Clinical Outcomes With and Without Plasma Exchange in the Treatment of Rapidly Progressive Interstitial Lung Disease Associated With Idiopathic Inflammatory Myopathy.

BACKGROUND/OBJECTIVE: A subset of patients with idiopathic inflammatory myopathy (IIM) develops highly fatal, rapidly progressive interstitial lung disease (RP-ILD). Treatment strategies consist of glucocorticoid and adjunctive immunosuppressive therapies. Plasma exchange (PE) is an alternative therapy, but its benefit is unclear. In this study, we aimed to determine whether PE benefited outcomes for patients with RP-ILD. METHODS: In this medical records review study, we compared baseline characteristics and clinical outcomes for 2 groups of patients with IIM-related RP-ILD: those who received and did not receive PE. RESULTS: Our cohort consisted of 15 patients, 9 of whom received PE. Baseline demographic characteristics and severity of lung, skin, and musculoskeletal disease between the 2 groups of patients were not significantly different. Five patients required mechanical ventilation (2, PE; 3, no PE). Plasma exchange was generally a third-line adjunctive treatment option. The PE group had a longer median (interquartile range) hospitalization (27.0 [23.0-36.0] days) than the non-PE group (12.0 [8.0-14.0] days) ( p = 0.02). There was a potential benefit in 30-day mortality improvement in those receiving PE (0% vs 33%, p = 0.14), with a statistically significant improvement in 2 important composite end points including 30-day mortality or need for lung transplant (0% vs 50%, p = 0.04) and 1-year mortality or need for lung transplant or hospital readmission for RP-ILD in those receiving PE (22% vs 83%, p = 0.04). CONCLUSIONS: Plasma exchange may be an underutilized, safe salvage therapy for patients with IIM-related RP-ILD when other immunosuppressive therapies fail.

The Role of Biofilms, Bacterial Phenotypes, and Innate Immune Response in Mycobacterium avium Colonization to Infection.

Mycobacterium avium complex (MAC), is known for colonizing and infecting humans following inhalation of the bacteria. MAC pulmonary disease is notoriously difficult to treat and prone to recurrence. Both the incidence and prevalence MAC pulmonary disease have been increasing globally. MAC is well known to form biofilms in the environment. In vitro, these biofilms have been shown to aid MAC in epithelial cell invasion, protect MAC from phagocytosis, and cause premature apoptosis in macrophages. In vivo, the system of interactions between MAC, biofilms and host macrophages is complex, difficult to replicate in vitro and in animal models, has not been fully characterized. Here we present a three-dimensional agent-based model of a lung airway to help understand how these interactions evolve in the first 14 days post-bacterial inhalation. We parameterized the model using published data and performed uncertainty analysis to characterize outcomes and parameters' effects on those outcomes. Model results show diverse outcomes, including wide ranges of macrophage recruitment levels, and bacterial loads and phenotype distribution. Though most bacteria are phagocytosed by macrophages and remain intracellular, there are also many simulations in which extracellular bacteria continue to drive the colonization and infection. Initial parameters dictating host immune levels, bacterial loads introduced to the airway, and biofilm conditions have significant and lasting impacts on the course of these results. Additionally, though macrophage recruitment is key for suppressing bacterial loads, there is evidence of significant excess recruitment that fail to impact bacterial numbers. These results highlight a need and identify a path for further exploration into the inhalation events in MAC infection. Early infection dynamics could have lasting impacts on the development of nodular bronchiectatic or fibrocavitary disease as well as inform possible preventative and treatment intervention targeting biofilm-macrophage interactions.

Fungal infection and colonization in lung transplant recipients with chronic lung allograft dysfunction.

BACKGROUND: The incidence and impact of de novo fungal airway colonization and infection in lung transplant recipients (LTRs) with known chronic lung allograft dysfunction (CLAD) has not been established. We aimed to determine the 1-year cumulative incidence and risk factors of de novo fungal colonization or infection in LTRs with CLAD and assess the impact of colonization or infection on post-CLAD survival. METHODS: Prospectively collected Toronto Lung Transplant Program database and chart review were used for double-LTRs who were diagnosed with CLAD from January 1, 2016 to January 1, 2020 and who were free of airway fungi within 1 year prior to CLAD onset. International Society for Heart and Lung Transplantation definitions were used to define clinical syndromes. Cox-Proportional Hazards Models were used for risk-factor analysis. Survival analysis could not be completed secondary to low number of fungal events; therefore, descriptive statistics were employed for survival outcomes. RESULTS: We found 186 LTRs diagnosed with CLAD meeting our inclusion criteria. The 1-year cumulative incidence for any fungal event was 11.8% (7.0% for infection and 4.8% for colonization). Aspergillus fumigatus was a causative pathogen in eight of 13 (61.5%) patients with infection and six of nine (66.7%) patients with colonization. No patients with fungal colonization post-CLAD developed fungal infection. Peri-CLAD diagnosis (3 months prior or 1 month after) methylprednisolone bolus (hazards ratio: 8.84, p = .001) increased the risk of fungal events. Most patients diagnosed with fungal infections (53.8%) died within 1-year of CLAD onset. CONCLUSION: De novo IFIs and fungal colonization following CLAD onset were not common. Fungal colonization did not lead to fungal infection. Methylprednisolone bolus was a significant risk factors for post-CLAD fungal events.

Epidemiology of candidemia in lung transplant recipients and risk factors for candidemia in the early posttransplant period in the absence of universal antifungal prophylaxis.

BACKGROUND: Lung transplant recipients are at increased risk of candidemia, especially in the early posttransplant period. However, the specific predisposing factors have not been established. The natural history of candidemia after lung transplantation, in the absence of universal antifungal prophylaxis, is not known. METHODS: We retrospectively examined the epidemiology of candidemia at any time posttransplant in patients who underwent lung transplantation at our center between 2016 and 2019. We undertook a case-control study and used logistic regression to evaluate the risk factors for candidemia during the first 30 days posttransplantation. RESULTS: During the study period 712 lung transplants were performed on 705 patients. Twenty-five lung transplant recipients (LTRs) (3.5%) experienced 31 episodes of candidemia. The median time to candidemia was 19.5 days (IQR 10.5-70.5), with 61.2% (n = 19) episodes of candidemia occurring within the first 30 days posttransplantation. Pretransplant hospitalization, posttransplant ECMO, and posttransplant renal replacement therapy were associated with an increased risk of candidemia in the first 30 days posttransplant. Of those with candidemia in the first 30 days, 31.2% died within 30 days of the index positive blood culture. Candidemia was associated with decreased survival within 30 days posttransplant. CONCLUSION: This study highlights the greatest risk period of lung transplant recipients for development of candidemia and identifies several factors associated with increased risk of candidemia. These findings will help guide future studies on antifungal prophylaxis.

Fungal Infection in Lung Transplantation.

Invasive fungal infections threaten lung transplant outcomes with high associated morbidity and mortality. Pharmacologic prophylaxis may be key to prevent posttransplant invasive fungal infections, but cost, adverse effects, and absorption issues are barriers to effective prophylaxis. Trends in fungal infection diagnostic strategies utilize molecular diagnostic methodologies to complement traditional histopathology and culture techniques. While lung transplant recipients are susceptible to a variety of fungal pathogens, Candida spp. and Aspergillus spp. infections remain the most common. With emerging resistant organisms and multiple novel antifungal agents in the research pipeline, it is likely that treatment strategies will continue to evolve.

Antifungal prophylaxis in lung transplant recipients: A systematic review and meta-analysis.

BACKGROUND: No consensus exists regarding optimal strategy for antifungal prophylaxis following lung transplant. OBJECTIVE: To review data regarding antifungal prophylaxis on the development of fungal infections. STUDY SELECTION/APPRAISAL: We searched MEDLINE, Embase, and Scopus for eligible articles through December 10, 2019. Observational or controlled trials published after January 1, 2001, that pertained to the prevention of fungal infections in adult lung recipients were reviewed independently by two reviewers for inclusion. METHODS: Of 1702 articles screened, 24 were included. Data were pooled using random effects model to evaluate for the primary outcome of fungal infection. Studies were stratified by prophylactic strategy, medication, and duration (short term < 6 months and long term ≥ 6 months). RESULTS: We found no difference in the odds of fungal infection with universal prophylaxis (49/101) compared to no prophylaxis (36/93) (OR 0.76, CI: 0.03-17.98; I2  = 93%) and preemptive therapy (25/195) compared to universal prophylaxis (35/222) (OR 0.91, CI: 0.06-13.80; I2  = 93%). The cumulative incidence of fungal infections within 12 months was not different with nebulized amphotericin (0.08, CI: 0.04-0.13; I2  = 87%) compared to systemic triazoles (0.07, CI: 0.03-0.11; I2  = 21%) (P = .65). Likewise, duration of prophylaxis did not impact the incidence of fungal infections (short term: 0.11, CI: 0.05-0.17; I2  = 89%; long term: 0.06, CI: 0.03-0.08; I2  = 51%; P = .39). CONCLUSIONS: We have insufficient evidence to support or exclude a benefit of antifungal prophylaxis.

Antifungal prophylaxis in lung transplant: A survey of United States' transplant centers.

BACKGROUND: Antifungal prophylaxis strategies for lung transplant recipients vary without consensus or standard of care. Our current study aims to identify antifungal prophylaxis practices in the United States. METHODS: From November 29, 2018, to February 15, 2019, we emailed surveys to medical directors of adult lung transplant centers. An alternate physician representative was approached if continued non-response after three survey attempts. Descriptive statistics were used to report findings. RESULTS: Forty-four of 62 (71.0%) eligible centers responded. All Organ Procurement and Transplantation Networks were represented. Only four (9.1%) centers used pre-transplant prophylaxis for prevention of tracheobronchitis (3 of 4) and invasive fungal disease (4 of 4). Thirty-nine of forty (97.5%) centers used post-transplant prophylaxis: 36 (90.0%) universal and 3 (7.5%) pre-emptive/selective prophylaxis. Most centers used nebulized amphotericin with a systemic agent (26 of 36, 72.2%). Thirty-two of thirty-six (88.9%) centers continued universal prophylaxis beyond the hospital setting. Duration of prophylaxis ranged from the post-transplant hospitalization to lifelong with most centers (25 of 36, 69.4%) discontinuing prophylaxis 6 months or less post-transplant. CONCLUSION: Most United States' lung transplant centers utilize a universal prophylaxis with nebulized amphotericin and a systemic triazole for 6 months or less post-transplant. Very few centers use pre-transplant antifungal prophylaxis.

Why do lung transplant patients discontinue triazole prophylaxis?

BACKGROUND: Lung transplant recipients are prone to invasive fungal infections prompting many transplant centers to use prolonged triazole antifungal prophylaxis. From a practical standpoint, it is unclear if lung transplant recipients are able to continue prolonged or lifelong prophylaxis without premature discontinuation from side effects, drug interactions, development of fungal disease, or medication cost. We examined the number of patients that are able to reach a prophylactic endpoint and understand the reasons for early termination. METHODS: We conducted a retrospective chart review of all lung and heart-lung transplant patients at Mayo Clinic Rochester from May 1, 2002 to December 31, 2017. Type, duration, and reason for discontinuation of triazole prophylaxis were examined. RESULTS: During the study period, 193 patients underwent lung or heart-lung transplantation. Itraconazole, voriconazole, and posaconazole were given to 180, 73, and 60 post-transplant patients, respectively. Providers switched itraconazole to another prophylactic antifungal medication for reasons other than prophylactic completion in 61.8% (126 out of 204) of exposure episodes; this was similar with voriconazole (68.8%, 53 out of 77, P = 0.41). Posaconazole was actively discontinued significantly less often (18.3%, 11 out of 60, P < 0.05). The most common reasons for discontinuing itraconazole were malabsorption (15.5% of exposure episodes) and concern for breakthrough fungal infection (10.2%). In comparison, the most common reason for voriconazole discontinuation was side effect or intolerance (54.5% of VR exposure episodes vs 9.8% of IT exposure episodes, P < 0.05). CONCLUSIONS: Itraconazole and posaconazole appeared to have fewer side effects prompting discontinuation than voriconazole, but itraconazole was discontinued more often because of malabsorption and clinical suspicion of fungal infections.

Duodenoscope reprocessing surveillance with adenosine triphosphate testing and terminal cultures: a clinical pilot study.

BACKGROUND AND AIMS: Recent reports of infectious outbreaks linked to duodenoscopes have led to proposals for duodenoscope surveillance culturing, which has inherent limitations. We aimed to assess the feasibility of real-time adenosine triphosphate (ATP) testing after manual cleaning and its ability to predict reprocessing adequacy, as determined by terminal duodenoscope cultures. METHODS: Clinically used duodenoscopes underwent reprocessing per current guidelines. After manual cleaning, ATP samples were obtained from the elevator, within the proximal biopsy port, and by flushing of the biopsy channel. After high-level disinfection (HLD), aerobic cultures of the elevator and biopsy channel were obtained using sterile technique. Duodenoscopes with any ATP sample ≥200 relative light units underwent repeated cycles of cleaning, ATP testing, HLD, and terminal culturing. RESULTS: Twenty clinically used duodenoscopes were included; 18 underwent a second reprocessing cycle, and 6 underwent a third reprocessing cycle because of detection of high ATP. After the initial reprocessing cycle, 12 of 20 (60%) duodenoscopes had positive culture results, most commonly yielding gram-negative bacilli (GNB, n = 11 from 9 duodenoscopes), and catalase-positive gram-positive cocci (CP-GPC, n = 7 from 7 duodenoscopes), suggesting staphylococcal organisms. Ambient environmental controls also showed GNB and CP-GPC growth. The overall sensitivity and specificity of ATP testing compared with terminal cultures were 30% and 53%, respectively. CONCLUSIONS: ATP sampling appears to correlate poorly with terminal culture results and cannot be recommended as a surrogate for terminal cultures. The performance and interpretation of cultures remains complicated by the potential recovery of environmental contaminants.

Reprocessing of single-use endoscopic variceal band ligation devices: a pilot study.

Background and study aims The preferred management of bleeding esophageal varices includes endoscopic band ligation. Endoscopic ligation devices (ELDs) are expensive and designed for single use, limiting their uptake in developing countries. We aimed to assess the efficacy of reprocessing ELDs using terminal microbial cultures and adenosine triphosphate (ATP) testing. Materials and methods ELDs were recovered after clinical use and their components (cap, handle, and cord) were subjected to reprocessing. This included manual cleaning, automated high-level disinfection (HLD), and drying with forced air. Using sterile technique, ELD components were sampled for ATP at three stages: before manual cleaning, after manual cleaning, and after HLD. Components were sent to an external laboratory for culturing. Cultures were interpreted as positive upon identification of Gram-negative bacilli. Results A total of 14 clinically used ELDs were studied, and 189 ATP tests and 41 cultures were evaluated. Overall, 95 % (39/41) of components and 86 % (12/14) of ELDs were culture-negative or did not yield Gram-negative bacilli. Two components (5 %; one handle and one cord) harbored Gram-negative bacilli in quantities of 1 CFU per component. There was no apparent correlation between ATP at any juncture of reprocessing and terminal cultures. Conclusions Reprocessing of ELDs is effective, resulting in infrequent and minimal microbial contamination. Microbial culturing can be used to ensure adequacy of ELD reprocessing if pursued. Until reusable ELDs are commercially available, continued efforts to better define the adequacy and long-term effects of reprocessing ELDs are needed.

Reliability and Validity of the Checklist for Early Recognition and Treatment of Acute Illness and Injury as a Charting Tool in the Medical Intensive Care Unit.

BACKGROUND: Resuscitation of critically ill patients is complex and potentially prone to diagnostic errors and therapeutic harm. The Checklist for early recognition and treatment of acute illness and injury (CERTAIN) is an electronic tool that aims to provide decision-support, charting, and prompting for standardization. This study sought to evaluate the validity and reliability of CERTAIN in a real-time Intensive Care Unit (ICU). MATERIALS AND METHODS: This was a prospective pilot study in the medical ICU of a tertiary care medical center. A total of thirty patient encounters over 2 months period were charted independently by two CERTAIN investigators. The inter-observer recordings and comparison to the electronic medical records (EMR) were used to evaluate reliability and validity, respectively. The primary outcome was reliability and validity measured using Cohen's Kappa statistic. Secondary outcomes included time to completion, user satisfaction, and learning curve. RESULTS: A total of 30 patients with a median age of 59 (42-78) years and median acute physiology and chronic health evaluation III score of 38 (23-50) were included in this study. Inter-observer agreement was very good (κ = 0.79) in this study and agreement between CERTAIN and the EMR was good (κ = 0.5). CERTAIN charting was completed in real-time that was 121 (92-150) min before completion of EMR charting. The subjective learning curve was 3.5 patients without differences in providers with different levels of training. CONCLUSIONS: CERTAIN provides a reliable and valid method to evaluate resuscitation events in real time. CERTAIN provided the ability to complete data in real-time.

Pulmonary, Hepatic, and Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Telomere Biology Disorders.

PURPOSE OF THE REVIEW: This study aimed to summarize evidence and provide consensus-based guidelines for management of transplantation in patients with telomere biology disorders (TBD). Specifically, this review focuses on clinical management of lung, liver, and bone marrow transplantation in TBD patients. RECENT FINDINGS: TBD patients have specific unique biological vulnerabilities such as T cell immunodeficiency, susceptibility to infections, hypersensitivity to chemotherapy and radiation, and cytopenias. Furthermore, multiple organ involvement at diagnosis makes clinical management especially challenging due to higher degree of organ damage, and stress-induced telomeric crisis. Sequential and combined organ transplants, development of novel radiation and alkylator-free conditioning regimen, and use of novel drugs for graft-versus-host disease prophylaxis are some of the recent updates in the field. Multidisciplinary management is essential to optimize transplant outcomes in patients with TBD. In this review, we provide consensus-based transplant management guidelines for clinical management of transplant in TBD.

Risk Factors for Early Fungal Disease in Solid Organ Transplant Recipients: A Systematic Review and Meta-analysis.

BACKGROUND: Invasive fungal infections are associated with high morbidity in solid organ transplant recipients. Risk factor modification may help with preventative efforts. The objective of this study was to identify risk factors for the development of fungal infections within the first year following solid organ transplant. METHODS: We searched for eligible articles through February 3, 2023. Studies published after January 1, 2001, that pertained to risk factors for development of invasive fungal infections in solid organ transplant were reviewed for inclusion. Of 3087 articles screened, 58 were included. Meta-analysis was conducted using a random-effects model to evaluate individual risk factors for the primary outcome of any invasive fungal infections and invasive candidiasis or invasive aspergillosis (when possible) within 1 y posttransplant. RESULTS: We found 3 variables with a high certainty of evidence and strong associations (relative effect estimate ≥ 2) to any early invasive fungal infections across all solid organ transplant groups: reoperation (odds ratio [OR], 2.92; confidence interval [CI], 1.79-4.75), posttransplant renal replacement therapy (OR, 2.91; CI, 1.87-4.51), and cytomegalovirus disease (OR, 2.97; CI, 1.78-4.94). Both posttransplant renal replacement therapy (OR, 3.36; CI, 1.78-6.34) and posttransplant cytomegalovirus disease (OR, 2.81; CI, 1.47-5.36) increased the odds of early posttransplant invasive aspergillosis. No individual variables could be pooled across groups for invasive candidiasis. CONCLUSIONS: Several common risk factors exist for the development of any invasive fungal infections in solid organ transplant recipients. Additional risk factors for invasive candidiasis and aspergillosis may be unique to the pathogen, transplanted organ, or both.

Adjusting diffusing capacity for anemia in patients undergoing allogeneic HCT: a comparison of two methodologies.

BACKGROUND: Diffusing capacity (DLCO) measurements are affected by hemoglobin. Two adjustment equations are used: Cotes (recommended by ATS/ERS) and Dinakara (used in the hematopoietic stem cell transplantation comorbidity index [HCT-CI]). It is unknown how these methods compare, and which is better from a prognostication standpoint. STUDY DESIGN: This is a retrospective cohort of 1273 adult patients who underwent allogeneic HCT, completed a pre-transplant DLCO and had a concurrent hemoglobin measurement. Non-relapse mortality was measured using competing risk analysis. RESULTS: Patients had normal spirometry (FEV1 99.7% [IQR: 89.4-109.8%; FVC 100.1% [IQR: 91.0-109.6%] predicted), left ventricular ejection fraction (57.2[6.7]%) and right ventricular systolic pressure (30.1[7.0] mmHg). Cotes-DLCO was 85.6% (IQR: 76.5-95.7%) and Dinakara-DLCO was 103.6% (IQR: 90.7-117.2%) predicted. For anemic patients (Hb<10g/dL), Cotes-DLCO was 84.2% (IQR: 73.9-94.1%) while Dinakara-DLCO 111.0% (97.3-124.7%) predicted. Cotes-DLCO increased HCT-CI score for 323 (25.4%) and decreased for 4 (0.3%) patients. Cotes-DLCO was superior for predicting non-relapse mortality: for both mild (66-80% predicted, HR 1.55 [95%CI: 1.26-1.92, p < 0.001]) and moderate (<65% predicted, HR 2.11 [95%CI: 1.55-2.87, p<0.001]) impairment. In contrast, for Dinakara-DLCO, only mild impairment (HR 1.69 [95%CI 1.26-2.27, p < 0.001]) was associated with lower survival while moderate impairment was not (HR 1.44 [95%CI: 0.64-3.21, p = 0.4]). In multivariable analyses, after adjusting for demographics, hematologic variables, cardiac function and FEV1, Cotes-DLCO was predictive of overall survival at 1-year (OR 0.98 [95%CI: 0.97-1.00], p = 0.01), but Dinakara-DLCO was not (OR 1.00 [95%CI: 0.98-1.00], p = 0.20). CONCLUSION: The ERS/ATS recommended Cotes method likely underestimates DLCO in patients with anemia, whereas the Dinakara (used in the HCT-CI score) overestimates DLCO. The Cotes method is superior to the Dinakara method score in predicting overall survival and relapse-free survival in patients undergoing allogeneic HCT.

Multiparameter immunoprofiling for the diagnosis and differentiation of progressive versus nonprogressive nontuberculous mycobacterial lung disease-A pilot study.

Clinical prediction of nontuberculous mycobacteria lung disease (NTM-LD) progression remains challenging. We aimed to evaluate antigen-specific immunoprofiling utilizing flow cytometry (FC) of activation-induced markers (AIM) and IFN-γ enzyme-linked immune absorbent spot assay (ELISpot) accurately identifies patients with NTM-LD, and differentiate those with progressive from nonprogressive NTM-LD. A Prospective, single-center, and laboratory technician-blinded pilot study was conducted to evaluate the FC and ELISpot based immunoprofiling in patients with NTM-LD (n = 18) and controls (n = 22). Among 18 NTM-LD patients, 10 NTM-LD patients were classified into nonprogressive, and 8 as progressive NTM-LD based on clinical and radiological features. Peripheral blood mononuclear cells were collected from patients with NTM-LD and control subjects with negative QuantiFERON results. After stimulation with purified protein derivative (PPD), mycobacteria-specific peptide pools (MTB300, RD1-peptides), and control antigens, we performed IFN-γ ELISpot and FC AIM assays to access their diagnostic accuracies by receiver operating curve (ROC) analysis across study groups. Patients with NTM-LD had significantly higher percentage of CD4+/CD8+ T-cells co-expressing CD25+CD134+ in response to PPD stimulation, differentiating between NTM-LD and controls. Among patients with NTM-LD, there was a significant difference in CD25+CD134+ co-expression in MTB300-stimulated CD8+ T-cells (p <0.05; AUC-ROC = 0.831; Sensitivity = 75% [95% CI: 34.9-96.8]; Specificity = 90% [95% CI: 55.5-99.7]) between progressors and nonprogressors. Significant differences in the ratios of antigen-specific IFN-γ ELISpot responses were also seen for RD1-nil/PPD-nil and RD1-nil/anti-CD3-nil between patients with nonprogressive vs. progressive NTM-LD. Our results suggest that multiparameter immunoprofiling can accurately identify patients with NTM-LD and may identify patients at risk of disease progression. A larger longitudinal study is needed to further evaluate this novel immunoprofiling approach.

Custom Silicone Y-Stents for the Management of Anastomotic Stenosis in Lung Transplant Recipients.

BACKGROUND: Airway stenting may be needed to manage anastomotic complications in lung transplant recipients. Conventional stenting strategies may be inadequate due to anatomic variations between the recipient and donor or involvement of both the anastomosis and lobar bronchi. METHODS: We investigated the efficacy of 3D-designed patient-specific silicone Y-stents in managing this scenario. 9 patients with complex airway stenosis underwent custom stent insertion after either failing traditional management strategies or having anatomy not suitable for conventional stents. CT images were uploaded to stent design software to make a virtual stent model. 3D printing technology was then used to make a mold for the final silicone stent which was implanted via rigid bronchoscopy. Forced expiratory volume in one second (FEV1) was measured pre- and post-stent placement. RESULTS: 78% of patients experienced an increase in their FEV1 after stent insertion, (p = 0.001, 0.02 at 30 and 90 days respectively). Unplanned bronchoscopies primarily occurred due to mucous plugging. 2 patients had sufficient airway remodeling allowing for stent removal. CONCLUSIONS: Personalized 3D-designed Y-stents demonstrate promising results for managing complicated airway stenosis, offering improved lung function and potential long-term benefits for lung transplant recipients.

Agent-based model indicates chemoattractant signaling caused by Mycobacterium avium biofilms in the lung airway increases bacterial loads by spatially diverting macrophages.

Incidence and prevalence of MAC infections are increasing globally, and reinfection is common. Thus, MAC infections present a significant public health challenge. We quantify the impact of MAC biofilms and repeated exposure on infection progression using a computational model of MAC infection in lung airways. MAC biofilms aid epithelial cell invasion, cause premature macrophage apoptosis, and limit antibiotic efficacy. In this computational work we develop an agent-based model that incorporates the interactions between bacteria, biofilm, and immune cells. In this computational model, we perform virtual knockouts to quantify the effects of the biofilm sources (deposited with bacteria vs. formed in the airway), and their impacts on macrophages (inducing apoptosis and slowing phagocytosis). We also quantify the effects of repeated bacterial exposures to assess their impact on infection progression. Our simulations show that chemoattractants released by biofilm-induced apoptosis bias macrophage chemotaxis towards pockets of infected and apoptosed macrophages. This bias results in fewer macrophages finding extracellular bacteria, allowing the extracellular planktonic bacteria to replicate freely. These spatial macrophage trends are further exacerbated with repeated deposition of bacteria. Our model indicates that interventions to abrogate macrophages' apoptotic responses to bacterial biofilms and/or reduce frequency of patient exposure to bacteria will lower bacterial load, and likely overall risk of infection.

Risk factors and outcomes of non-tuberculous mycobacteria infection in lung transplant recipients: A systematic review and meta-analysis.

BACKGROUND: Patients with structural lung disease and immunocompromised status are at increased risk of pulmonary non-tuberculous mycobacteria (NTM) infection. However, literature on NTM in lung transplant recipients (LTR) is limited. We sought to systematically review the literature and perform a meta-analysis to examine associations with NTM disease and isolation in LTRs and their influence on mortality and chronic lung allograft dysfunction (CLAD). METHODS: A literature search of MEDLINE and Embase was performed on February 23, 2022. NTM disease was defined according to international guidelines. Isolation was defined as any growth of NTM in culture. Odds ratios (OR) were pooled for risk factors of NTM disease or isolation, and hazard ratios (HR) were pooled for mortality or CLAD. RESULTS: Eleven studies totaling 3,371 patients were eligible for inclusion, 10 of which underwent meta-analysis. Cystic fibrosis (OR 1.84, 95% confidence interval [CI] 1.03-3.30; I2 = 0%) and pre-transplant NTM isolation (OR 2.40, 95% CI 1.20-4.83; I2 = 0%) were associated with NTM disease. Only male sex was associated with NTM isolation (OR 1.45, 95% CI 1.01-2.10; I2 = 0%). NTM disease was associated with increased mortality (HR 2.69, 95% CI 1.70-4.26; I2 = 0%) and CLAD (HR 2.11, 95% CI 1.03-4.35; I2 = 44%). NTM isolation was not associated with mortality in pooled analysis or CLAD in 1 included study. CONCLUSIONS: NTM disease, but not isolation, is associated with worse outcomes. Several factors were associated with development of NTM disease, including cystic fibrosis and pretransplant NTM isolation. Strategies to optimize prevention and treatment of NTM disease in lung transplant recipients are needed.