Extrapulmonary Disease Research Articles

Imaging of cystic fibrosis manifestations in the abdomen.

Cystic fibrosis is a common inherited autosomal recessive disease affecting 35,000 persons in the United States. It is caused by mutations of the cystic fibrosis transmembrane regulator (CFTR) gene, located on the long arm of chromosome 7.This protein carries chlorine in the membranes of epithelial cells of exocrine glands. Mutations in the CFTR gene results in production of abnormally viscous mucus. Although it primarily affects the lungs, cystic fibrosis is a multisystem disease with involvement of extra thoracic organs including the liver, pancreas, kidneys and digestive tract.With advances in the management of cystic fibrosis resulting in improved life expectancy, cystic fibrosis patients are surviving into adulthood and extrapulmonary disease has become more commonplace. It is essential that radiologists are aware of the spectrum of potential manifestations of cystic fibrosis to allow accurate diagnosis.The purpose of this manuscript is to provide an overview of the pathophysiology and imaging findings of abdominal entities unique to patients with cystic fibrosis. We will present a wide spectrum of renal, pancreatic, gastrointestinal, hepatobiliary and post-transplant cases describing the typical findings that will assist radiologists in providing a timely diagnosis for patients with cystic fibrosis.

Urine lipoarabinomannan concentrations among HIV-negative adults with pulmonary or extrapulmonary tuberculosis disease in Vietnam.

Lipoarabinomannan (LAM) is a promising target biomarker for diagnosing subclinical and clinical tuberculosis (TB). Urine LAM (uLAM) testing using rapid diagnostic tests (RDTs) has been approved for people living with HIV (PLWH), however there is limited data regarding uLAM levels in HIV-negative (HIV-ve) adults with clinical TB. We conducted a clinical study of adults presenting with clinical TB-related symptoms at the National Lung Hospital in Hanoi, Vietnam. The uLAM concentrations were measured using electrochemiluminescent (ECL) immunoassays and compared to a microbiological reference standard (MRS) using GeneXpert Ultra and TB culture testing. Estimated uLAM concentrations above plate specific calculated limit of detection (LOD) were considered uLAM positive. Additional microbiological testing was conducted for possible extrapulmonary TB (EPTB). Among 745 participants enrolled, 335 (44.9%) participants with presumptive pulmonary TB (PTB) and 6 (11.3%) participants with presumptive EPTB had confirmed TB disease. Overall, the S/A antibody pair had a sensitivity of 39% (95% Confidence Interval [CI] 0.33, 0.44) and a specificity of 97% (95% CI 0.96, 0.99) compared to the MRS. The F/A antibody pair had a sensitivity of 41% (95% CI 0.35, 0.47) and a specificity of 79% (95% CI 0.75, 0.84). S/A provided greater discriminatory ability compared to F/A for both individuals with presumptive PTB (AUROC: 0.74 vs 0.63, p<0.0001) and presumptive EPTB (0.76 vs 0.54, p = 0.045) when using the MRS. Among HIV-ve participants in an adult cohort in Vietnam, the concentrations of uLAM remained relatively low for people with clinical TB, which may present challenges for improving RDT sensitivity.

Pathogen and host determinants of extrapulmonary tuberculosis among 1035 patients in Frankfurt am Main, Germany, 2008-2023

ObjectivesExtrapulmonary tuberculosis (EPTB) presents with nonspecific symptoms which can pose a significant diagnostic challenge. Various factors, including age, sex, and HIV status, have been associated with an increased risk of developing EPTB. However, the influence of the lineage of the infecting Mycobacterium tuberculosis complex (Mtbc) strain remains controversial. MethodsBetween 2008 and 2023, comprehensive clinical data from 1035 cases, along with whole genome sequencing (WGS) data of the respective Mtbc strains have been collected. To examine the association between Mtbc lineage and EPTB, we calculated crude and adjusted odds ratios (OR) using logistic regression and performed propensity score matching with a subset of the cohort. ResultsOf the 1035 patients, 272 had exclusively extrapulmonary disease and 138 had both pulmonary and extrapulmonary disease. Patients infected with a lineage 1 strain had the highest odds of developing EPTB in the univariate analysis (OR: 3.30, 95% CI: 1.97-5.49). However, Mtbc lineage was not a significant predictor in the multivariable model, while the odds of developing extrapulmonary disease were higher among patients born in the South-East Asian region (adjusted OR: 6.00, 95% CI: 3.41-10.69) and the Eastern Mediterranean Region (adjusted OR: 5.95, 95% CI: 3.61-9.96) compared to those born in the European region. Further, female sex and age were significant positive predictors for EPTB. ConclusionsOur results demonstrate that host factors, such as geographic origin, age and sex are stronger predictors for EPTB than infection with a Mtbc strain of a particular lineage. Further investigation of this host-pathogen interaction is needed.

Determinants of tuberculosis site among 1035 cases in Frankfurt, 2008-2023: does lineage matter?

Abstract Extrapulmonary tuberculosis (EPTB) presents with nonspecific symptoms which can pose a diagnostic challenge. Currently, there are no clear predictors for EPTB. We aimed to identify these factors for better diagnosis and disease control. We included tuberculosis cases reported in Frankfurt from 2008-2023, with available clinical and whole genome sequencing data. According to WHO criteria, cases with pulmonary or combined pulmonary and extrapulmonary symptoms were categorised as pulmonary tuberculosis, while exclusively extrapulmonary symptoms were categorised as extrapulmonary tuberculosis. We assessed the association between EPTB and M. tuberculosis lineage, comorbidities and demographic characteristics using logistic regression, calculating crude and adjusted odds ratios (aOR). Of the 1035 reported tuberculosis cases, 272 had exclusively extrapulmonary disease and 136 had both pulmonary and extrapulmonary disease. In the univariable analysis, lineages 1 and 3 were significantly associated with extrapulmonary disease compared to lineage 4. However, this association was not observed in the multivariable analysis. In the final regression model, females were more likely to develop EPTB than men (aOR: 1.65, CI: 1.19-2.27). The odds of developing extrapulmonary disease were higher among patients born in the South-East Asian (aOR: 6.48, CI: 3.72-11.43) and Eastern Mediterranean (aOR: 5.54, CI: 3.41-9.11) than in other regions. Among the comorbidities, diabetes was found to be negatively associated with extrapulmonary disease (aOR: 0.50, CI: 0.26-0.91). Our results indicate that host factors such as geographic origin and sex are stronger predictors for extrapulmonary presentation of tuberculosis than a specific lineage. We recommend increasing physicians’ awareness of the nonspecific presentation of EPTB and adapting screening programmes, particularly for patients from South-East Asian and Eastern Mediterranean regions to foster more effective tuberculosis control measures. Key messages • Our study highlights the importance of considering host factors in predicting extrapulmonary tuberculosis, indicating their stronger influence compared to specific M. tuberculosis lineages. • Increased physicians’ awareness of the nonspecific symptoms of EPTB and targeted screening programs for high-risk populations are crucial for enhancing tuberculosis control measures.

Association of computed tomography-derived pectoralis muscle area and density with disease severity and respiratory symptoms in patients with chronic obstructive pulmonary disease: A case-control study

Rationale and objectivesComputed tomography (CT) is commonly used and offers an additional viewpoint for evaluating extrapulmonary symptoms, disease severity, and muscle atrophy. This study assessed whether the pectoralis muscle area (PMA) and pectoralis muscle density (PMD) are lower in patients with chronic obstructive pulmonary disease (COPD) than in healthy controls and elucidated their relationships with these variables. Materials and methodsThe participants were enrolled in the hospital outpatient clinic between October 2023 and May 2024. Information was obtained from questionnaires, lung function, and CT imaging findings. On full-inspiratory CT, the PMA and PMD were measured at the aortic arch level using predetermined attenuation ranges of −29 and 150 Hounsfield units. We observed lower PMA and PMD and evaluated their associations with lung function, respiratory symptoms, and CT imaging findings in patients with COPD. ResultsOverall, 120 participants were enrolled at baseline (60 healthy controls and 60 patients with COPD). PMA and PMD were lower with progressive airflow limitation severity in those with COPD. The degree of emphysema and air trapping, as well as lung function, were correlated with PMA and PMD (P < 0.05), although not with the COPD Assessment Test or modified Medical Research Council scores (P > 0.05). ConclusionParticipants with COPD had smaller PMA and PMD. These measurements were correlated with the severity of airflow limitation, lung function, emphysema, and air trapping, suggesting that these features of the pectoralis muscle obtained from CT are helpful in assessments of patients with COPD.

Clinical Characteristics and Mortality Risks Among Patients With Culture-Proven Coccidioidomycosis Who Are Critically Ill: A Multicenter Study in an Endemic Region.

Coccidioidomycosis is an endemic mycosis in the southwestern United States. While most infections are mild, severe cases can be devastating. We aimed to describe the clinical characteristics and mortality risks of patients in the intensive care unit (ICU) with culture-proven coccidioidomycosis. We performed a retrospective chart review of patients in the ICU with positive Coccidioides spp culture in a large health care system in Arizona between 1 October 2017 and 1 July 2022. All data were entered into REDCap. An overall 145 patients were identified and included. The median age was 51 years, with the majority male (69%) and non-Hispanic White (39%). Most patients (n = 104, 72%) had pulmonary coccidioidomycosis, and 41 had extrapulmonary disease (17 meningitis, 13 fungemia, 10 musculoskeletal disease, and 4 pericardial or aortic involvement). Seventy patients (48%) died during hospitalization, and most (91%) received antifungal therapy during hospitalization. In the multivariate logistic regression model, age ≥60 years (odds ratio [OR], 7.0; 95% CI, 2.6-18.8), cirrhosis (OR, 13.1; 95% CI, 1.6-108.8), and mechanical ventilation or vasopressor support (OR, 15.4; 95% CI, 3.9-59.6) were independently associated with increased all-cause mortality, but pre-ICU antifungal use had a statistically insignificant mortality risk association (OR, 0.5; 95% CI, .2-1.2). In our study of patients in the ICU with coccidioidomycosis and multiple comorbidities, the mortality rate was high. Older age, cirrhosis, and mechanical ventilation or vasopressor support were significantly associated with high mortality. Future studies are recommended to evaluate those risk factors and the efficacy of rapid diagnosis and early therapy in patients at high risk.

Current Practices and Considerations in Lung Biopsy for Suspected Granulomatous-Lymphocytic Interstitial Lung Disease: A Clinician Survey

Introduction: This study explores clinicians’ diagnostic practices and perceptions in the context of granulomatous-lymphocytic interstitial lung disease (GLILD), a pulmonary manifestation of common variable immunodeficiency disorder. The aim was to gain valuable insights into key aspects, such as the utilization of radiological features for diagnostic purposes, indications for lung biopsy, preferred biopsy techniques, and the relative importance of different histopathological findings in confirming GLILD. Method: A survey targeting expert clinicians was conducted, focusing on their experiences, practices, and attitudes towards lung biopsy in suspected GLILD cases. Results: The survey revealed that the majority of respondents accepted high-resolution computed tomography as a sufficient alternative to biopsy for making a probable GLILD diagnosis in most patients. There was a consensus among most respondents that the presence of extrapulmonary granulomatous disease is adequate for making a diagnosis of GLILD where the chest imaging and clinical picture are consistent. When a biopsy was recommended, there was notable variation in the preferred initial biopsy technique, with 35% favouring transbronchial biopsy. Conclusion: Our findings underscore the complexity of diagnosing GLILD, indicating varied clinician opinions on the necessity and efficacy of lung biopsies. They highlight the need for further research and the development of consistent diagnostic criteria and management protocols, ultimately aiming to enhance the accuracy and safety of GLILD diagnosis and treatment strategies.

Clinical and genomic features of Mycobacterium avium complex: a multi-national European study

BackgroundThe Mycobacterium avium complex (MAC) comprises the most frequent non-tuberculous mycobacteria (NTM) in Central Europe and currently includes twelve species. M. avium (MAV), M. intracellulare subsp. intracellulare (MINT), and M. intracellulare subsp. chimaera (MCH) are clinically most relevant. However, the population structure and genomic landscape of MAC linked with potential pathobiological differences remain little investigated.MethodsWhole genome sequencing (WGS) was performed on a multi-national set of MAC isolates from Germany, France, and Switzerland. Phylogenetic analysis was conducted, as well as plasmids, resistance, and virulence genes predicted from WGS data. Data was set into a global context with publicly available sequences. Finally, detailed clinical characteristics were associated with genomic data in a subset of the cohort.ResultsOverall, 610 isolates from 465 patients were included. The majority could be assigned to MAV (n = 386), MCH (n = 111), and MINT (n = 77). We demonstrate clustering with less than 12 SNPs distance of isolates obtained from different patients in all major MAC species and the identification of trans-European or even trans-continental clusters when set into relation with 1307 public sequences. However, none of our MCH isolates clustered closely with the heater-cooler unit outbreak strain Zuerich-1. Known plasmids were detected in MAV (325/1076, 30.2%), MINT (62/327, 19.0%), and almost all MCH-isolates (457/463, 98.7%). Predicted resistance to aminoglycosides or macrolides was rare. Overall, there was no direct link between phylogenomic grouping and clinical manifestations, but MCH and MINT were rarely found in patients with extra-pulmonary disease (OR 0.12 95% CI 0.04–0.28, p < 0.001 and OR 0.11 95% CI 0.02–0.4, p = 0.004, respectively) and MCH was negatively associated with fulfillment of the ATS criteria when isolated from respiratory samples (OR 0.28 95% CI 0.09-0.7, p = 0.011). With 14 out of 43 patients with available serial isolates, co-infections or co-colonizations with different strains or even species of the MAC were frequent (32.6%).ConclusionsThis study demonstrates clustering and the presence of plasmids in a large proportion of MAC isolates in Europe and in a global context. Future studies need to urgently define potential ways of transmission of MAC isolates and the potential involvement of plasmids in virulence.

Double lung transplantation in patients with metastatic lung-limited non-small cell lung carcinoma (NSCLC): A case series.

8643 Background: Despite technological advances and expanded indications in lung transplantation, lung cancer constituted less than 0.1% of the lung transplantation over the past two decades. Double lung transplantation (DLT) may offer curative treatment for metastatic lung-limited NSCLC patients without extrapulmonary disease. We present a case series of consecutive NSCLC patients who underwent DLT. Methods: Patients treated with DLT were identified between 09/2021 and 02/2024 at Canning Thoracic Institute of Northwestern University. All patients had enrolled in the DLT registry aimed for lung-limited malignancies (DREAM) study cohort A (NCT05671887). Exclusion criteria includes presence of extrapulmonary disease. Results: Six patients with stage IVA NSCLC who underwent lung transplantation were included. Five (83.3%) patients underwent double lung, and one (16.7%) patient single lung transplantation. Four (66.7%) patients had invasive mucinous, and two (33.3%) had invasive non-mucinous adenocarcinoma histology. One of the two invasive non-mucinous patients had acinar, and the other had mixed lepidic, papillary, and acinar histology. Patients were aged 56-71; one (16.7%) was Asian, five (83.3%) were White, four (66.7%) were male, and three (50%) had a history of smoking. One (16.7%) patient had a past medical history of interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD). The median pretransplant treatment lines were 2 (1-5). All patients had high oxygen requirements before DLT due to cancer progression. Pre-transplant endobronchial ultrasound and evaluation of bilateral pneumonectomy lungs found no lymph node involvement (pN0). One patient had an epidermal growth factor receptor (EGFR) mutated cancer but had failed relevant targeted therapy prior to transplant. All patients had disease progression on standard of care treatments with/without clinical trials. The indication for DLT was respiratory failure or refractory cancer for all patients. After DLT, one patient had a recurrence of the disease at 18 months with a 1cm solid nodule and was treated with stereotactic body radiotherapy (SBRT). Both original and recurrent tumors had invasive mucinous adenocarcinoma histology, negative PD-L1 expression, and the same JAK3 c.2174C &gt; T, P725L mutated clone. It suggests that the recurrence likely arose from the original cancer. Transplant rejection did not occur in any of the cases. Following the transplant, there was no requirement for oxygen therapy for any patient. All patients are alive with 28, 18, 8, 8, 5, and 4-month posttransplant follow-up. Conclusions: Six patients underwent DLT successfully without significant complications. All patients were alive and in good health. Ongoing DREAM study will continue to investigate the role of DLT in metastatic lung-limited NSCLC patients (especially in pN0). Clinical trial information: NCT05671887 .

Double lung transplantation in patients with recent history of malignancy.

e20614 Background: Recent history of malignancy has been considered as a contraindication for double lung transplantation (DLT) due to concerns for risk of cancer recurrence and worse outcomes. However, the relationship between the recent malignancy history and lung transplantation mortality remains unclear. Methods: Among patients treated with DLT between 09/2021 and 02/2024 in single institution, patients with a recent history of other cancers were included in this study. All patients had enrolled in cohort C of the DLT registry aimed for lung-limited malignancies (DREAM) study (NCT05671887). Exclusion criteria include extrapulmonary metastatic disease and medical ineligibility for DLT. All patients were followed up with computed tomography every 12 weeks. Results: Four patients were included; three (75%) patients with a histology of NSCLC (squamous cell, stage Ib-IIIb), and one (25%) with prostate adenocarcinoma (stage IIc). The median no-evidence-of-disease (NED) time was 19.5 months (0-41). Patients were aged 57-68, three (75%) were male. The indication for DLT was chronic obstructive pulmonary disease (1/4, 25%), interstitial lung disease (2/4, 50%), and idiopathic pulmonary fibrosis (1/4, 25%). All patients had high oxygen requirements before DLT. The median duration of the waitlist for DLT was sixteen days (3-61). There was no in-hospital mortality and the median hospital stay was 20.5 days (16-32). During a median follow-up of 2.5 months (range 0-9), rejection and post-transplant malignancy did not occur in any of the cases (Table 1). Conclusions: Four patients with history of cancers underwent DLT without significant complications. The median post-transplant follow-up was 2.5 months (0-9). Ongoing DREAM study cohort C will continue to investigate the role of DLT in patients with a recent history of malignancy. Clinical trial information: NCT05671887 . [Table: see text]

Acute Tuberculous Appendicitis, a Rare Entity

Tuberculous appendicitis is a rare disease, with an overall incidence of between 1.5-3.0% among tuberculosis patients. It was first described by Corbin et al in 1873 and since then has been rarely recorded in publications and case reports. In the USA, extrapulmonary disease is seen in around 20-30% of tuberculosis patients, with the most common extrapulmonary manifestations being bone (30%), urinary tract (24%) and lymph node (13%) involvement. A high index of suspicion is required to make the diagnosis of appendicular tuberculosis, although it can cause damage to the appendix without other signs of localized disease. We report a case of a woman diagnosed with primary tuberculous appendicitis in a patient with human immunodeficiency virus (HIV), with evidence of extra-intestinal disease.

Transcriptomic signatures of progression to TB disease among close contacts in Brazil.

Approximately 5% of people infected with Mycobacterium tuberculosis progress to tuberculosis (TB) disease without preventive therapy. There is a need for a prognostic test to identify those at highest risk of incident TB, so that therapy can be targeted. We evaluated host blood transcriptomic signatures for progression to TB disease. Close contacts (≥4 hours exposure per week) of adult patients with culture-confirmed pulmonary TB were enrolled in Brazil. Investigation for incident, microbiologically-confirmed or clinically-diagnosed pulmonary or extra-pulmonary TB disease through 24 months of follow-up was symptom-triggered. Twenty previously validated blood TB transcriptomic signatures were measured at baseline by real-time quantitative PCR. Prognostic performance for incident TB was tested using receiver operating characteristic curve (ROC) analysis at 6, 9, 12, and 24 months of follow-up. Between June 2015 and June 2019, 1,854 close contacts were enrolled; Twenty-five progressed to incident TB, of whom 13 had microbiologically-confirmed disease. Baseline transcriptomic signature scores were measured in 1,789 close contacts. Prognostic performance for all signatures was best within 6 months of diagnosis. Seven signatures (Gliddon4, Suliman4, Roe3, Roe1, Penn-Nicholson6, Francisco2, and Rajan5) met the minimum World Health Organization target product profile (TPP) for a prognostic test through 6 months; three (Gliddon4, Rajan5, and Duffy9) through 9 months. None met the TPP threshold through 12 or more months of follow-up. Blood transcriptomic signatures may be useful for predicting TB risk within 9 months of measurement among TB-exposed contacts, to target preventive therapy administration.

Point-of-care ultrasound for diagnosing extrapulmonary TB.

<sec id="st1"><title>BACKGROUND</title>Despite the high morbidity and mortality globally, standard microbiologic diagnosis for TB requires laboratory infrastructure inaccessible in many resource-limited areas and may be insufficient for identifying extrapulmonary disease. Point-of-care (POC) ultrasound facilitates visualization of extrapulmonary manifestations, permitting laboratory-independent diagnosis, but its diagnostic utility remains unclear.</sec><sec id="st2"><title>METHODS</title>We conducted a systematic review of five online databases for studies reporting ultrasound findings among cases with and without extrapulmonary TB (EPTB). A minimum of two authors independently screened and reviewed each article, and extracted data elements of interest. We conducted a series of univariate meta-analyses using a random-effects model to calculate the pooled effect estimate and 95% confidence interval (CI) for each outcome: sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).</sec><sec id="st3"><title>RESULTS</title>Of 279 articles identified, 6 were included. There were 699 cases of EPTB among 1,633 participants. The pooled sensitivity estimate was 0.72 (95% CI 0.57-0.88). The pooled specificity estimate was 0.77 (95% CI 0.63-0.90). The pooled PPV and NPV estimates were respectively 0.67 (95% CI 0.47-0.87) and 0.85 (95% CI 0.77-0.93).</sec><sec id="st4"><title>CONCLUSION</title>POC ultrasound showed modest test characteristics for diagnosing EPTB, which may constitute an improvement over some currently available diagnostics.</sec>.

SHIFTing goals in cystic fibrosis—managing extrapulmonary disease in the era of CFTR modulator therapy; Proceedings of the International Shaping Initiatives and Future Trends (SHIFT) Symposium

AbstractBackgroundCystic fibrosis (CF) is a life‐shortening multisystem genetic disease. Although progressive pulmonary disease is the predominant cause of morbidity and mortality, improvements in treatment for CF‐related lung disease, with associated increase in longevity, have increased the prevalence of extrapulmonary manifestations1.MethodsTo discuss these issues, a multidisciplinary meeting of international leaders and experts in the field was convened in November 2021 at the Shaping Initiatives and Future Trends Symposium with the goal of highlighting shifting management paradigms in CF. The main topics covered were: (1) nutrition and obesity, (2) exocrine pancreas, (3) CF‐related diabetes, (4) CF liver disease, (5) CF‐related bone disease, and (6) post‐lung transplant care. This document summarizes the proceedings, highlighting the key priorities and important research questions that were discussed.ResultsImproved life expectancy, the advent of cystic fibrosis transmembrane conductance regulator modulators, and the increasing appreciation of the heterogeneity or spectrum of disease are leading to a shift in management for patients with cystic fibrosis. Care should be individualized to ensure that increased longevity is accompanied by improved extra‐pulmonary care and reduced morbidity.

Comparative Analysis of LSTM and BiLSTM in Image Detection Processing

Tuberculosis is an infectious disease and requires serious treatment. Extrapulmonary Tuberculosis is detected using a microscope. Currently it will take a long time because the fluid preparations are viewed in a microscope one by one carefully and in the fluid preparations there are 150 fields of vision. Examination for Extra Pulmonary Tuberculosis by culture takes between 1-2 weeks or even more. Examination by biopsy will take a long time because the fluid preparations are looked at carefully under the microscope one by one. The image of Tuberculosis is expressed if in the image there is a bacillus object in red, and it turns out that apart from the bacillus object there are other objects also in red. So that examinations for tuberculosis can be more efficient, examinations using computer technology are needed. This research aims to compare the Long Short-Term Memory (LSTM) and Bidirectional Long Short-Term Memory (BiLSTM) classification methods in the detection of extra-pulmonary tuberculosis disease to obtain better accuracy results. This research carried out HSI color space transformation, segmentation using global thresholding, feature extraction using 13 features based on shape and texture using the Correlation Based Feature Selection (CFS) feature selection method. The results show that BiLSTM has the best accuracy with a value of 88.40% at the number of features = 3, namely Short Run High Gray-Level Emphasis, Run Length Nonuniformity, Minor axis length, while LSTM produces an accuracy of 63.19% at the number of features = 5. BiLSTM is capable of detecting opposite features, meaning that BiLSTM can detect opposite features in data sequences and BiLSTM's ability to understand multiple contexts, so it tends to provide more accurate results in some data classification tasks.

The Known and Unknown "Knowns" of Human Susceptibility to Coccidioidomycosis.

Coccidioidomycosis occurs after inhalation of airborne spores of the endemic, dimorphic fungus, Coccidioides. While the majority of individuals resolve the infection without coming to medical attention, the fungus is a major cause of community-acquired pneumonia in the endemic region, and chronic pulmonary and extrapulmonary disease poses significant personal and economic burdens. This review explores the literature surrounding human susceptibility to coccidioidomycosis, including chronic pulmonary and extrapulmonary dissemination. Over the past century of study, themes have emerged surrounding factors impacting human susceptibility to severe disease or dissemination, including immune suppression, genetic susceptibility, sex, pregnancy, and genetic ancestry. Early studies were observational, frequently with small numbers of cases; several of these early studies are highly cited in review papers, becoming part of the coccidioidomycosis "canon". Specific genetic variants, sex, and immune suppression by TNF inhibitors have been validated in later cohort studies, confirming the original hypotheses. By contrast, some risk factors, such as ABO blood group, Filipino ancestry, or lack of erythema nodosum among black individuals, are repeated in the literature despite the lack of supporting studies or biologic plausibility. Using examination of historical reports coupled with recent cohort and epidemiology studies, evidence for commonly reported risk factors is discussed.

Latent class analysis of chest CT abnormalities to define subphenotypes in patients with MPO-ANCA-positive microscopic polyangiitis

BackgroundPatients with microscopic polyangiitis (MPA) and positive myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) may present with various abnormalities in chest computed tomography (CT). This study aimed to identify subphenotypes using latent class analysis (LCA) and to explore the relationship between the subphenotypes and clinical patterns, as well as compare the clinical characteristics of these subphenotypes in patients with MPO-ANCA-positive MPA (MPO-MPA). MethodsThe study identified subphenotypes using LCA based on chest CT findings in 178 patients with MPO-MPA and pulmonary involvement from June 2014 to August 2022. ResultsLCA identified 27 participants (15.2%) in class 1, 43 (24.1%) in class 2, 35 (19.7%) in class 3, and 73 (41.0%) in class 4. Class 1 was characterized by prominent inflammatory exudation, class 2 by fibrosis and architectural distortion, class 3 by predominantly bronchiectasis, and class 4 by lesions mixed with inflammation and fibrosis. Class 1 had the highest level of extrapulmonary disease activity, with 77.8% of patients experiencing diffuse alveolar hemorrhage. Class 2 had the lowest level of extrapulmonary disease activity, with 41.9% of patients showing usual interstitial pneumonia. Class 3 patients were more likely to have complications involving the ear, nose, and throat, as well as pulmonary infections before treatment, and they exhibited the best outcomes. The characteristics and outcomes of class 4 were intermediate among the four classes. ConclusionsThese findings suggest that bronchiectasis may represent a unique pattern of pulmonary involvement in MPO-MPA, highlighting the importance of screening for bronchiectasis in MPO-MPA and identifying optimal management strategies.

Abstract 2397: Double lung transplantation (DLT) in patients with stage IVA lung-limited non-small cell lung carcinoma (NSCLC): A case series

Abstract Introduction: Despite technological advances and expanded indications in lung transplantation, lung cancer constituted less than 0.1% of the lung transplantation over the past two decades. DLT may offer curative treatment for stage IVA NSCLC patients without extrapulmonary disease. We present a case series of consecutive NSCLC patients who underwent DLT. Methods: Patients treated with DLT were identified between 09/2021 and 09/2023 at Canning Thoracic Institute of Northwestern University. All patients had enrolled in the DLT registry aimed for lung-limited malignancies (DREAM) study (NCT05671887). Exclusion criteria include: presence of extrapulmonary disease and medical ineligibility for lung transplantation. All patients were followed up with computed tomography and tumor-informed ctDNA assay every 12 weeks. Results: Five patients with stage IVA NSCLC who underwent DLT were included. Three (60%) patients had invasive mucinous, and two (40%) had invasive non-mucinous adenocarcinoma histology. One of the two invasive non-mucinous patients had acinar, and the other had mixed lepidic, papillary, and acinar histology. Patients were aged 56-70; one (20%) was Asian, four (80%) were White, three (60%) were male, and two (40%) had a history of smoking. No patient had a past medical history of interstitial lung disease (ILD) or chronic obstructive pulmonary disease (COPD). All patients had high oxygen requirements before DLT due to cancer progression. Pre-transplant endobronchial ultrasound and evaluation of bilateral pneumonectomy lungs found no lymph node involvement (pN0). One patient had an epidermal growth factor receptor (EGFR) mutated cancer and but had failed relevant targeted therapy prior to transplant. All patients had disease progression on standard of care treatments with/without clinical trials. The indication for DLT was respiratory failure or refractory cancer for all patients. After DLT, one patient had a recurrence of the disease at 18 months with a 1cm solid nodule and was treated with stereotactic body radiotherapy (SBRT). Both original and recurrent tumors had invasive mucinous adenocarcinoma histology, negative PD-L1 expression, and the same JAK3 c.2174C&amp;gt;T, P725L mutated clone. It suggests that the recurrence likely arose from the original cancer. Transplant rejection did not occur in any of the cases. Following the transplant, there was no requirement for oxygen therapy for any patient. All patients are alive with 25, 15, 6, 3, and 1-month posttransplant follow-up. Conclusion: Five patients underwent DLT successfully without significant complications. Notably, one patient (25 months post-transplant) experienced cancer recurrence 18 months post-transplant and was effectively treated with SBRT. Ongoing DREAM study will continue to investigate the role of DLT in stage IVA NSCLC patients (especially in pN0). Citation Format: Young Kwang Chae, Tarik Demir, Liam Il-Young Chung, Carolyn Moloney, Rade Tomic, Ankit Bharat. Double lung transplantation (DLT) in patients with stage IVA lung-limited non-small cell lung carcinoma (NSCLC): A case series [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2397.

Definitive results of a prospective non-randomized phase 2 study on stereotactic body radiation therapy (sbrt) for medically inoperable lung and liver oligometastases from breast cancer

Background and purposeTo report mature results for local control and survival in oligometastatic (OM) breast cancer patients treated with stereotactic body radiotherapy (SBRT) on lung and/or liver lesions in a phase II trial. MethodsThis is a prospective non-randomized phase II trial (NCT02581670) which enrolled patients from 2015 to 2021. Eligibility criteria included: age > 18 years, ECOG 0–2, diagnosis of breast cancer, maximum of 4 lung/liver lesions (with a maximum diameter < 5 cm), metastatic disease confined to the lungs and liver or extrapulmonary or extrahepatic disease stable or responding to systemic therapy. The primary end-points were local control (LC) and treatment-related toxicities. The secondary end-points included overall survival (OS), distant metastasis-free survival (DMFS), time to next systemic therapy (TTNS), poly-progression free survival (PPFS). ResultsThe study included 64 patients with a total of 90 lesions treated with SBRT. LC at 1 and 2 years was 94.9 %, 91 % at 3 years. Median local control was not reached.Median OS was 16.5 months, OS at 1, 2 and 3 years was 87.5 %, 60.9 % and 51.9 %, respectively. Median DMFS was 8.3 months, DMFS at 1, 2 and 3 years was 38.1 %, 20.6 % and 16 % respectively. At univariate analysis, local response to SBRT was found to be statistically linked with better OS, DMFS and STFS. ConclusionSBRT is a safe and valid option in oligometastatic breast cancer patients, with very high rates of local control. An optimal selection of patients is likely needed to improve survival outcomes and reduce the rate of distant progression.

Nationwide Increasing Incidence of Nontuberculous Mycobacterial Diseases Among Adults in Denmark: Eighteen Years of Follow-Up

BackgroundThe epidemiology of nontuberculous mycobacteria (NTM) infections is not well described. In this study, we determined the incidence and prevalence of NTM infections and focused on social risk factors. Additionally, we described persons suffering from pulmonary and extrapulmonary NTM. Research questionWhat is the incidence and prevalence of NTM and what are the characteristics of the affected patients? MethodsThis is a nationwide retrospective register-based cohort study in Denmark. Adult patients with NTM diagnosis in the Danish national registers from 2000-2017 were classified as having either pulmonary or extrapulmonary NTM disease. ResultsWe identified 1,146 adults with an NTM diagnosis. 661 patients had pulmonary NTM of which 50.4% were male, while 485 had extrapulmonary NTM of which 59.6% were male. The median age (Interquartile range), was 66 years (18) and 57 years (32), respectively. The yearly incidence rate per 100,000 increased between 2000 and 2017 for both pulmonary (0.4 to 1.3) and extrapulmonary NTM (0.3 to 0.6). The annual prevalence per 100,000 increased from 0.4 to 3.5 for pulmonary and 0.3 to 1.0 for extrapulmonary NTM. The incidence rate increased with age. The incidence of pulmonary NTM was highest in 70+ year-olds (19.3 per 100,000). Compared to pulmonary NTM patients, extrapulmonary NTM patients were more likely to be employed and had a higher educational level. InterpretationThe prevalence of NTM disease in Denmark increased between 2000 and 2017. Pulmonary and extrapulmonary NTM patients are two distinct groups that differ in age, gender, education, and employment status. Increased suspicion of pulmonary NTM disease is warranted in the elderly after exclusion of more common lung infections.