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BACKGROUND: Pulmonary antibody-mediated rejection is still a challenging diagnosis as C4d immunostaining has poor sensitivity. Previous studies have indicated that the phosphorylated S6 ribosomal protein, a component of the mammalian target of rapamycin (mTOR) pathway, is correlated with de novo donor-specific antibodies in lung transplantation. The objective of this study was to evaluate the phosphorylation of S6 ribosomal protein as a surrogate for antibody-mediated rejection diagnosis in lung transplant patients. METHODS: This multicentre retrospective study analyzed transbronchial biopsies from 216 lung transplanted patients, 114 with antibody-mediated rejection and 102 without (19 with acute cellular rejection, 17 with ischemia/reperfusion injury, 18 with infection, and 48 without post-transplant complications). Immunohistochemistry was used to quantify phosphorylated S6 ribosomal protein expression in macrophages, endothelium, epithelium, and inter-pathologist agreement was assessed. RESULTS: Median phosphorylated S6 ribosomal protein expression values were higher in antibody-mediated rejection cases than in controls for all cell components, with the highest sensitivity in macrophages (0.9) and the highest specificity in endothelial expression (0.8). The difference was mainly significant in macrophages compared to other post-lung transplantation complications. Inter-pathologist agreement was moderate for macrophages and endothelium, with higher agreement when phosphorylated S6 ribosomal protein expression was dichotomized into positive/negative. The inclusion of phosphorylated S6 ribosomal protein in the diagnostic algorithm could have increased antibody-mediated rejection certainty levels by 25%. CONCLUSIONS: The study supports the role of the mTOR pathway in antibody-mediated rejection-related graft injury and suggests that tissue phosphorylation of S6 ribosomal protein could be a useful surrogate for a more accurate pathological diagnosis of lung antibody-mediated rejection.
Assuntos
Anticorpos , Proteínas Ribossômicas , Humanos , Estudos Retrospectivos , Pulmão/metabolismo , Sirolimo , Serina-Treonina Quinases TOR/metabolismoRESUMO
BACKGROUND: Restless legs syndrome (RLS) is a sensorimotor disorder that is prevalent in chronic inflammatory conditions. RLS prevalence, risk factors, and impact on sleep in CF have not been extensively characterized to date. METHODS: An initial cohort was examined, including 75 persons with CF (PwCF) and 75 control subjects, to look at the prevalence and severity of RLS. A second validation cohort of 191 PwCF was then enrolled from two CF centers to examine risk factors for RLS. A diagnosis of RLS was made according to the International RLS Study Group (IRLSSG) criteria. Sleep quality was identified using the Pittsburgh sleep quality index (PSQI). Epworth sleepiness scale (ESS) was used to measure daytime sleepiness. We then analyzed laboratory and clinical risk factors and sleep symptoms for potential risk factors for RLS. RESULTS: In the initial cohort, 36 % of PwCF had RLS, and 9 % of these had significant RLS. In contrast, only 15 % of controls had RLS, and none had significant RLS. In the second larger validation cohort with 191 subjects, a comparable prevalence of RLS was identified. Higher hemoglobin A1c, use of SSRI/SNRI medications, worse PSQI and ESS sleep quality scores, lower lung function, and higher antibiotic usage were significantly associated with a diagnosis of RLS. By multivariate multinominal logistic regression analysis, higher HbA1c and worse PSQI global sleep quality scores were independent predictors of significant RLS. CONCLUSIONS: RLS is highly prevalent in CF. Higher HbA1c and poor sleep quality, signified by higher PSQI, were each independent predictors of RLS.
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Fibrose Cística , Síndrome das Pernas Inquietas , Adulto , Humanos , Qualidade do Sono , Hemoglobinas Glicadas , Síndrome das Pernas Inquietas/diagnóstico , Síndrome das Pernas Inquietas/epidemiologia , Síndrome das Pernas Inquietas/etiologia , Fibrose Cística/complicações , Fibrose Cística/epidemiologia , Índice de Gravidade de Doença , PrevalênciaRESUMO
BACKGROUND: It is unclear whether continuing anti-fibrotic therapy until the time of lung transplant increases the risk of complications in patients with idiopathic pulmonary fibrosis. OBJECTIVES: To investigate whether the time between discontinuation of anti-fibrotic therapy and lung transplant in patients with idiopathic pulmonary fibrosis affects the risk of complications. METHODS: We assessed intra-operative and post-transplant complications among patients with idiopathic pulmonary fibrosis who underwent lung transplant and had been treated with nintedanib or pirfenidone continuously for ⩾ 90 days at listing. Patients were grouped according to whether they had a shorter (⩽ 5 medication half-lives) or longer (> 5 medication half-lives) time between discontinuation of anti-fibrotic medication and transplant. Five half-lives corresponded to 2 days for nintedanib and 1 day for pirfenidone. RESULTS: Among patients taking nintedanib (n = 107) or pirfenidone (n = 190), 211 (71.0%) had discontinued anti-fibrotic therapy ⩽ 5 medication half-lives before transplant. Anastomotic and sternal dehiscence occurred only in this group (anastomotic: 11 patients [5.2%], p = 0.031 vs patients with longer time between discontinuation of anti-fibrotic medication and transplant; sternal: 12 patients [5.7%], p = 0.024). No differences were observed in surgical wound dehiscence, length of hospital stay, or survival to discharge between groups with a shorter versus longer time between discontinuation of anti-fibrotic therapy and transplant. CONCLUSION: Anastomotic and sternal dehiscence only occurred in patients with idiopathic pulmonary fibrosis who discontinued anti-fibrotic therapy < 5 medication half-lives before transplant. The frequency of other intra-operative and post-transplant complications did not appear to differ depending on when anti-fibrotic therapy was discontinued. REGISTRATION: clinicaltrials.gov NCT04316780: https://clinicaltrials.gov/ct2/show/NCT04316780.
Assuntos
Fibrose Pulmonar Idiopática , Transplante de Pulmão , Humanos , Fibrose , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/cirurgia , Transplante de Pulmão/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have shown beneficial effects on both forced expiratory volume in 1 s (FEV1 ) and frequency of pulmonary exacerbations in people with cystic fibrosis (CF). These positive outcomes may be related to changes in bacterial colonization within the lungs. Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is the first triple therapy CFTR modulator approved for use in people with CF 6 years and older. This study aimed to determine the impact of ELX/TEZ/IVA on the isolation of Pseudomonas aeruginosa (Pa), methicillin-resistant and methicillin-susceptible Staphylococcus aureus (MRSA and MSSA, respectively) in respiratory cultures. METHODS: A retrospective chart review of the electronic medical record at the University of Iowa was completed for individuals 12 years and older taking ELX/TEZ/IVA for at least 12 months. The primary outcome was determined by assessing bacterial cultures pre- and postinitiation of ELX/TEZ/IVA. Baseline demographic and clinical characteristics were summarized using mean and standard deviation for continuous outcomes and count and percentage for categorical outcomes. Culture positivity for Pa, MSSA, and MRSA was compared among enrolled subjects between pre- and posttriple combination therapy periods using an exact McNemar's test. RESULTS: One hundred and twenty-four subjects prescribed ELX/TEZ/IVA for at least 12 months met the requirements for inclusion within our analysis. Culture positivity for Pa, MSSA, and MRSA was approximately 54%, 33%, and 31%, respectively, for the pre-ELX/TEZ/IVA period. Prevalence decreased to approximately 30%, 32%, and 24% (-24.2% [p < 0.0001], -0.7% [p = 1.00], and -6.5% [p = 0.0963], respectively) post-ELX/TEZ/IVA. The source of bacterial culture was predominantly sputum (70.2%) in the pre-ELX/TEZ/IVA group, whereas a throat source (66.1%) was more common post-ELX/TEZ/IVA. CONCLUSIONS: ELX/TEZ/IVA treatment has an appreciable impact on the detection of common bacterial pathogens in CF respiratory cultures. While previous studies have found a similar effect with single and double CFTR modulator therapies, this is the first single-center study to show the impact of triple therapy, ELX/TEZ/IVA, on bacterial isolation from airway secretions.
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Fibrose Cística , Humanos , Fibrose Cística/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/uso terapêutico , Estudos Retrospectivos , Aminofenóis/uso terapêutico , Benzodioxóis/uso terapêutico , Pseudomonas aeruginosa , MutaçãoRESUMO
BACKGROUND: Lung transplantation is an acceptable and potentially life-saving treatment option for coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome and pulmonary fibrosis. This study was conducted to determine whether recipients of lung transplantation (LT) for COVID-19-related lung disease have comparable outcomes to other recipients with a similar level of lung dysfunction. METHODS: The Organ Procurement and Transplant Network database was queried for adult LT candidates between 2006 and 2021. Recipients with COVID-19-related respiratory failure were matched 1:2 using a nearest-neighbor algorithm. Kaplan-Meier methods with log-rank tests were used to compare long-term survival. A proportional hazards model was used to calculate risk of death. RESULTS: A total of 37,333 LT candidates from all causes were compared with 334 candidates from COVID-19-related respiratory failure. COVID-19 recipients were more likely to be younger (50 vs 57 years, P < .001), male (79% vs 60%, P < .001), require extracorporeal membrane oxygenation (56.3% vs 4.0%, P < .001), and have worse lung function (lung allocation score, 82.4 vs 47.8; P < .001) at transplantation. Subsequently, 227 COVID-19 recipients were matched with 454 controls. Patients who received a transplant for COVID-19 had similar rates of mechanical ventilation, extracorporeal membrane oxygenation, postoperative complications, and functional status at discharge compared with controls. There was no difference in overall survival or risk of death from COVID-19 (hazard ratio, 0.82; 95% CI, 0.45-1.53; P = .54). CONCLUSIONS: Six-month survival for recipients of LT for COVID-19-related respiratory failure was comparable to that of other LT recipients.
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COVID-19 , Transplante de Pulmão , Fibrose Pulmonar , Insuficiência Respiratória , Adulto , Humanos , Masculino , COVID-19/complicações , Transplantados , Estudos Retrospectivos , Análise de Sobrevida , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/cirurgia , Transplante de Pulmão/métodos , Pulmão , Taxa de SobrevidaRESUMO
Rationale: Staphylococcus aureus and Pseudomonas aeruginosa often infect the airways in cystic fibrosis (CF). Because registry studies show higher prevalence of P. aeruginosa versus S. aureus in older patients with CF, a common assumption is that P. aeruginosa replaces S. aureus over time. In vitro, P. aeruginosa can outgrow and kill S. aureus. However, it is unknown how rapidly P. aeruginosa replaces S. aureus in patients with CF.Methods: We studied a longitudinal cohort of children and adults with CF who had quantitative sputum cultures. We determined the abundance of P. aeruginosa and S. aureus in cfu/ml. We determined the duration and persistence of infections and measured longitudinal changes in culture positivity and abundance for each organism.Measurements and Main Results: Between 2004 and 2017, 134 patients had ≥10 quantitative cultures, with median observation time of 10.15 years. One hundred twenty-four patients had at least one positive culture for P. aeruginosa, and 123 had at least one positive culture for S. aureus. Both species had median abundance of >106 cfu/ml. Culture abundance was stable over time for both organisms. There was an increase in the prevalence of S. aureus/P. aeruginosa coinfection but no decrease in S. aureus prevalence within individuals over time.Conclusions: S. aureus and P. aeruginosa are abundant in CF sputum cultures. Contrary to common assumption, we found no pattern of replacement of S. aureus by P. aeruginosa. Many patients with CF have durable long-term coinfection with these organisms. New strategies are needed to prevent and treat these infections.
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Antibacterianos/uso terapêutico , Fibrose Cística/complicações , Fibrose Cística/microbiologia , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/etiologia , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Coinfecção , Feminino , Humanos , Iowa , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pseudomonas aeruginosa/isolamento & purificação , Estudos Retrospectivos , Staphylococcus aureus/isolamento & purificação , Adulto JovemRESUMO
BACKGROUND: Antibody-mediated rejection (AMR) plays an important role in allograft dysfunction. Acute lung injury (ALI), endotheliitis, capillary inflammation, and C4d positivity have been described as morphological features conventionally associated with lung AMR. A multidisciplinary, international task force reviewed AMR cases in the context of four face-to-face meetings. Septal widening was a frequent, striking histological feature recognized first and easily at low-power magnification. This study aimed to evaluate whether septal widening could represent an "alert" signal for AMR. METHODS: Following the face-to-face meetings that enabled the classification of cases as AMR or non-AMR, morphometry was performed on biopsies from 48 recipients with definite, probable or possible AMR, 31 controls (negative for any posttransplant injury) and 10 patients with nonimmune-related ALI. RESULTS: Mean alveolar septal thickness was greater in AMR patients than in controls (P < 0.001). Septal thickness was not significantly different between AMR-ALI and non-AMR-ALI. Unexpectedly septal widening was the only histological change detected in some cases with probable or possible AMR that lacked the histological lesions conventionally associated with AMR. The thickness in these cases was similar to that observed in AMR cases with more severe histological injury such as ALI or neutrophilic capillaritis. CONCLUSIONS: Our data suggest that, even if unspecific as the other lesions conventionally associated with AMR, septal widening may represent an "alert" signal to look into lung AMR. A larger prospective study is mandatory to confirm the potential value of septal widening in the multidisciplinary approach of AMR.
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Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/imunologia , Pneumopatias/imunologia , Pneumopatias/cirurgia , Transplante de Pulmão , Pulmão/imunologia , Alvéolos Pulmonares/patologia , Adulto , Biópsia , Feminino , Humanos , Comunicação Interdisciplinar , Pneumopatias/diagnóstico , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Pneumologia/normas , Estudos Retrospectivos , Doadores de Tecidos , Transplante HomólogoRESUMO
RATIONALE: Obliterative bronchiolitis (OB) is a major cause of mortality after lung transplantation. Depletion of airway stem cells (SCs) may lead to fibrosis in OB. OBJECTIVES: Two major SC compartments in airways are submucosal glands (SMGs) and surface airway p63 (also known as TP63 [tumor protein 63])-positive/K5 (also known as KRT5 [keratin 5])-positive basal cells (BCs). We hypothesized that depletion of these SC compartments occurs in OB. METHODS: Ferret orthotopic left lung transplants were used as an experimental model of OB, and findings were corroborated in human lung allografts. Morphometric analysis was performed in ferret and human lungs to evaluate the abundance of SMGs and changes in the expression of phenotypic BC markers in control, lymphocytic bronchiolitis, and OB airways. The abundance and proliferative capacity of proximal and distal airway SCs was assessed using a clonogenic colony-forming efficiency assay. MEASUREMENTS AND MAIN RESULTS: Ferret allografts revealed significant loss of SMGs with development of OB. A progressive decline in p63+/K5+ and increase in K5+/K14+ and K14+ BC phenotypes correlated with the severity of allograft rejection in large and small ferret airways. The abundance and proliferative capacity of basal SCs in large allograft airways declined with severity of OB, and there was complete ablation of basal SCs in distal OB airways. Human allografts mirrored phenotypic BC changes observed in the ferret model. CONCLUSIONS: SMGs and basal SC compartments are depleted in large and/or small airways of lung allografts, and basal SC proliferative capacity declines with progression of disease and phenotypic changes. Global airway SC depletion may be a mechanism for pulmonary allograft failure.
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Remodelação das Vias Aéreas/fisiologia , Bronquiolite Obliterante/fisiopatologia , Fibrose/fisiopatologia , Rejeição de Enxerto/fisiopatologia , Transplante de Pulmão/efeitos adversos , Células-Tronco/fisiologia , Animais , Bronquiolite Obliterante/etiologia , Furões/fisiologia , Fibrose/etiologia , Humanos , Modelos AnimaisRESUMO
Mycobacterial infections are uncommon in solid organ and hematopoietic stem cell transplant recipients but carry significant morbidity and mortality. Donor screening strategies for tuberculosis should be emphasized in high-risk populations. Both tuberculosis and nontuberculous mycobacterial infections can have pulmonary and extrapulmonary manifestations of infections. Recommended treatment regimens typically involve multiple drugs with significant adverse effects and drug interactions.
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Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções por Mycobacterium não Tuberculosas/etiologia , Condicionamento Pré-Transplante/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Infecções por Mycobacterium não Tuberculosas/microbiologia , Infecções por Mycobacterium não Tuberculosas/patologia , Fatores de Risco , Condicionamento Pré-Transplante/métodosAssuntos
Pulmão , Resultado do Tratamento , Humanos , Transplante de Pulmão , Reperfusão , Traumatismo por ReperfusãoRESUMO
Mechanical ventilation (MV) is an important aspect in the intraoperative and early postoperative management of lung transplant (LTx)-recipients. There are no randomized-controlled trials of LTx-recipient MV strategies; however there are LTx center experiences and international survey studies reported. The main early complication of LTx is primary graft dysfunction (PGD), which is similar to the adult respiratory distress syndrome (ARDS). We aim to summarize information pertinent to LTx-MV, as well as PGD, ARDS, and intraoperative MV and to synthesize these available data into recommendations. Based on the available evidence, we recommend lung-protective MV with low-tidal-volumes (≤6 mL/kg predicted body weight [PBW]) and positive end-expiratory pressure for the LTx-recipient. In our opinion, the MV strategy should be based on donor characteristics (donor PBW as a parameter of actual allograft size), rather than based on recipient characteristics; however this donor-characteristics-based protective MV is based on indirect evidence and requires validation in prospective clinical studies.
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Chronic cavitary pulmonary aspergillosis (CCPA) has been associated with advanced lung diseases. Pulmonary sarcoidosis, a granulomatous inflammatory disorder, is associated with CCPA. We identified CCPA in 2% of cases in a large cohort of sarcoidosis patients. We found a lack of response to medical treatment and poor outcome in this subgroup.