RESUMO
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.
Assuntos
Fibrose Cística , Lipídeo A , Infecções por Pseudomonas , Pseudomonas aeruginosa , Pseudomonas aeruginosa/imunologia , Humanos , Lipídeo A/metabolismo , Lipídeo A/imunologia , Fibrose Cística/microbiologia , Fibrose Cística/imunologia , Fibrose Cística/metabolismo , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/metabolismo , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/imunologia , Citocinas/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Líquido da Lavagem Broncoalveolar/imunologia , Pulmão/microbiologia , Pulmão/imunologia , Pulmão/metabolismoRESUMO
BACKGROUND: Little is known about the immune responses during acute asthma exacerbation. In this study, we examined immune responses in children following an acute asthma exacerbation. METHODS: We evaluated pro-inflammatory cytokine levels and gene expression profiles in blood samples from pediatric patients admitted for acute asthma exacerbation. Viral PCR was performed to differentiate between viral or non-viral-associated exacerbations. RESULTS: Following informed consent, clinical data were obtained from 20 children with asthma (median [interquartile range, IQR]: age 11.5 [8.0, 14.2]) years and 14 healthy age-matched controls (10.5 [7.0, 13.0]). Twelve had positive nasopharyngeal Polymerase chain reaction (PCR) for viral infection (11 rhinoviruses and 1 respiratory syncytial virus (RSV)). Nine were in the pediatric intensive care unit (PICU) and among them five required continuous positive airway pressure (CPAP). Mean (±SD) days on systemic steroids before drawing blood sample were 2.5 ± 1.6. Twelve had history of environmental allergies with 917 (274, 1396) IU/mL total IgE (median (IQR)). Compared with controls, IL-1RA and IL-10 levels were significantly increased and TNF-α significantly decreased in asthma subjects (p < .05 for all). RNA-seq analysis revealed 852 differentially expressed genes in subjects with asthma. Pathway analysis found upregulated genes and pathways involved in innate immune responses in subjects with asthma. Significantly reduced genes included pathways associated with T helper cell differentiation and activation. CONCLUSIONS: In acute asthma exacerbation, innate immune pathways remained increased while adaptive immune responses related to T helper cells are blunted and are independent of trigger or asthma severity. Our novel findings highlight the need to identify new therapies to target persistent innate immune responses to improve outcomes in acute asthma.
Assuntos
Asma , Citocinas , Imunidade Inata , Humanos , Asma/imunologia , Criança , Feminino , Masculino , Adolescente , Citocinas/sangue , Doença Aguda , Progressão da Doença , Estudos de Casos e Controles , Pré-EscolarRESUMO
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.
Assuntos
Fibrose Cística , Humanos , Fibrose Cística/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Cloretos/metabolismo , Agonistas dos Canais de Cloreto/uso terapêutico , Mutação , Macrófagos/metabolismoRESUMO
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.
Assuntos
Síndrome Torácica Aguda , Anemia Falciforme , Humanos , Anemia Falciforme/complicações , Anemia Falciforme/terapia , Síndrome Torácica Aguda/etiologia , Fatores de Risco , PulmãoRESUMO
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.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Fibrose Cística/patologia , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Humanos , Inflamação/patologia , Macrófagos/metabolismo , FagocitoseRESUMO
Humans are exposed to multiple exogenous substances, notably through food consumption. Many of these compounds are suspected to impact human health, and their combination could exacerbate their harmful effects. We previously observed in human cells that, among the six most prevalent food contaminant complex mixtures identified in the French diet, synergistic interactions between component appeared in two mixtures compared with the response with the chemicals alone. In the present study, we demonstrated in human cells that these properties are driven only by two heavy metals in each mixture: tellurium (Te) with cadmium (Cd) and Cd with inorganic arsenic (As), respectively. It appeared that the predicted effects for these binary mixtures using the mathematical model of Chou and Talalay confirmed synergism between these heavy metals. Based on different cell biology experiments (cytotoxicity, genotoxicity, mutagenesis and DNA repair inhibition experiments), a detailed mechanistic analysis of these two mixtures suggests that concomitant induction of oxidative DNA damage and decrease of their repair capacity contribute to the synergistic toxic effect of these chemical mixtures. Overall, these results may have broad implications for the fields of environmental toxicology and chemical mixture risk assessment.
RESUMO
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.
Assuntos
Infecções por Burkholderia/imunologia , Burkholderia cenocepacia/fisiologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/imunologia , Mutação/genética , Neutrófilos/imunologia , Pneumonia/imunologia , Adolescente , Animais , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Sinalização do Cálcio , Criança , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Feminino , Homeostase , Humanos , Imunidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidases/metabolismo , Infiltração de Neutrófilos , Espécies Reativas de Oxigênio/metabolismoRESUMO
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.
Assuntos
Ácidos Araquidônicos/metabolismo , Fibrose Cística/metabolismo , Fibrose Cística/patologia , Poluição por Fumaça de Tabaco/efeitos adversos , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/etiologia , Criança , Pré-Escolar , Estudos de Coortes , Fibrose Cística/microbiologia , Feminino , Humanos , Lactente , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Fatores de RiscoRESUMO
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.
Assuntos
Infecções por Burkholderia/imunologia , Burkholderia cenocepacia/imunologia , Fibrose Cística/imunologia , Macrófagos/imunologia , NADPH Oxidases/metabolismo , Proteína Quinase C/metabolismo , Explosão Respiratória , Animais , Cálcio/metabolismo , Células Cultivadas , Regulação para Baixo , Humanos , Camundongos , Fosforilação , Espécies Reativas de Oxigênio/metabolismoRESUMO
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.
Assuntos
Fibrose Cística/cirurgia , Hospitais/estatística & dados numéricos , Transplante de Pulmão , Adolescente , Adulto , Criança , Feminino , Humanos , Pulmão/cirurgia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Transplantes , Resultado do Tratamento , Estados Unidos , Adulto JovemRESUMO
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.
Assuntos
Teste de Histocompatibilidade , Histocompatibilidade , Isoanticorpos/sangue , Transplante de Pulmão , Doença Aguda , Adolescente , Biomarcadores/sangue , Criança , Pré-Escolar , Feminino , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Transplante de Pulmão/efeitos adversos , Transplante de Pulmão/mortalidade , Masculino , Análise Multivariada , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Obtenção de Tecidos e Órgãos , Resultado do Tratamento , Estados UnidosRESUMO
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.
Assuntos
Adaptação Fisiológica , Peptídeos Catiônicos Antimicrobianos/metabolismo , DNA Bacteriano/metabolismo , Mutagênese , Infecções por Pseudomonas/metabolismo , Pseudomonas aeruginosa/metabolismo , Adolescente , Adulto , Peptídeos Catiônicos Antimicrobianos/química , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Criança , Doença Crônica , Fibrose Cística/genética , Fibrose Cística/metabolismo , Fibrose Cística/patologia , DNA Bacteriano/química , DNA Bacteriano/genética , Evolução Molecular , Feminino , Humanos , Masculino , Modelos Moleculares , Infecções por Pseudomonas/genética , Infecções por Pseudomonas/patologia , Pseudomonas aeruginosa/química , Pseudomonas aeruginosa/genética , CatelicidinasRESUMO
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.
Assuntos
Fibrose Cística/terapia , Progressão da Doença , Hospitalização/estatística & dados numéricos , Adolescente , Adulto , Criança , Pré-Escolar , Fibrose Cística/fisiopatologia , Bases de Dados Factuais , Feminino , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Análise Multivariada , Modelos de Riscos Proporcionais , Estados Unidos , Adulto JovemRESUMO
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.
Assuntos
Infecções por Acinetobacter/microbiologia , Acinetobacter/isolamento & purificação , Infecção Hospitalar/microbiologia , Centros Médicos Acadêmicos , Acinetobacter/efeitos dos fármacos , Acinetobacter/genética , Acinetobacter/fisiologia , Infecções por Acinetobacter/diagnóstico , Infecções por Acinetobacter/tratamento farmacológico , Infecções por Acinetobacter/etiologia , Adolescente , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Biofilmes , Criança , Pré-Escolar , Infecção Hospitalar/diagnóstico , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/etiologia , Farmacorresistência Bacteriana Múltipla , Feminino , Hospitais Pediátricos , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
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.
Assuntos
Bronquiolite Obliterante/epidemiologia , Fibrose Cística/cirurgia , Transplante de Pulmão , Oxigênio/sangue , Doadores de Tecidos , Adulto , Índice de Massa Corporal , Bronquiolite Obliterante/etiologia , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Transplante de Pulmão/efeitos adversos , Masculino , Pressão Parcial , Modelos de Riscos Proporcionais , Sistema de Registros , Taxa de Sobrevida , Síndrome , Resultado do Tratamento , Estados Unidos/epidemiologia , Adulto JovemRESUMO
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.
Assuntos
Bronquiectasia/mortalidade , Fibrose Cística/mortalidade , Transplante de Pulmão , Listas de Espera/mortalidade , Adulto , Bronquiectasia/fisiopatologia , Bronquiectasia/cirurgia , Fibrose Cística/fisiopatologia , Fibrose Cística/cirurgia , Feminino , Volume Expiratório Forçado , Humanos , Hipertensão Pulmonar/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Taxa de Sobrevida , Estados Unidos/epidemiologia , Adulto JovemRESUMO
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.
Assuntos
Fibrose Cística/complicações , Hipertensão Pulmonar/etiologia , Pulmão/fisiopatologia , Polissonografia , Transtornos do Sono-Vigília/etiologia , Sono , Adulto , Pressão Arterial , Gasometria , Capnografia , Cateterismo Cardíaco , Fibrose Cística/diagnóstico , Fibrose Cística/fisiopatologia , Teste de Esforço , Tolerância ao Exercício , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/fisiopatologia , Masculino , Ohio , Projetos Piloto , Valor Preditivo dos Testes , Artéria Pulmonar/fisiopatologia , Troca Gasosa Pulmonar , Estudos Retrospectivos , Fatores de Risco , Transtornos do Sono-Vigília/diagnóstico , Transtornos do Sono-Vigília/fisiopatologiaRESUMO
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.
Assuntos
Anemia Falciforme , Pneumopatias , Humanos , Anemia Falciforme/terapia , Anemia Falciforme/fisiopatologia , Anemia Falciforme/complicações , Anemia Falciforme/diagnóstico , Anemia Falciforme/epidemiologia , Criança , Pneumopatias/diagnóstico , Pneumopatias/terapia , Pneumopatias/fisiopatologia , Pneumopatias/etiologiaRESUMO
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.