Peikert, Tobias

Introduction Bronchoscopic lung volume reduction with endobronchial valves (EBV) is an effective procedure for patient with severe emphysema to improve lung function, exercise tolerance, dyspnoea and quality of life. Optimisation of patient and treatment lobe selection is essential for successful EBV outcomes. While clinical selection criteria are rigorous, many centres use a multidisciplinary team and rely on previous clinical experience for the selection process. To aid objective clinical decision making, we present a mathematical model to facilitate patient and target lobe selection. Methods A multidisciplinary team reviewed quantitative high-resolution computed tomography (HRCT) analysis from 119 patients to select candidates for EBV and to select a treatment lobe. Two logistic regression models, (1) candidacy for EBV placement and (2) target-lobe selection, were developed based on the normalised distributions of the four quantitative HRCT variables (fissure completeness score, per cent of voxel density with HU < −910 and HU < −950, and lobar volumes) across all five lung lobes. An external cohort of 50 patients (25 candidates and 25 non-candidates) was used to validate the prediction model. Results Performance measures of the training cohort demonstrated an area under the curve (AUC) of 0.91, accuracy of 81%, sensitivity of 93% and specificity of 78% compared with the multidisciplinary teams’ target lobe selection. The validation cohort demonstrated an AUC of 0.89, accuracy of 84%, sensitivity of 88% and specificity of 83% compared with the multidisciplinary team decision making. Conclusions Endobronchial valve lung volume reduction remains a potent palliative measure to improve quality of life in patients with hyperinflated emphysema. Our model for target lobe selection harnesses the multidisciplinary experience at a tertiary care centre to objectively select candidates and target lobes to assist clinicians’ decision making. Future studies investigating prediction of lobar collapse and functional improvement after target lobe selection using our model are needed.

Abstract Non-tubercular mycobacteria (NTM) present a serious challenge in managing lung transplant candidates and recipients. Pretransplant NTM isolation has been associated with post-transplant NTM infection and significantly increased mortality risk. Strategies for managing pre-transplant NTM isolation vary widely in clinical practice. We present a 35-year-old lung transplant candidate from a tuberculosis-endemic country with severe pulmonary hypertension and Eisenmenger Syndrome due to unrepaired atrial septal defect, who underwent bilateral lung transplantation. Two years prior to transplant, she was successfully treated for pulmonary tuberculosis with six months of an unknown regimen in her home country. After moving to the U.S., she received M. tuberculosis (MTB) clearance from her state tuberculosis board, with three negative sputum samples six months prior to transplant. During her transplant evaluation, multi-drug-resistant M. fortuitum complex was isolated from one mycobacterial sputum culture. There was no clinical or radiographic evidence of active lung infection, and no targeted therapies were added. Standard peri-transplant antibiotics (vancomycin, cefepime, and caspofungin) were given. The patient received basilixamab for induction immunosuppression, and tacrolimus, mycophenolate mofetil, and prednisone for maintenance immunosuppression. Explant pathology showed necrotizing granuloma in the right upper lobe with acid-fast bacilli (AFB). The differential diagnosis included non-viable MTB, viable MTB despite prior clearance, or M. fortuitum. Three bronchoscopy washings were obtained in the first week post-transplant and returned negative for MTB by PCR, AFB stain, and culture. In collaboration with the Mycobacteriology laboratory, broad-range PCR testing was performed on the formalin-fixed paraffin-embedded samples from the explanted right lung, which was positive for MTB complex DNA. In total, the patient completed six sputum samples within the year pre-transplant and six respiratory samples within a month post-transplant, all of which returned negative for MTB by PCR, AFB stain, and culture. Blood flow cytometric (FC) immunoprofiling with mycobacterial antigens and controls was conducted (Escalante et al. 2015). The patient's FC antigen-specific activated T-cell profiling was consistent with a reduced risk of latent TB infection (FC CD4+ CD25+CD134+ T-cells (RD1-peptides-nil) = 0.19%). T-cell reactivity to MTB300 and PPD antigens suggested prior MTB, NTM, and/or BCG vaccination exposures. She progressed well without any preventive therapy for LTBI. FC immunoprofiling one year after transplantation showed similar results. She continues to have good pulmonary function and quality of life in her second-year post-transplant without evidence of NTM or MTB infection. Escalante P, et al. Combinatorial Immunoprofiling in Latent Tuberculosis Infection. Am J Respir Crit Care Med. 2015;192(5):605-17. PMCID: PMC4595688.

Abstract RATIONALE: Understanding co-isolation patterns between fungi and other potentially pathogenic microorganisms in the airways of bronchiectasis patients is important for uncovering possible microbial interactions and informing treatment. Although numerous organisms have been identified in respiratory cultures, the specific patterns of their co-isolation are underexplored. OBJECTIVES: To examine the patterns of co-isolation between fungi and bacteria or mycobacteria in respiratory samples from patients with bronchiectasis across a large national health system. METHODS: We reviewed 58,170 respiratory culture tests from 8,194 patients with bronchiectasis (identified using ICD-10-CM codes J47.0, J47.1, and J47.9) across Mayo Clinic. These tests were analyzed for fungal, bacterial, and mycobacterial growth, focusing on co-isolation from the same sample. Chi-square statistics were used to compute p-values. RESULTS: Of all 18,983 samples cultured for fungi, 59% were positive. Of these, 72% yielded yeasts and 40% molds. Among the 11,372 samples cultured for both fungi and bacteria, 681 (6%) showed co-isolation, representing 54% of positive bacterial cultures. The odds of bacterial co-isolation with fungi were 1.4 (95% CI: 1.3-1.6; p &lt; 0.01), driven by yeasts (OR: 1.5, 95% CI: 1.3-1.7; p &lt; 0.01), rather than molds (OR: 1.0, 95% CI: 0.9-1.2; p = 0.8). Pseudomonas species, the most common bacterial isolate, had a higher likelihood of co-isolation with fungi (OR: 1.6, 95% CI: 1.3-1.9; p &lt; 0.01), particularly yeasts (OR: 1.6, 95% CI: 1.4-2.0; p &lt; 0.01). Molds, including those from genera such as aspergillus and penicillium, did not show a significant association with the isolation of pseudomonas. On the other hand, among the 15,859 samples cultured for both fungi and mycobacteria, 1352 (9%) showed co-isolation, representing 62% of positive mycobacterial cultures. Odds of co-isolation were 1.7 (95% CI: 1.5-1.8; p &lt; 0.01). Molds showed a stronger association with isolation of mycobacteria (OR: 1.7, 95% CI: 1.5-1.9; p &lt; 0.01) compared to bacteria, while yeasts also had elevated odds (OR: 1.4, 95% CI: 1.2-1.5). CONCLUSIONS: Distinct patterns of fungal co-isolation with bacteria and mycobacteria have been observed in bronchiectasis, which may influence key aspects of the disease, such as inflammation and mucociliary dysfunction. Advanced metagenomic and immunoprofiling techniques could provide deeper insights into these co-isolation patterns while considering other factors like clinical demographics, previous antibiotic exposure, and disease severity. Understanding whether altering the mycobiome could modify these aspects and improve outcomes remains an important avenue for research.

Abstract Rationale Fibrosing mediastinitis (FM) is an uncommon fibroinflammatory condition without established or effective medical therapies. Infiltrating B lymphocytes are commonly present, and progressive fibrosis compromises mediastinal structures, including blood vessels and airways, resulting in significant morbidity and mortality. Objective To evaluate the benefits and side effects of rituximab in patients with progressive and symptomatic FM. Methods We treated 22 patients (median age, 35 yr; range, 15–68 yr; 45% female) with metabolically active, progressive FM with rituximab on an off-label basis. Additionally, patients were administered pneumocystis and antifungal prophylaxis when immunosuppressed with rituximab. Modeling of longitudinal treatment response based on changes in relative lesion volume from baseline was performed retrospectively using functional data analysis, and time-to-event modeling was performed to estimate treatment response rates based on a &gt;30% reduction in pretreatment volume. The primary endpoints were lack of disease progression and change in mediastinal lesion volume on computed tomography (evaluated retrospectively). Results No patient experienced disease progression after rituximab therapy. Median clinical follow-up was 42 months (range, 7–94 mo) and imaging follow-up 21 months (range, 7–62 mo). A total of 82% of patients had confirmed histoplasmosis-associated FM. After rituximab treatment, a 49.6% (95% confidence interval, 17.5–64.4%) mean estimated decrease in pretreatment lesion volume was observed at 24 months. The estimated objective treatment response rate was 47.9% (95% confidence interval, 26.7–70.3%). Conclusions This observational study suggests that rituximab is a well tolerated and potentially effective therapy in a cohort of patients with symptomatic and progressive FM.