence interval, .95–2.26]).ConclusionsClinicians evaluating TNF-α inhibitor–treated patients should have a high index of suspicion for TB and be aware that extrapulmonary or sputum smear–negative TB disease is more common in these patients. No significantly diminished survival of TB patients treated with TNF-α inhibitor therapy before TB diagnosis was noted.

261 A case of metastatic myxoid liposarcoma causing cardiac tamponade

Abstract Aims Primary cardiac tumors are generally benign. In one series of over 12 000 autopsies, only seven cases of malignant primary cardiac tumors were identified, for an incidence of less than 0.1%. By comparison, metastatic involvement of the heart is over 20 times more common and has been reported in autopsy series in up to one in five patients dying of cancer. Myxoid liposarcoma (MLS) is the second most common subtype of liposarcoma and it usually occurs in deep tissues of the extremity, especially in the calf or thigh. Some tumors have round cell areas that represent histologic progression to high-grade tumours. Round cells, defined as &amp;gt; 5% of the total cells, are associated with higher malignancy and metastatic potential, resulting in an unfavourable outcome in patients affected. Patients with MLS tend to have metastases to extra pulmonary sites, such as abdominal wall, abdominal cavity, retroperitoneum, and bone, even in the absence of pulmonary metastases. Although several authors have reported a high proportion of extra pulmonary metastases of MLS, cardiac metastasis is extremely rare. Methods and results We present a case of a young woman who underwent resection of calf liposarcoma with the onset of cardiac metastases after 18 years, with cardiac tamponade as a clinical onset. MRI confirmed the cardiac solid mass already evident on CT scan, located along the free anterior wall of the right ventricle in the mid-basal area; the lesion seemed to have pericardial implantation with the free wall of the right ventricle was not well cleaved by the lesion in the Cine-MRI sequences. However it was always visible in the post-contrast sequences without evident protrusion of the lesion into the cavity or signs of thrombosis. The parietal pericardium was located on the periphery of the lesion and was not recognizable in some points. The lesion consisted of two portions, a lower one in which some components with characteristics of adipose signal were recognizable, while the upper one was more solid and vascularized. There was persistence of inhomogeneous and diffuse late enhancement at the lesion level. PET revealed pathological hyper accumulations of radiopharmaceuticals in the heart lesion along the anterior wall of the right ventricle, with central hypocaptation area, possible expression of necrotic-colliquative phenomena. Other hyper accumulations were found in the mediastinal lymph node in the pre-carenal area. These findings were referable to the presence of glucose hyper metabolic tissue of suspected neoplastic significance. The patient temporarily declined surgical excision, but after one month, due to the worsening of her symptoms, she returned to emergency room: The CT scan showed a volumetric increase in cardiac mass with a vertical diameter of 8 cm and adhering to the right ventricle for 7 cm. Thanks to the possibility of surgery, patient underwent exeresis of the capsulated epicardial mass adhering to the anterior wall of the right ventricle and to the pericardium, with removal of the ventricular wall and reconstruction with a bovine pericardium patch and without postoperative complications. Conclusions In MLS the time intervals between the onset of primary disease and cardiac metastasis were reported to be relatively long, ranging from 1 to 25 years. The initial site of metastatic disease in our patient was the heart: she had a solitary cardiac tumour that presented 18 years after the primary surgery in the absence of metastases at other sites. When a cardiac metastasis is found incidentally, it is usually incurable.

1402. NTM Infections; A Rising Global Health Problem/Clinical Characteristics and Outcomes of Patients with Non-Tuberculous Mycobacterial Infections at Two Tertiary Academic Medical Centers

BackgroundNon-Tuberculous Mycobacteria (NTM) cause infections in immunocompetent as well as immunocompromised individuals affecting pulmonary and extra pulmonary sites. These pathogens are widely distributed globally and recent reports have shown their rise in many developed countries. Our study aimed to assess the disease magnitude, describe patient characteristics and risk factors, assess diagnostic and therapeutic measures and review outcomes furthering our understanding of the overall disease process. MethodsWe conducted a retrospective, multicenter review of patients with positive NTM cultures treated at University Hospital System and South Texas Veterans Health Care System (STVHCS) from 2011 to 2018. Infections were classified as pulmonary or extrapulmonary, and we recorded demographics, microbiological data, treatment regimens, duration, complications, follow-up and mortality. All categorical variables were described using percentages and compared between groups using the chi-square test. ResultsA total of 176 patients were included for analysis, of which 111 (63.1%) met criteria for NTM disease (2020 ATS/IDSA). The most common cultured mycobacterium was M. Avium Complex (MAC). M. abscessus-chelonae was more commonly associated with clinical disease and isolated from an extra pulmonary site whereas M. simiae complex had similar distribution between the infected and un-infected groups. Over 50% of patients received treatment (80% in the infected group). Cure was seen in 47.2%, all-cause mortality was 27% at last follow-up. Median duration of therapy was 10 months. 47% of patients experienced adverse effects which led to treatment discontinuation in one third of patients. Patients who were able to achieve a cure received a longer duration of therapy (12 vs 7 months; not statistically significant) and treatment was halted more commonly in the group that did not achieve eventual cure (42.6% vs. 16.7%, p=0.007). ConclusionNTM infections represent a therapeutic challenge with low cure rates and high mortality. An understanding of the risk factors, treatment options and outcomes is essential to guide appropriate management. Our study highlights high rates of adverse effects and discontinuation which precludes prolonged courses of therapy required to achieve cure.Disclosures All Authors: No reported disclosures

798. Incomplete Contact Investigation and Risk of Developing Tuberculosis Among Healthcare Professionals After Tuberculosis Exposure

BackgroundTuberculosis (TB) contact investigation is recommended for healthcare professionals (HCPs) after TB exposure. However, association between no participation in or incomplete contact investigation and subsequent TB development has not been well-described. This study aims to determine TB incidences and factors associated with TB development among HCPs requiring contact investigations.MethodsWe conducted a prospective cohort study among Thai HCPs with TB exposure from January 2013 to December 2017. Contact investigations, including baseline TB and latent tuberculosis infection (LTBI) screening and follow-up at 3 months after TB exposure, were recommended to all HCPs. The two-step tuberculin skin test (TST) was used for LTBI testing. All HCPs were followed for 2 years for TB development.ResultsOf the 342 HCPs with TB exposure included in the study, 311 (91%) participated in the contact investigations and 252 (74%) completed baseline TB and LTBI screening. Among the 210 HCPs with negative baseline TST, 45 (21%) completed the follow-up tests. The overall incidence of TB was 2.92/100 person-years. HCPs who did not complete follow-up TST had significantly higher TB incidence than those completed baseline and follow-up TST (3.55 vs. 0/100 person-years; P=0.01). No participation in the contact investigation and no chest radiograph performed at baseline were the independent factors associated with TB development among the HCPs [adjusted odds ratio (aOR) 6.69; P< 0.001 and aOR 8.85; P=0.01, respectively]. Contact with an index patient with concomitant TB at extrapulmonary sites (aOR 49.76, 10.03-246.99; P< 0.001) and with negative sputum AFB but positive sputum GeneXpert MTB/RIF (aOR 3.18, 1.35-7.50; P=0.008) were independently associated with no participation in the contact investigation.ConclusionThe findings indicate the risk of TB development among the HCPs who did not undergo or complete contact investigations and underscore the need for interventions to improve contact investigation participation and completeness.Disclosures All Authors: No reported disclosures

645. Rapid Diagnosis of Disseminated Mycobacterium kansasii infection in Renal Transplant Recipients Using Plasma Microbial Cell Free DNA Next Generation Sequencing

BackgroundDisseminated Mycobacterium kansasii infection is rare in kidney transplant recipients. The diagnosis may not be suspected readily due to non-specific clinical presentation. The diagnosis and treatment can be further delayed due to poor sensitivity of culture (especially of extra-pulmonary sites) and slow growth in culture media. Accurate and rapid diagnosis of disseminated M. kansasii infections in transplant recipients is important for antimicrobial management.MethodsTwo cases of disseminated M. kansasii infections with unusual presentation in which rapid diagnosis was made using the Karius test (KT) are presented. The KT is a CLIA certified/CAP-accredited next-generation sequencing (NGS) plasma test that detects microbial cell-free DNA (mcfDNA). After mcfDNA is extracted and NGS performed, human reads are removed, and remaining sequences are aligned to a curated database of >1400 organisms. Organisms present above a statistical threshold are reported.ResultsCase 1: A 31-year female kidney transplant recipient presented with a thyroglossal duct cyst, as well as swelling of her right metacarpophalangeal joint and left 3rd finger. AFB culture of the thyroglossal cyst aspiration done on post admission day (PAD) 2 took 27 days to be identified as M. kansasii (on PAD 29) whereas plasma sent for KT on PAD 5 reported a positive test for M. kansasii at 284 molecules/microliter (MPM) in 4 days (on PAD 9). Case 2: A 59-year male kidney transplant recipient presented with generalized weakness, arthralgia, pericardial effusion, cytopenia, weight loss and intermittent fevers. Plasma sent for KT on PAD 12 was reported positive for M. kansasii at 1314 MPM in 3 days (on PAD 15). PET CT done simultaneously was consistent with an infection of an old AV graft in the left upper extremity. The AFB culture of the resected graft was confirmed as M. kansasii in 22 days on PAD 36. After the KT was available (before confirmation of M. kansasii on culture), the first patient underwent modification of empiric treatment and the second patient was started on specific treatment for M. kansasii.Table of M. kansasii cases Rapid diagnosis of disseminated M. kansasii infectionConclusionOpen-ended NGS plasma testing for mcfDNA identified disseminated M kansasii infection much earlier than standard microbiology and thus helped in initiation and modification of pathogen directed treatment.Disclosures All Authors: No reported disclosures

260. The Unfortunate Consequence of Immunosuppression in a Renal Transplant Patient

BackgroundNocardia is a slow-growing aerobic-actinomycete that belongs to the family Nocardiaceae. Major predisposing factors include corticosteroid use, organ transplantation, low CD4 count, and hematologic malignancies. The most commonly affected organs are lungs, mainly via inhalation; however, the most common extrapulmonary site is central nervous system.MethodsMatrix Assisted Laser Desorption Ionization - Time of Flight (MALDI-ToF) or 16srRNA sequencing are more reliable methodologies for accurate identification of Nocardia to the species level. To our knowledge, our patient represented the first U.S. case of N. bejingensis opportunistic disseminated infection in a renal transplant patient although similar cases have been previously reported outside the U.S.GMS stain Gram Stain of Nocardia ResultsWe present a 31-year-old Caucasian male status post renal transplant four years ago on immunosuppressants with left arm myoclonic jerks. In addition, there was an associated unilateral left frontal headache of four to five day duration. His chest CT revealed consolidative process in the right lower lobe and pleural effusion. MRI of the brain revealed multiple ring-enhancing lesions. Patient underwent left frontal craniotomy with resection and a complete evacuation of brain abscess. His brain abscess and pleural fluid cultures revealed Gram positive rods, which were subsequently identified as Nocardia beijingensis by MALDI-TOF and confirmed by 16srRNA sequencing. He was treated with intravenous imipenem & trimethoprim – sulfamethoxazole with subsequent clinical improvement.MRI Brain w/ contrast Head CT s/p left frontal craniotomy with resection & evacuation of abscess Chest CT ConclusionDifferent Nocardia species have a wide geographic distribution with varying pathogenic traits, and antimicrobial susceptibility. Hence, the identification of the specific species of Nocardia is crucial to provide a proficient level of patient care. Nocardia bejingensis is a newly discovered species of Nocardia that was first isolated in 2001 in China. Only six cases of N. beijingensis affecting CNS have been reported up to date in the United States. It is unclear of the geographic distribution and variable antimicrobial susceptibility of Nocardia bejingensis but we can confirm the first reported case of an opportunistic disseminated infection in a renal transplant patient in the United States.Agar Disclosures All Authors: No reported disclosures

Abstract 16926: Outside The Box But All Squeezed In: A 23-year-old Man With Progressive Dyspnea After Overseas Travel

Case Presentation: A 23-year-old previously healthy man presented with progressive dyspnea. Physical examination revealed jugular venous distension and lower extremity edema. Laboratory testing demonstrated elevated B-type natriuretic peptide (193 pg/mL) and normal high sensitivity troponin. Echocardiogram revealed small pericardial effusion, respiratory variation in diastolic flow across the mitral valve, diastolic septal bounce, and annulus reversus ( Figure ). The differential diagnosis for constrictive pericarditis was broadly considered in the context of a recent febrile illness and frequent travel to Hawaii and Vietnam; we included infectious, autoimmune, and malignant etiologies. Cardiac magnetic resonance imaging revealed thickening and diffuse enhancement in the pericardium as well as ventricular interdependence. Chest CT identified hilar and anterior mediastinal lymphadenopathy. Laboratory testing was positive for QuantiFERON gold and negative for COVID-19, HIV, and ANA. Transbronchial biopsy demonstrated non-necrotizing granulomas with negative acid-fast bacilli smear, culture, and polymerase chain reaction for mycobacterial DNA. Re-examination identified a red-brown plaque on the patient’s thigh; biopsy showed granulomatous inflammation and rod-shaped organism with positive FITE staining. A presumed unifying diagnosis was made of extrapulmonary tuberculosis (TB) complicated by constrictive pericarditis. Discussion: Despite being a primarily pulmonary disease, systemic involvement can occur with TB with the heart being one of the most common extrapulmonary sites. This case highlights 1) the utility of extra-cardiac diagnostic testing (e.g., dermatologic biopsy) in the diagnosis of constrictive pericarditis, and 2) the diagnostic challenge associated with extrapulmonary TB, particularly paucibacillary disease that requires a detailed social history with “out-of-the-box” thinking.

Epidemiology of concurrent extrapulmonary tuberculosis in inpatients with extrapulmonary tuberculosis lesions in China: a large-scale observational multi-centre investigation

A high proportion of all patients with tuberculosis (TB) present with extrapulmonary TB (EPTB), including concurrent EPTB involving more than one extrapulmonary lesion site. However, previous reports only characterized lesions of single-site EPTB cases. This study aimed to investigate epidemiological characteristics and association rules of concurrent EPTB cases in China. An observational multi-centre study of 208,214 patients with EPTB lesions was undertaken in China from January 2011 to December 2017. Multi-variable logistic regression analysis was used to identify associations between gender and concurrent EPTB, and age and concurrent EPTB. Association rules were analysed for significance using the Apriori algorithm. The most common EPTB lesion was tuberculous pleurisy (49.8%), followed by bronchial TB (14.8%) and tuberculous meningitis (7.6%). The most common type of concurrent EPTB was tuberculous pleurisy concurrent with tuberculous peritonitis (1.80%). In total, 22 association rules, including 20 strong association rules, were identified; among these, the highest confidence rates were found for tuberculous myelitis concurrent with tuberculous meningitis, and sacral TB concurrent with lumbar vertebral TB. The association rules of EPTB concurrent with other EPTB types were found to vary with gender and age. The confidence rate of tuberculous myelitis concurrent with tuberculous meningitis was higher in females (83.67%) than males, and was highest in patients aged 25-34 years (87.50%). Many types of concurrent EPTB were found. Greater awareness of concurrent EPTB disease characteristics is needed to ensure timely clinical diagnosis and treatment of this disease.

Epidemiology of Nontuberculous Mycobacterial Infection in Tuberculosis Suspects.

Nontuberculosis mycobacteria (NTM) are opportunistic pathogens that cause a wide range of illnesses. Here, the species distribution and prevalence of NTM infections in tuberculosis suspects was analyzed. A total of 7,073 specimens from pulmonary and extrapulmonary sites were analyzed, and 709 (10%) were found to be culture positive for mycobacteria. Of these, 85.2% were identified as Mycobacterium tuberculosis complex and 14.8% as NTM (65.7% rapid growers and 34.3% slow growers). Speciation of the NTM isolates (n = 69) identified 19 NTM species. M. abscessus (33.3%) and M. fortuitum (24.6%) were the most dominant NTM species isolated from the patients, followed by M. porcinum (5.8%) and M. parascrofulaceum (4.3%). We also report peritonitis caused by rapidly growing NTM among the patients undergoing continuous ambulatory peritoneal dialysis and a case of M. senegalense peritonitis. A low prevalence but high species diversity of NTM was detected in our study. The high species diversity of NTM necessitates the need to unequivocally identify mycobacterial isolates for appropriate treatment.

English

Black carbon is a product of incomplete combustion and is associated with a number of adverse health outcomes in epidemiologic studies. To date, anatomic studies investigating the pathogenic mechanisms of black carbon in humans have confirmed black carbon particles accumulate in the lung and in the placenta of pregnant women, and are excreted in urine. In this feasibility study, the presence of black carbon particles was demonstrated in post-mortem spleen, myocardium, and hilar lymph node samples obtained from three de-identified sources. A protocol validated for extraction of chemically inert particles from fish tissue was utilized to extract black carbon particles from human tissue. Visual examination and micro-Raman scattering spectroscopy were used to identify recovered black carbon particles. Recovered particles ranged from 2 to 45 ?m in greatest dimension. The highest concentrations of black carbon particles were recovered from hilar lymph nodes, followed by the myocardium, with lowest concentrations recovered from the spleen. Particles extracted from the spleen were, on average, larger than particles extracted from the heart or hilar lymph nodes. These findings confirm black carbon particles accumulate in human extrapulmonary organs. Based on the size and concentrations of recovered particles, it is suggested that black carbon particles are transported to extrapulmonary sites via the lymphatic system. Furthermore, the noted concentration differentials suggest reduced black carbon particle clearance from the myocardium compared with the spleen. Key words: Black carbon, soot, human, heart, spleen.&nbsp

The key factors contributing to the risk, diagnosis and treatment of non-tuberculous mycobacterial opportunistic infections

Abstract The incidence and prevalence of diseases caused by non-tuberculous mycobacteria (NTM) have been steadily increasing worldwide. NTM are environmental saprophytic organisms; however, a few strains are known to produce diseases in humans affecting pulmonary and extra-pulmonary sites. Although the environment is a major source of NTM infection, recent studies have shown that person-to-person dissemination could be an important transmission route for these microorganisms. Structural and functional lung defects and immunodeficiency are major risk factors for acquiring NTM infections. Diagnosis of NTM diseases is very complex owing to the necessity of distinguishing between a true pathogen and an environmental contaminant. Identification at the species level is critical due to differences in the antibiotic susceptibility patterns of various NTM strains. Such identification is mainly achieved by molecular methods; additionally, mass spectrometry (e.g., MALDI-TOF) is useful for NTM species determination. Natural resistance of NTM species to a wide spectrum of antibiotics makes prescribing treatment for NTM diseases very difficult. NTM therapy usually takes more than one year and requires multi-drug regimens, yet the outcome often remains poor. Therefore, alternatives to antibiotic therapy treatment methods is an area under active exploration. NTM infections are an active global health problem imposing the necessity for better diagnostic tools and more effective treatment methods.

Autopsy-Based Pulmonary and Vascular Pathology: Pulmonary Endotheliitis and Multi-Organ Involvement in COVID-19 Associated Deaths

Background: Findings from autopsies have provided evidence on systemic microvascular damage as one of the underlying mechanisms of Coronavirus disease 2019 (CO­VID-19). The aim of this study was to correlate autopsy-based cause of death in SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive patients with chest imaging and severity grade of pulmonary and systemic morphological vascular pathology. Methods: Fifteen SARS-CoV-2 positive autopsies with clinically distinct presentations (age 22–89 years) were retrospectively analyzed with focus on vascular, thromboembolic, and ischemic changes in pulmonary and in extrapulmonary sites. Eight patients died due to COVID-19 associated respiratory failure with diffuse alveolar damage in various stages and/or multi-organ failure, whereas other reasons such as cardiac decompensation, complication of malignant tumors, or septic shock were the cause of death in 7 further patients. The severity of gross and histopathological changes was semi-quantitatively scored as 0 (absent), 1 (mild), and 3 (severe). Severity scores between the 2 groups were correlated with selected clinical parameters, initial chest imaging, autopsy-based cause of death, and compared using Pearson χ² and Mann-Whitney U tests. Results: Severe pulmonary endotheliitis (p = 0.031, p = 0.029) and multi-organ involvement (p = 0.026, p = 0.006) correlated significantly with COVID-19 associated death. Pulmonary microthrombi showed limited statistical correlation, while tissue necrosis, gross pulmonary embolism, and bacterial superinfection did not differentiate the 2 study groups. Chest imaging at hospital admission did not differ either. Conclusions: Extensive pulmonary endotheliitis and multi-organ involvement are characteristic autopsy features in fatal CO­VID-19 associated deaths. Thromboembolic and ischemic events and bacterial superinfections occur frequently in SARS-CoV-2 infection independently of outcome.

Pulmonary delivery of the broad-spectrum matrix metalloproteinase inhibitor marimastat diminishes multiwalled carbon nanotube-induced circulating bioactivity without reducing pulmonary inflammation

BackgroundMultiwalled carbon nanotubes (MWCNT) are an increasingly utilized engineered nanomaterial that pose the potential for significant risk of exposure-related health outcomes. The mechanism(s) underlying MWCNT-induced toxicity to extrapulmonary sites are still being defined. MWCNT-induced serum-borne bioactivity appears to dysregulate systemic endothelial cell function. The serum compositional changes after MWCNT exposure have been identified as a surge of fragmented endogenous peptides, likely derived from matrix metalloproteinase (MMP) activity. In the present study, we utilize a broad-spectrum MMP inhibitor, Marimastat, along with a previously described oropharyngeal aspiration model of MWCNT administration to investigate the role of MMPs in MWCNT-derived serum peptide generation and endothelial bioactivity.ResultsC57BL/6 mice were treated with Marimastat or vehicle by oropharyngeal aspiration 1 h prior to MWCNT treatment. Pulmonary neutrophil infiltration and total bronchoalveolar lavage fluid protein increased independent of MMP blockade. The lung cytokine profile similarly increased following MWCNT exposure for major inflammatory markers (IL-1β, IL-6, and TNF-α), with minimal impact from MMP inhibition. However, serum peptidomic analysis revealed differential peptide compositional profiles, with MMP blockade abrogating MWCNT-derived serum peptide fragments. The serum, in turn, exhibited differential potency in terms of inflammatory bioactivity when incubated with primary murine cerebrovascular endothelial cells. Serum from MWCNT-treated mice led to inflammatory responses in endothelial cells that were significantly blunted with serum from Marimastat-treated mice.ConclusionsThus, MWCNT exposure induced pulmonary inflammation that was largely independent of MMP activity but generated circulating bioactive peptides through predominantly MMP-dependent pathways. This MWCNT-induced lung-derived bioactivity caused pathological consequences of endothelial inflammation and barrier disruption.

Skipped multilevel lesion as an atypical tuberculous spondylitis mimicking spinal metastasis: A case report

Tuberculosis (TB) is one of major global health threats and leads to morbidity and mortality. TB is prevalent in low and middle income countries especially in Sub-Saharan Africa and South East Asia. M. tuberculosis usually affects the lungs. Spine is the most common extrapulmonary sites for TB after lymph nodes, accounts for 1% of all TB cases, and 50 to 60% of osteoarticular TB. In the case of spinal TB, two or more adjacent vertebrae are usually involved due to hematogenous spread of bacteria in which the vertebral arteries feed the two adjacent vertebrae. The incidence of multiplelevel non-contiguous spinal TB is 1.1 to 16% of all skeletal TB. Multiple-level non-contiguous, an atypical form of spinal TB is rare. It has insidious symptoms, often with diagnostic delays and a higher risk of permanent neurological deficits. We report a case of atypical TB spondylitis with non-contiguous multiple level of lesions mimicking multiple bone metastases.