Faculty Bibliography

RATIONALE/BACKGROUND:Lower airway enrichment with oral commensals has been previously associated with grade 3 severe primary graft dysfunction (PGD) after lung transplantation (LT). We aimed to determine whether this dysbiotic signature is present across all PGD severity grades, including milder forms, and whether it is associated with a distinct host inflammatory endotype. METHODS:Lower airway samples from 96 LT recipients with varying degrees of PGD were used to evaluate the lung allograft microbiota via 16S rRNA gene sequencing. Bronchoalveolar lavage (BAL) cytokine concentrations and cell differential percentages were compared across PGD grades. In a subset of samples, we evaluated the lower airway host transcriptome using RNA sequencing methods. RESULTS:Differential analyses demonstrated lower airway enrichment with supraglottic-predominant taxa (SPT) in both moderate and severe PGD. Dirichlet Multinomial Mixtures (DMM) modeling identified two distinct microbial clusters. A greater percentage of subjects with moderate-severe PGD were identified within the dysbiotic cluster (C-SPT) than within the no PGD group (48 and 29%, respectively) though this difference did not reach statistical significance (p=0.06). PGD severity associated with increased BAL neutrophil concentration (p=0.03) and correlated with BAL concentrations of MCP-1/CCL2, IP-10/CXCL10, IL-10, and TNF-α (p<0.05). Furthermore, microbial signatures of dysbiosis correlated with neutrophils, MCP-1/CCL-2, IL-10, and TNF-α (p<0.05). C-SPT exhibited differential expression of TNF, SERPINE1 (PAI-1), MPO, and MMP1 genes and upregulation of MAPK pathways, suggesting that dysbiosis regulates host signaling to promote neutrophilic inflammation. CONCLUSIONS:Lower airway dysbiosis within the lung allograft is associated with a neutrophilic inflammatory endotype, an immune profile commonly recognized as the hallmark for PGD pathogenesis. This data highlights a putative role for lower airway microbial dysbiosis in the pathogenesis of this syndrome.

New methods and technologies within the field of lung biology are beginning to shed new light into the microbial world of the respiratory tract. Long considered to be a sterile environment, it is now clear that the human lungs are frequently exposed to live microbes and their by-products. The nature of the lung microbiome is quite distinct from other microbial communities inhabiting our bodies such as those in the gut. Notably, the microbiome of the lung exhibits a low biomass and is dominated by dynamic fluxes of microbial immigration and clearance, resulting in a bacterial burden and microbiome composition that is fluid in nature rather than fixed. As our understanding of the microbial ecology of the lung improves, it is becoming increasingly apparent that certain disease states can disrupt the microbial-host interface and ultimately affect disease pathogenesis. In this Review, we provide an overview of lower airway microbial dynamics in health and disease and discuss future work that is required to uncover novel therapeutic targets to improve lung health.

Variations in the airway microbiome are associated with inflammatory responses in the lung and pulmonary disease outcomes. Regional changes in microbiome composition could have spatial effects on the metabolic environment, contributing to differences in the host response. Here, we profiled the respiratory microbiome (metagenome/metatranscriptome) and metabolome of a patient cohort, uncovering topographical differences in microbial function, which were further delineated using isotope probing in mice. In humans, the functional activity of taxa varied across the respiratory tract and correlated with immunomodulatory metabolites such as glutamic acid/glutamate and methionine. Common oral commensals, such as Prevotella, Streptococcus, and Veillonella, were more functionally active in the lower airways. Inoculating mice with these commensals led to regional increases in several metabolites, notably methionine and tyrosine. Isotope labeling validated the contribution of Prevotella melaninogenica in generating specific metabolites. This functional characterization of microbial communities reveals topographical changes in the lung metabolome and potential impacts on host responses.

The benefits of bilateral lung transplantation (BLT) versus single lung transplantation (SLT) are still debated. One impediment to clinical recommendations is that BLT vs. SLT advantages may vary based on underlying disease. Since both options are clinically tenable in patients with emphysema, we conducted a comprehensive assessment of lung allograft survival in this population. Using U.S. registry data, we studied time to all-cause allograft failure in 8,092 patients 12 years or older transplanted from 2006 to 2022, adjusting for recipient, donor, and transplant factors by inverse propensity weighting. Median allograft survival was 6.6 years in BLT compared to 5.3 years in SLT, a 25% risk-adjusted survival advantage of _0.81.3_1.8 years. Risk-adjusted bilateral survival advantages varied between 0.9 and 2.4 years across eleven subgroups. Median allograft survival in BLT was 1.2 years greater than right SLT and 2.0 years greater than left SLT. During the 16-year study period, allograft survival steadily improved for BLT but not for SLT. Although the 25% BLT survival advantage pre-dated the pandemic, COVID-19 may have contributed to an apparent SLT survival decline. Recognizing the possible influence of residual confounding due to selection biases, these findings may aid offer decision-making when both donor lungs are available.

Tacrolimus is highly effective at preventing allograft rejection and prolonging survival after lung transplantation. However, erratic pharmacokinetics may limit efficacy and predispose to greater adverse effects. We conducted a prospective, open-label trial of lung transplant recipients who underwent early conversion (within 30 days) to LCP tacrolimus (LCPT, n = 40) and compared first-year outcomes to an historical control of patients who remained on immediate-release tacrolimus (IRT, n = 24). Subjects were converted 1:1 from IRT to LCPT. The first dose of LCPT overlapped with the last morning dose of IRT. Conversion to LCPT occurred at a median of 17.5 [IQR 12-25] days. The conversion dose ratio was 1.0 mg:mg [IQR 0.75-1.50] at 14 days. At 1 year, there were no differences between LCPT and IRT in the incidence of biopsy-proven (12.5% vs. 25.0%, p = 0.30) or clinically treated (20.0% vs. 25.0%, p = 0.64) acute cellular rejection. However, the severity of any biopsy-proven rejection was significantly higher in the IRT cohort (27.5% vs. 54.2%, p = 0.03). Although not achieving statistical significance, de novo donor-specific antibodies were more commonly observed in the LCPT group (20.0% vs. 4.2%, p = 0.14). Despite this, the incidence of antibody-mediated rejection (7.5% vs. 0.0%, p = 0.29) and early-onset chronic lung allograft dysfunction (7.5% vs. 9.1%, p = 1.00) were similar. The incidence of chronic kidney disease stage 4 or greater at 1-year was similar (7.5% vs. 12.5%, p = 0.66). In conclusion, early conversion to LCPT was feasible and similarly efficacious to IRT in a cohort of lung transplant recipients. Trial Registration: ClinicalTrials.gov identifier: NCT04420195.

OBJECTIVE:We provide evidence-based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease. METHODS:We developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and strength of each recommendation. RESULTS:Fifteen recommendations were developed. For screening people with these SARDs at risk for ILD, we conditionally recommend pulmonary function tests (PFTs) and high-resolution computed tomography of the chest (HRCT chest); conditionally recommend against screening with 6-minute walk test distance (6MWD), chest radiography, ambulatory desaturation testing, or bronchoscopy; and strongly recommend against screening with surgical lung biopsy. We conditionally recommend monitoring ILD with PFTs, HRCT chest, and ambulatory desaturation testing and conditionally recommend against monitoring with 6MWD, chest radiography, or bronchoscopy. We provide guidance on ILD risk factors and suggestions on frequency of testing to evaluate for the development of ILD in people with SARDs. CONCLUSION/CONCLUSIONS:This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the screening and monitoring of ILD in people with SARDs.

OBJECTIVE:We provide evidence-based recommendations regarding the treatment of interstitial lung disease (ILD) in adults with systemic autoimmune rheumatic diseases (SARDs). METHODS:We developed clinically relevant population, intervention, comparator, and outcomes questions. A systematic literature review was then performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A panel of clinicians and patients reached consensus on the direction and strength of the recommendations. RESULTS:Thirty-five recommendations were generated (including two strong recommendations) for first-line SARD-ILD treatment, treatment of SARD-ILD progression despite first-line ILD therapy, and treatment of rapidly progressive ILD. The strong recommendations were against using glucocorticoids in systemic sclerosis-ILD as a first-line ILD therapy and after ILD progression. Otherwise, glucocorticoids are conditionally recommended for first-line ILD treatment in all other SARDs. CONCLUSION/CONCLUSIONS:This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the treatment of ILD in people with SARDs.

OBJECTIVE:We provide evidence-based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease. METHODS:We developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and strength of each recommendation. RESULTS:Fifteen recommendations were developed. For screening people with these SARDs at risk for ILD, we conditionally recommend pulmonary function tests (PFTs) and high-resolution computed tomography of the chest (HRCT chest); conditionally recommend against screening with 6-minute walk test distance (6MWD), chest radiography, ambulatory desaturation testing, or bronchoscopy; and strongly recommend against screening with surgical lung biopsy. We conditionally recommend monitoring ILD with PFTs, HRCT chest, and ambulatory desaturation testing and conditionally recommend against monitoring with 6MWD, chest radiography, or bronchoscopy. We provide guidance on ILD risk factors and suggestions on frequency of testing to evaluate for the development of ILD in people with SARDs. CONCLUSION/CONCLUSIONS:This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the screening and monitoring of ILD in people with SARDs.

OBJECTIVE:We provide evidence-based recommendations regarding the treatment of interstitial lung disease (ILD) in adults with systemic autoimmune rheumatic diseases (SARDs). METHODS:We developed clinically relevant population, intervention, comparator, and outcomes questions. A systematic literature review was then performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A panel of clinicians and patients reached consensus on the direction and strength of the recommendations. RESULTS:Thirty-five recommendations were generated (including two strong recommendations) for first-line SARD-ILD treatment, treatment of SARD-ILD progression despite first-line ILD therapy, and treatment of rapidly progressive ILD. The strong recommendations were against using glucocorticoids in systemic sclerosis-ILD as a first-line ILD therapy and after ILD progression. Otherwise, glucocorticoids are conditionally recommended for first-line ILD treatment in all other SARDs. CONCLUSION/CONCLUSIONS:This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the treatment of ILD in people with SARDs.