RESUMEN
Pseudomonas aeruginosa causes chronic lung infection in cystic fibrosis (CF), resulting in structural lung damage and progressive pulmonary decline. P. aeruginosa in the CF lung undergoes numerous changes, adapting to host-specific airway pressures while establishing chronic infection. P. aeruginosa undergoes lipid A structural modification during CF chronic infection that is not seen in any other disease state. Lipid A, the membrane anchor of LPS (i.e., endotoxin), comprises the majority of the outer membrane of Gram-negative bacteria and is a potent Toll-like receptor 4 (TLR4) agonist. The structure of P. aeruginosa lipid A is intimately linked with its recognition by TLR4 and subsequent immune response. Prior work has identified P. aeruginosa strains with altered lipid A structures that arise during chronic CF lung infection; however, the impact of the P. aeruginosa lipid A structure on airway disease has not been investigated. Here, we show that P. aeruginosa lipid A lacks PagL-mediated deacylation during human airway infection using a direct-from-sample mass spectrometry approach on human BAL fluid. This structure triggers increased proinflammatory cytokine production by primary human macrophages. Furthermore, alterations in lipid A 2-hydroxylation impact cytokine response in a site-specific manner, independent of CF transmembrane conductance regulator function. It is interesting that there is a CF-specific reduction in IL-8 secretion within the epithelial-cell compartment that only occurs in CF bronchial epithelial cells when infected with CF-adapted P. aeruginosa that lacks PagL-mediated lipid A deacylation. Taken together, we show that P. aeruginosa alters its lipid A structure during acute lung infection and that this lipid A structure induces stronger signaling through TLR4.
Asunto(s)
Fibrosis Quística , Lípido A , Infecciones por Pseudomonas , Pseudomonas aeruginosa , Pseudomonas aeruginosa/inmunología , Humanos , Lípido A/metabolismo , Lípido A/inmunología , Fibrosis Quística/microbiología , Fibrosis Quística/inmunología , Fibrosis Quística/metabolismo , Infecciones por Pseudomonas/inmunología , Infecciones por Pseudomonas/microbiología , Infecciones por Pseudomonas/metabolismo , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/inmunología , Citocinas/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/microbiología , Líquido del Lavado Bronquioalveolar/inmunología , Pulmón/microbiología , Pulmón/inmunología , Pulmón/metabolismoRESUMEN
BACKGROUND: Abnormal macrophage function caused by dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) is a critical contributor to chronic airway infections and inflammation in people with cystic fibrosis (PWCF). Elexacaftor/tezacaftor/ivacaftor (ETI) is a new CFTR modulator therapy for PWCF. Host-pathogen and clinical responses to CFTR modulators are poorly described. We sought to determine how ETI impacts macrophage CFTR function, resulting effector functions and relationships to clinical outcome changes. METHODS: Clinical information and/or biospecimens were obtained at ETI initiation and 3, 6, 9 and 12â months post-ETI in 56 PWCF and compared with non-CF controls. Peripheral blood monocyte-derived macrophages (MDMs) were isolated and functional assays performed. RESULTS: ETI treatment was associated with increased CF MDM CFTR expression, function and localisation to the plasma membrane. CF MDM phagocytosis, intracellular killing of CF pathogens and efferocytosis of apoptotic neutrophils were partially restored by ETI, but inflammatory cytokine production remained unchanged. Clinical outcomes including increased forced expiratory volume in 1â s (+10%) and body mass index (+1.0â kg·m-2) showed fluctuations over time and were highly individualised. Significant correlations between post-ETI MDM CFTR function and sweat chloride levels were observed. However, MDM CFTR function correlated with clinical outcomes better than sweat chloride. CONCLUSION: ETI is associated with unique changes in innate immune function and clinical outcomes.
Asunto(s)
Fibrosis Quística , Humanos , Fibrosis Quística/tratamiento farmacológico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Cloruros/metabolismo , Agonistas de los Canales de Cloruro/uso terapéutico , Mutación , Macrófagos/metabolismoRESUMEN
Comorbid pulmonary complications in people with sickle cell disease (pwSCD) are associated with high rates of morbidity and mortality, and poor access to care contributes to poor outcomes among this particularly high-risk pwSCD. Our purpose was to describe the population served and the resources required for hematology, pulmonary, nursing, respiratory therapy, social work, genetics, psychology, and school liaison providers to see these patients in an integrated clinic. We abstracted demographic, medication, clinical, and diagnostics data of the pwSCD seen at least once in this clinic from February 1, 2014 to December 10, 2020 from the electronic medical record and identified 145 unique pwSCD. Abnormal lung function and bronchodilator responsiveness were detected in 31% and 42% of participants respectively. Sleep abnormalities were found in over two-thirds of those screened and 65% had ≥1 previous acute chest syndrome episode. This clinic also allowed for direct provider communication and required relatively limited resources to serve a large number of severely affected pwSCD. Given the degree of abnormal respiratory variables detected and the limited resources required to implement this model, studies are warranted to evaluate whether it has the potential to improve outcomes in high-risk populations.
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Síndrome Torácico Agudo , Anemia de Células Falciformes , Humanos , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/terapia , Síndrome Torácico Agudo/etiología , Factores de Riesgo , PulmónRESUMEN
Cystic fibrosis (CF) is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Chronic inflammation and decline in lung function are major reasons for morbidity in CF. Mutant CFTR expressed in phagocytic cells such as macrophages contributes to persistent infection, inflammation, and lung disease in CF. Macrophages play a central role in innate immunity by eliminating pathogenic microbes by a process called phagocytosis. Phagocytosis is required for tissue homeostasis, balancing inflammation, and crosstalk with the adaptive immune system for antigen presentation. This review focused on (1) current understandings of the signaling underlying phagocytic mechanisms; (2) existing evidence for phagocytic dysregulation in CF; and (3) the emerging role of CFTR modulators in influencing CF phagocytic function. Alterations in CF macrophages from receptor initiation to phagosome formation are linked to disease progression in CF. A deeper understanding of macrophages in the context of CFTR and phagocytosis proteins at each step of phagosome formation might contribute to the new therapeutic development of dysregulated innate immunity in CF. Therefore, the review also indicates future areas of research in the context of CFTR and macrophages.
Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística , Fibrosis Quística , Fibrosis Quística/patología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Humanos , Inflamación/patología , Macrófagos/metabolismo , FagocitosisRESUMEN
Cystic fibrosis (CF), one of the most common human genetic diseases worldwide, is caused by a defect in the CF transmembrane conductance regulator (CFTR). Patients with CF are highly susceptible to infections caused by opportunistic pathogens (including Burkholderia cenocepacia), which induce excessive lung inflammation and lead to the eventual loss of pulmonary function. Abundant neutrophil recruitment into the lung is a key characteristic of bacterial infections in CF patients. In response to infection, inflammatory neutrophils release reactive oxygen species and toxic proteins, leading to aggravated lung tissue damage in patients with CF. The present study shows a defect in reactive oxygen species production by mouse Cftr-/- , human F508del-CFTR, and CF neutrophils; this results in reduced antimicrobial activity against B. cenocepacia Furthermore, dysregulated Ca2+ homeostasis led to increased intracellular concentrations of Ca2+ that correlated with significantly diminished NADPH oxidase response and impaired secretion of neutrophil extracellular traps in human CF neutrophils. Functionally deficient human CF neutrophils recovered their antimicrobial killing capacity following treatment with pharmacological inhibitors of Ca2+ channels and CFTR channel potentiators. Our findings suggest that regulation of neutrophil Ca2+ homeostasis (via CFTR potentiation or by the regulation of Ca2+ channels) can be used as a new therapeutic approach for reestablishing immune function in patients with CF.
Asunto(s)
Infecciones por Burkholderia/inmunología , Burkholderia cenocepacia/fisiología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/inmunología , Mutación/genética , Neutrófilos/inmunología , Neumonía/inmunología , Adolescente , Animales , Calcio/metabolismo , Canales de Calcio/metabolismo , Señalización del Calcio , Niño , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Femenino , Homeostasis , Humanos , Inmunidad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , NADPH Oxidasas/metabolismo , Infiltración Neutrófila , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Mechanisms that facilitate early infection and inflammation in cystic fibrosis (CF) are unclear. We previously demonstrated that children with CF and parental-reported secondhand smoke exposure (SHSe) have increased susceptibility to bacterial infections. SHSe hinders arachidonic acid (AA) metabolites that mediate immune function in patients without CF, and may influence CF immune dysfunction. We aimed to define SHSe's impact on inflammation mediators and infection in children with CF. METHODS: Seventy-seven children with CF <10 years of age (35 infants <1 year; 42 children 1-10 years) were enrolled and hair nicotine concentrations measured as an objective surrogate of SHSe. AA signalling by serum and macrophage lipidomics, inflammation using blood transcriptional profiles and in vitro macrophage responses to bacterial infection after SHSe were assessed. RESULTS: Hair nicotine concentrations were elevated in 63% of patients. Of the AA metabolites measured by plasma lipidomics, prostaglandin D2 (PGD2) concentrations were decreased in children with CF exposed to SHSe, and associated with more frequent hospitalisations (p=0.007) and worsened weight z scores (p=0.008). Children with CF exposed to SHSe demonstrated decreased expression of the prostaglandin genes PTGES3 and PTGR2 and overexpression of inflammatory pathways. These findings were confirmed using an in vitro model, where SHSe was associated with a dose-dependent decrease in PGD2 and increased methicillin-resistant Staphylococcus aureus survival in human CF macrophages. CONCLUSIONS: Infants and young children with CF and SHSe have altered AA metabolism and dysregulated inflammatory gene expression resulting in impaired bacterial clearance. Our findings identified potential therapeutic targets to halt early disease progression associated with SHSe in the young population with CF.
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Ácidos Araquidónicos/metabolismo , Fibrosis Quística/metabolismo , Fibrosis Quística/patología , Contaminación por Humo de Tabaco/efectos adversos , Infecciones Bacterianas/diagnóstico , Infecciones Bacterianas/etiología , Niño , Preescolar , Estudios de Cohortes , Fibrosis Quística/microbiología , Femenino , Humanos , Lactante , Inflamación/etiología , Inflamación/metabolismo , Inflamación/patología , Masculino , Factores de RiesgoRESUMEN
Macrophage intracellular pathogen killing is defective in cystic fibrosis (CF), despite abundant production of reactive oxygen species (ROS) in lung tissue. Burkholderia species can cause serious infection in CF and themselves affect key oxidase components in murine non-CF cells. However, it is unknown whether human CF macrophages have an independent defect in the oxidative burst and whether Burkholderia contributes to this defect in terms of assembly of the NADPH oxidase complex and subsequent ROS production. In this article, we analyze CF and non-CF human monocyte-derived macrophages (MDMs) for ROS production, NADPH assembly capacity, protein kinase C expression, and calcium release in response to PMA and CF pathogens. CF MDMs demonstrate a nearly 60% reduction in superoxide production after PMA stimulation compared with non-CF MDMs. Although CF MDMs generally have increased total NADPH component protein expression, they demonstrate decreased expression of the calcium-dependent protein kinase C conventional subclass α/ß leading to reduced phosphorylation of NADPH oxidase components p47 phox and p40 phox in comparison with non-CF MDMs. Ingestion of B. cenocepacia independently contributes to and worsens the overall oxidative burst deficits in CF MDMs compared with non-CF MDMs. Together, these results provide evidence for inherent deficits in the CF macrophage oxidative burst caused by decreased phosphorylation of NADPH oxidase cytosolic components that are augmented by Burkholderia These findings implicate a critical role for defective macrophage oxidative responses in persistent bacterial infections in CF and create new opportunities for boosting the macrophage immune response to limit infection.
Asunto(s)
Infecciones por Burkholderia/inmunología , Burkholderia cenocepacia/inmunología , Fibrosis Quística/inmunología , Macrófagos/inmunología , NADPH Oxidasas/metabolismo , Proteína Quinasa C/metabolismo , Estallido Respiratorio , Animales , Calcio/metabolismo , Células Cultivadas , Regulación hacia Abajo , Humanos , Ratones , Fosforilación , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Transplant volume represents lung transplant (LTx) expertise and predicts outcomes, so we sought to determine outcomes related to center volumes in cystic fibrosis (CF). United Network for Organ Sharing data were queried for patients with CF in the United States (US) receiving bilateral LTx from 2005 to 2015. Multivariable Cox regression was used to model survival to 1 year and long-term (>1 year) survival, conditional on surviving at least 1 year. A total of 2025 patients and 67 centers were included in the analysis. The median annual LTx volumes were three in CF [interquartile range (IQR): 2, 6] and 17 in non-CF (IQR: 8, 33). Multivariable Cox regression in cases with complete data and surviving at least 1 year (n = 1510) demonstrated that greater annual CF LTx volume (HR per 10 LTx = 0.66; 95% CI: 0.49, 0.89; P = 0.006) but not greater non-CF LTx volume (HR = 1.00; 95% CI: 0.96, 1.05; P = 0.844) was associated with improved long-term survival in LTx recipients with CF. A Wald interaction test confirmed that CF LTx volume was more strongly associated with long-term outcomes than non-CF LTx volume (P = 0.012). In a US cohort, center volume was not associated with 1-year survival. CF-specific expertise predicted improved long-term outcomes of LTx for CF, whereas general LTx expertise was unassociated with CF patients' survival.
Asunto(s)
Fibrosis Quística/cirugía , Hospitales/estadística & datos numéricos , Trasplante de Pulmón , Adolescente , Adulto , Niño , Femenino , Humanos , Pulmón/cirugía , Masculino , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Sistema de Registros , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia , Trasplantes , Resultado del Tratamiento , Estados Unidos , Adulto JovenRESUMEN
Background Pre-lung transplant (LTx) panel reactive antibody (PRA) levels are associated with adverse outcomes in adult LTx recipients, but their impact in pediatric LTx recipients is unknown. Methods The United Network for Organ Sharing registry was queried from 2004 to 2013 to compare survival between pediatric LTx recipients with PRA class I and II levels = 0 versus > 0. Results Overall, 333 pediatric LTx recipients had data on class I or II PRA and were included in the analysis. Univariate analysis demonstrated that PRA > 0 was not associated with survival benefit for class I (hazard ratio [HR] = 0.985; 95% confidence interval [CI]: 0.623, 1.555; p = 0.947) or class II (HR = 1.080; 95% CI: 0.657, 1.774; p = 0.762) PRA. Multivariate Cox models confirmed no significant association with mortality hazard for both class I (HR = 1.230; 95% CI: 0.641, 2.363; p = 0.533) and class II (HR = 0.847; 95% CI: 0.359, 1.997; p = 0.704) PRA. Multivariate logistic regression models identified no association between class I or class II and acute rejection within 3 years of LTx. Conclusions Pretransplant class I and II PRA levels > 0 were not associated with mortality or acute rejection in pediatric LTx recipients.
Asunto(s)
Prueba de Histocompatibilidad , Histocompatibilidad , Isoanticuerpos/sangre , Trasplante de Pulmón , Enfermedad Aguda , Adolescente , Biomarcadores/sangre , Niño , Preescolar , Femenino , Rechazo de Injerto/inmunología , Supervivencia de Injerto , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Trasplante de Pulmón/efectos adversos , Trasplante de Pulmón/mortalidad , Masculino , Análisis Multivariante , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Sistema de Registros , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Obtención de Tejidos y Órganos , Resultado del Tratamiento , Estados UnidosRESUMEN
Acquisition of adaptive mutations is essential for microbial persistence during chronic infections. This is particularly evident during chronic Pseudomonas aeruginosa lung infections in cystic fibrosis (CF) patients. Thus far, mutagenesis has been attributed to the generation of reactive species by polymorphonucleocytes (PMN) and antibiotic treatment. However, our current studies of mutagenesis leading to P. aeruginosa mucoid conversion have revealed a potential new mutagen. Our findings confirmed the current view that reactive oxygen species can promote mucoidy in vitro, but revealed PMNs are proficient at inducing mucoid conversion in the absence of an oxidative burst. This led to the discovery that cationic antimicrobial peptides can be mutagenic and promote mucoidy. Of specific interest was the human cathelicidin LL-37, canonically known to disrupt bacterial membranes leading to cell death. An alternative role was revealed at sub-inhibitory concentrations, where LL-37 was found to induce mutations within the mucA gene encoding a negative regulator of mucoidy and to promote rifampin resistance in both P. aeruginosa and Escherichia coli. The mechanism of mutagenesis was found to be dependent upon sub-inhibitory concentrations of LL-37 entering the bacterial cytosol and binding to DNA. LL-37/DNA interactions then promote translesion DNA synthesis by the polymerase DinB, whose error-prone replication potentiates the mutations. A model of LL-37 bound to DNA was generated, which reveals amino termini α-helices of dimerized LL-37 bind the major groove of DNA, with numerous DNA contacts made by LL-37 basic residues. This demonstrates a mutagenic role for antimicrobials previously thought to be insusceptible to resistance by mutation, highlighting a need to further investigate their role in evolution and pathoadaptation in chronic infections.
Asunto(s)
Adaptación Fisiológica , Péptidos Catiónicos Antimicrobianos/metabolismo , ADN Bacteriano/metabolismo , Mutagénesis , Infecciones por Pseudomonas/metabolismo , Pseudomonas aeruginosa/metabolismo , Adolescente , Adulto , Péptidos Catiónicos Antimicrobianos/química , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Niño , Enfermedad Crónica , Fibrosis Quística/genética , Fibrosis Quística/metabolismo , Fibrosis Quística/patología , ADN Bacteriano/química , ADN Bacteriano/genética , Evolución Molecular , Femenino , Humanos , Masculino , Modelos Moleculares , Infecciones por Pseudomonas/genética , Infecciones por Pseudomonas/patología , Pseudomonas aeruginosa/química , Pseudomonas aeruginosa/genética , CatelicidinasRESUMEN
OBJECTIVE: To assess whether geographic location influences hospitalizations for pulmonary exacerbations for patients with cystic fibrosis (CF) in the US, as there is no existing literature regarding this subject. STUDY DESIGN: The CF Foundation Patient Registry was analyzed during the years 2007-2012 via geographic grouping of states. The impact of geographic region on recovery from hospitalization, hospitalization length, and time to next hospitalization were analyzed using multivariate models. RESULTS: Posthospitalization lung function and nutritional measures were similar among regions for 1 year following hospitalization. The West region was associated with risk of longer hospital stays (OR 1.60, CI 1.45-1.77), however, dornase alfa use (OR 3.85, CI 1.15-12.92) was the only specific factor. History of allergic bronchopulmonary aspergillosis (OR 1.58, CI 1.11-2.25) and adult age (OR 2.48, CI 1.17-5.25) in the Northeast, chronic macrolide use in the South (OR 1.36, CI 1.03-1.79), and infection with Candida albicans (OR 1.47, CI 1.18-1.82) and Pseudomonas aeruginosa (OR 1.44, CI 1.02-2.04) in the Midwest were associated with increased hospitalization length. There was a significantly decreased risk for subsequent hospitalizations in the Northeast compared with other regions (P = .038). Sociodemographic analysis identified Caucasians in the South having a significantly lower risk of future hospitalization compared with African Americans (hazard ratio 0.79, CI 0.69-0.91, P = .0009). CONCLUSIONS: There is significant regional variability in hospitalization length and risks for subsequent hospitalizations for patients with CF in the US. Regional variation should be subject to further study to determine if benchmarking standards can be achieved nationally.
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Fibrosis Quística/terapia , Progresión de la Enfermedad , Hospitalización/estadística & datos numéricos , Adolescente , Adulto , Niño , Preescolar , Fibrosis Quística/fisiopatología , Bases de Datos Factuales , Femenino , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Análisis Multivariante , Modelos de Riesgos Proporcionales , Estados Unidos , Adulto JovenRESUMEN
BACKGROUND: Acinetobacter species are associated with increasing mortality due to emerging drug-resistance. Pediatric Acinetobacter infections are largely undefined in developed countries and clinical laboratory identification methods do not reliably differentiate between members of the Acinetobacter calcoaceticus-baumannii complex, leading to improper identification. Therefore we aimed to determine risk factors for invasive Acinetobacter infections within an academic, pediatric setting as well as defining microbiologic characteristics of predominant strains. METHODS: Twenty-four invasive Acinetobacter isolates were collected from 2009-2013. Comparative sequence analysis of the rpoB gene was performed coupled with phenotypic characterization of antibiotic resistance, motility, biofilm production and clinical correlation. RESULTS: Affected patients had a median age of 3.5 years, and 71 % had a central catheter infection source. rpoB gene sequencing revealed a predominance of A. pittii (45.8 %) and A. baumannii (33.3 %) strains. There was increasing incidence of A. pittii over the study. Two fatalities occurred in the A. pittii group. Seventeen percent of isolates were multi-drug resistant. A pittii and A. baumannii strains were similar in motility, but A pittii strains had significantly more biofilm production (P value = 0.018). CONCLUSIONS: A. pittii was the most isolated species highlighting the need for proper species identification. The isolated strains had limited acute mortality in children, but the occurrence of more multi-drug resistant strains in the future is a distinct possibility, justifying continued research and accurate species identification.
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Infecciones por Acinetobacter/microbiología , Acinetobacter/aislamiento & purificación , Infección Hospitalaria/microbiología , Centros Médicos Académicos , Acinetobacter/efectos de los fármacos , Acinetobacter/genética , Acinetobacter/fisiología , Infecciones por Acinetobacter/diagnóstico , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/etiología , Adolescente , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Biopelículas , Niño , Preescolar , Infección Hospitalaria/diagnóstico , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/etiología , Farmacorresistencia Bacteriana Múltiple , Femenino , Hospitales Pediátricos , Humanos , Lactante , Recién Nacido , Masculino , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
INTRODUCTION: Donor PaO2 levels are used for assessing organs for lung transplantation (LTx), but survival implications of PaO2 levels in adult cystic fibrosis (CF) patients receiving LTx are unclear. METHODS: UNOS registry data spanning 2005-2013 were used to test for associations of donor PaO2 with patient survival and bronchiolitis obliterans syndrome (BOS) in adult (age ≥ 18 years) first-time LTx recipients diagnosed with CF. RESULTS: The analysis included 1587 patients, of whom 1420 had complete data for multivariable Cox models. No statistically significant differences among donor PaO2 categories of ≤200, 201-300, 301-400, or >400 mmHg were found in univariate survival analysis (log-rank test p = 0.290). BOS onset did not significantly differ across donor PaO2 categories (Chi-square p = 0.480). Multivariable Cox models of patient survival supported the lack of difference across donor PaO2 categories. Interaction analysis found a modest difference in survival between the two top categories of donor PaO2 when examining patients with body mass index (BMI) in the lowest decile (≤16.5 kg/m(2)). CONCLUSIONS: Donor PaO2 was not associated with survival or BOS onset in adult CF patients undergoing LTx. Notwithstanding statistically significant interactions between donor PaO2 and BMI, there was no evidence of post-LTx survival risk associated with donor PaO2 below conventional thresholds in any subgroup of adults with CF.
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Bronquiolitis Obliterante/epidemiología , Fibrosis Quística/cirugía , Trasplante de Pulmón , Oxígeno/sangre , Donantes de Tejidos , Adulto , Índice de Masa Corporal , Bronquiolitis Obliterante/etiología , Femenino , Humanos , Incidencia , Estimación de Kaplan-Meier , Trasplante de Pulmón/efectos adversos , Masculino , Presión Parcial , Modelos de Riesgos Proporcionales , Sistema de Registros , Tasa de Supervivencia , Síndrome , Resultado del Tratamiento , Estados Unidos/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Survival in non-cystic fibrosis (CF) bronchiectasis is not well studied. METHODS: The United Network for Organ Sharing database was queried from 1987 to 2013 to compare survival in adult patients with non-CF bronchiectasis to patients with CF listed for lung transplantation (LTx). Each subject was tracked from waitlist entry date until death or censoring to determine survival differences between the two groups. RESULTS: Of 2112 listed lung transplant candidates with bronchiectasis (180 non-CF, 1932 CF), 1617 were used for univariate Cox and Kaplan-Meier survival function analysis, 1173 for multivariate Cox models, and 182 for matched-pairs analysis based on propensity scores. Compared to CF, patients with non-CF bronchiectasis had a significantly lower mortality by univariate Cox analysis (HR 0.565; 95 % CI 0.424, 0.754; p < 0.001). Adjusting for potential confounders, multivariate Cox models identified a significant reduction in risk for death associated with non-CF bronchiectasis who were lung transplant candidates (HR 0.684; 95 % CI 0.475, 0.985; p = 0.041). Results were consistent in multivariate models adjusting for pulmonary hypertension and forced expiratory volume in one second. CONCLUSIONS: Non-CF bronchiectasis with advanced lung disease was associated with significantly lower mortality hazard compared to CF bronchiectasis on the waitlist for LTx. Separate referral and listing criteria for LTx in non-CF and CF populations should be considered.
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Bronquiectasia/mortalidad , Fibrosis Quística/mortalidad , Trasplante de Pulmón , Listas de Espera/mortalidad , Adulto , Bronquiectasia/fisiopatología , Bronquiectasia/cirugía , Fibrosis Quística/fisiopatología , Fibrosis Quística/cirugía , Femenino , Volumen Espiratorio Forzado , Humanos , Hipertensión Pulmonar/epidemiología , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Tasa de Supervivencia , Estados Unidos/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Pulmonary hypertension (PH) commonly occurs in patients with cystic fibrosis (CF), but there is no current data regarding alterations of sleep in patients with PH. METHODS: A single-center, retrospective review was performed in patients with advanced lung disease due to CF who completed both nocturnal polysomnography and right heart catheterization (RHC) from January 2010 to June 2013. For statistical analysis, two-tailed unpaired t tests and Pearson correlation coefficient analysis were performed after normal distribution was confirmed. RESULTS: A total of 18 consecutive CF patients were enrolled with RHC identifying PH in 56 % (10/18) of patients. The PH group had significantly lower mean sleep efficiency (72 ± 4 vs. 87 ± 3 %, p = 0.01), significantly higher ETCO(2) levels (54.5 ± 2.2 vs. 43.8 ± 3.0 mmHg, p = 0.01) on capnography, and significantly lower PO(2) (53.8 ± 3.1 vs. 65.5 ± 3.9 mmHg, p = 0.03) on capillary blood gas. Correlations with poor sleep efficiency included mean PAP (r = - 0.55, p = 0.01), systolic PAP (r = -0.5, p = 0.03), ETCO(2) (r = - 0.53, p = 0.02), and PO(2)) (r = 0.62, p = 0.01); ETCO(2) with systolic PAP (r = 0.47, p = 0.04) and PCO(2) (r = - 0.57, p = 0.01); and PO(2) to 6-min walk distance (r = 0.55, p = 0.02). CONCLUSIONS: We found significant differences in sleep efficiency and gas exchange associated with PH in CF patients with advanced lung disease.
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Fibrosis Quística/complicaciones , Hipertensión Pulmonar/etiología , Pulmón/fisiopatología , Polisomnografía , Trastornos del Sueño-Vigilia/etiología , Sueño , Adulto , Presión Arterial , Análisis de los Gases de la Sangre , Capnografía , Cateterismo Cardíaco , Fibrosis Quística/diagnóstico , Fibrosis Quística/fisiopatología , Prueba de Esfuerzo , Tolerancia al Ejercicio , Femenino , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/fisiopatología , Masculino , Ohio , Proyectos Piloto , Valor Predictivo de las Pruebas , Arteria Pulmonar/fisiopatología , Intercambio Gaseoso Pulmonar , Estudios Retrospectivos , Factores de Riesgo , Trastornos del Sueño-Vigilia/diagnóstico , Trastornos del Sueño-Vigilia/fisiopatologíaRESUMEN
Sickle cell lung disease presents a challenging care paradigm involving acute and chronic lower airway disease, sleep-disordered breathing, pulmonary vascular disease, and modification by environmental factors. Understanding the presentation, pathophysiology, and diagnostic approaches is essential for accurate identification and management. While significant progress has been made, there remains a need for research to develop effective treatments and interventions to decrease disease burden in these children. Additionally, the long-term impact of interventions on cardiopulmonary outcomes is unknown. Collaborative efforts among health care providers, researchers, advocacy groups, and policy makers are crucial to improving the lives of children with SCD.
Asunto(s)
Anemia de Células Falciformes , Enfermedades Pulmonares , Humanos , Anemia de Células Falciformes/terapia , Anemia de Células Falciformes/fisiopatología , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/diagnóstico , Anemia de Células Falciformes/epidemiología , Niño , Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/terapia , Enfermedades Pulmonares/fisiopatología , Enfermedades Pulmonares/etiologíaRESUMEN
There are limited published data on surveillance TBB for the identification of allograft rejection in infants after lung or heart-lung transplantation. We performed a retrospective review of children under one yr of age who underwent lung or heart-lung transplant at our institution. Since 2005, four infants were transplanted (three heart-lung and one lung). The mean age (±s.d.) at the time of transplant was 5.5 ± 2.4 (range 3-8) months. A total of 16 surveillance TBB procedures were completed in both inpatient and outpatient settings, with a range of 3-7 performed per patient. A minimum of five acceptable tissue pieces with expanded alveoli were obtained in 81% (13/16) of TBB procedures and a minimum of three pieces in 88% (14/16). There was no evidence of acute allograft rejection in 88% (14/16) of TBB procedures. One TBB procedure yielded two tissue specimens demonstrating A2 acute allograft rejection. One TBB procedure failed to yield tissue with sufficient alveoli. Additionally, B-grade assessment identified B0 in 50% (8/16), B1R in 12% (2/16), and BX (ungradeable or insufficient sample) in 38% (6/16) of biopsy procedures, respectively. In conclusion, TBB may be safely performed as an inpatient and outpatient procedure in infant lung and heart-lung transplant recipients and may provide adequate tissue for detecting acute allograft rejection and small airway inflammation.
Asunto(s)
Bronquios/patología , Broncoscopía , Trasplante de Corazón-Pulmón , Trasplante de Pulmón , Biopsia/métodos , Femenino , Rechazo de Injerto , Humanos , Lactante , Inflamación , Pacientes Internos , Hígado/patología , Pulmón/patología , Masculino , Pacientes Ambulatorios , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
People with sickle cell disease (pwSCD) are at risk of developing lung conditions that complicate their SCD but often face health care access barriers. An interdisciplinary clinic providing pulmonary care for pwSCD was created in 2014 at the Nationwide Children's Hospital (NCH) to address access barriers that may prevent optimized treatment. We hypothesize that pwSCD and pulmonary disease would have fewer hospitalizations for acute chest syndrome (ACS), asthma, and vaso-occlusive episodes in the 2 years after their initial SCD-pulmonary clinic visit compared with the 2 years before. From 2014 to 2020, 119 pwSCD were evaluated in the SCD-pulmonary clinic and followed up at the NCH for at least 2 years before and after this initial visit. Acute care outcomes, pulmonary function, polysomnography, echocardiogram, laboratory, and medication prescribing data were collected and analyzed using the Wilcoxon signed ranked and McNemar tests. The median number of acute care visits for ACS (P < .001) and asthma (P = .006) were significantly lower during the 2 years after pwSCD's initial SCD-pulmonary clinic evaluation compared with the 2 years before. Asthma and allergic rhinitis were more frequently diagnosed and prescriptions for hydroxyurea (P = .005) and inhaled corticosteroids (P = .005) were more common in the post-SCD-pulmonary clinic period. The median number of prescribed systemic corticosteroids was lower in the 2 years after SCD-pulmonary clinic evaluation (P < .0001). Lactate dehydrogenase and white blood cell counts also significantly decreased. Implementing a multidisciplinary SCD-pulmonary clinic is feasible and may allow improved management of pulmonary problems and lead to improvements in the usage of health and acute care.
Asunto(s)
Síndrome Torácico Agudo , Anemia de Células Falciformes , Asma , Hematología , Humanos , Niño , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/terapia , Síndrome Torácico Agudo/terapia , Síndrome Torácico Agudo/complicaciones , Asma/complicaciones , CorticoesteroidesRESUMEN
BACKGROUND: Cystic fibrosis (CF) is a multisystem disease with progressive deterioration. Recently, CF transmembrane conductance regulator (CFTR) modulator therapies were introduced that repair underlying protein defects. Objective of this study was to determine the impact of elexacaftor-tezacaftor-ivacaftor (ETI) on clinical parameters and inflammatory responses in people with CF (pwCF). METHODS: Lung function (FEV1 ), body mass index (BMI) and microbiologic data were collected at initiation and 3-month intervals for 1 year. Blood was analyzed at baseline and 6 months for cytokines and immune cell populations via flow cytometry and compared to non-CF controls. RESULTS: Sample size was 48 pwCF, 28 (58.3%) males with a mean age of 28.8 ± 10.7 years. Significant increases in %predicted FEV1 and BMI were observed through 6 months of ETI therapy with no change thereafter. Changes in FEV1 and BMI at 3 months were significantly correlated (r = 57.2, p < 0.01). There were significant reductions in Pseudomonas and Staphylococcus positivity (percent of total samples) in pwCF through 12 months of ETI treatment. Healthy controls (n = 20) had significantly lower levels of circulating neutrophils, interleukin (IL)-6, IL-8, and IL-17A and higher levels of IL-13 compared to pwCF at baseline (n = 48). After 6 months of ETI, pwCF had significant decreases in IL-8, IL-6, and IL-17A levels and normalization of peripheral blood immune cell composition. CONCLUSIONS: In pwCF, ETI significantly improved clinical outcomes, reduced systemic pro-inflammatory cytokines, and restored circulating immune cell composition after 6 months of therapy.