RESUMEN
Muscle dysfunction is common in patients with adult respiratory distress syndrome and is associated with morbidity that can persist for years after discharge. In a mouse model of severe influenza A pneumonia, we found the proinflammatory cytokine IL-6 was necessary for the development of muscle dysfunction. Treatment with a Food and Drug Administration-approved Ab antagonist to the IL-6R (tocilizumab) attenuated the severity of influenza A-induced muscle dysfunction. In cultured myotubes, IL-6 promoted muscle degradation via JAK/STAT, FOXO3a, and atrogin-1 upregulation. Consistent with these findings, atrogin-1+/- and atrogin-1-/- mice had attenuated muscle dysfunction following influenza infection. Our data suggest that inflammatory endocrine signals originating from the injured lung activate signaling pathways in the muscle that induce dysfunction. Inhibiting these pathways may limit morbidity in patients with influenza A pneumonia and adult respiratory distress syndrome.
Asunto(s)
Virus de la Influenza A/fisiología , Gripe Humana/inmunología , Interleucina-6/metabolismo , Pulmón/fisiología , Proteínas Musculares/metabolismo , Músculos/patología , Infecciones por Orthomyxoviridae/inmunología , Neumonía Viral/inmunología , Proteínas Ligasas SKP Cullina F-box/metabolismo , Síndrome Debilitante/inmunología , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Proteína Forkhead Box O3/metabolismo , Humanos , Interleucina-6/genética , Quinasas Janus/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Musculares/genética , Proteínas Ligasas SKP Cullina F-box/genética , Factores de Transcripción STAT/metabolismo , Transducción de SeñalRESUMEN
Rationale: The contributions of diverse cell populations in the human lung to pulmonary fibrosis pathogenesis are poorly understood. Single-cell RNA sequencing can reveal changes within individual cell populations during pulmonary fibrosis that are important for disease pathogenesis. Objectives: To determine whether single-cell RNA sequencing can reveal disease-related heterogeneity within alveolar macrophages, epithelial cells, or other cell types in lung tissue from subjects with pulmonary fibrosis compared with control subjects. Methods: We performed single-cell RNA sequencing on lung tissue obtained from eight transplant donors and eight recipients with pulmonary fibrosis and on one bronchoscopic cryobiospy sample from a patient with idiopathic pulmonary fibrosis. We validated these data using in situ RNA hybridization, immunohistochemistry, and bulk RNA-sequencing on flow-sorted cells from 22 additional subjects. Measurements and Main Results: We identified a distinct, novel population of profibrotic alveolar macrophages exclusively in patients with fibrosis. Within epithelial cells, the expression of genes involved in Wnt secretion and response was restricted to nonoverlapping cells. We identified rare cell populations including airway stem cells and senescent cells emerging during pulmonary fibrosis. We developed a web-based tool to explore these data. Conclusions: We generated a single-cell atlas of pulmonary fibrosis. Using this atlas, we demonstrated heterogeneity within alveolar macrophages and epithelial cells from subjects with pulmonary fibrosis. These results support the feasibility of discovery-based approaches using next-generation sequencing technologies to identify signaling pathways for targeting in the development of personalized therapies for patients with pulmonary fibrosis.
Asunto(s)
Células Cultivadas/patología , Células Epiteliales/patología , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/patología , Análisis de Secuencia de ARN , Células Madre/patología , Transcriptoma , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND AND OBJECTIVE: Acute exacerbations of cystic fibrosis (CF) occur frequently throughout the course of the disease. Dyspnoea is the most common and distressing symptom experienced by patients during these episodes. We tested the hypothesis that pulmonary hyperinflation is an important determinant of dyspnoea severity during acute exacerbations. METHODS: We studied patients during an acute exacerbation of CF. Lung volumes, spirometry and dyspnoea scores were measured at Day 0, Day 7, at the end of treatment (EOT) and 14 days following the EOT. RESULTS: At the start of treatment, mean residual volume (RV)/total lung capacity (TLC) was 54.9%, which decreased significantly with treatment, as did vital capacity (VC), inspiratory capacity (IC) and dyspnoea scores. IC was the only independent predictor of dyspnoea severity. CONCLUSION: Our study demonstrates significant improvements in hyperinflation, spirometry and dyspnoea scores with treatment of acute exacerbations of CF. Hyperinflation, rather than airflow limitation, may contribute towards the increased dyspnoea during exacerbations.
Asunto(s)
Fibrosis Quística , Disnea , Adulto , Fibrosis Quística/complicaciones , Fibrosis Quística/fisiopatología , Disnea/diagnóstico , Disnea/etiología , Disnea/fisiopatología , Femenino , Volumen Espiratorio Forzado/fisiología , Humanos , Capacidad Inspiratoria/fisiología , Pulmón/fisiopatología , Masculino , Índice de Severidad de la Enfermedad , Espirometría/métodos , Estadística como Asunto , Evaluación de Síntomas/métodos , Brote de los Síntomas , Capacidad Vital/fisiologíaAsunto(s)
Quiste Mediastínico/diagnóstico por imagen , Quiste Mediastínico/cirugía , Pleura/diagnóstico por imagen , Pleura/cirugía , Tejido Adiposo/diagnóstico por imagen , Tejido Adiposo/cirugía , Epitelio/diagnóstico por imagen , Epitelio/cirugía , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Cirugía Torácica Asistida por Video , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Acute exacerbations of Cystic Fibrosis (AECF) are associated with significant morbidity. Recommendations are to treat for 2-3 weeks despite limited data. Spirometry is a measure of clinical response yet appears to plateau at 7-10 days. While durations <9 days have been associated with poorer outcomes, a duration of 10 days may be as effective as 14 days, potentially conferring advantages in terms of cost and adverse events. A 2019 Cochrane review by Abbott et al. did not identify any randomised controlled trials (RCT) comparing durations of treatment. Utilising data from non-randomised studies (NRS), we report a systematic review of intravenous antibiotic treatment, exploring changes in FEV1 (Forced Expiratory Volume in 1 second), CRP (C-reactive protein) and peripheral WBC (white blood cell) count in studies with different treatment durations. STUDY DESIGN AND METHODS: Systematic review of published literature following a search of MEDLINE, Embase, CINAHL and the Cochrane Clinical Trials register. Guidelines from the Preferred Reporting items for Systematic reviews and Meta-Analysis (PRISMA) and reporting Meta-analysis of Observational studies (MOOSE) statement were followed. RESULTS: No randomised controlled trials were identified that specifically examined duration of treatment during AECF. This study included all relevant RCTs and also NRS, grouping according to study characteristics, such as length of treatment, location, year, and also characteristics of the patient population. 52 studies, comprising 79 subgroups, and 1,597 patients, were identified. Mean change (95%CI) in ppFEV1 was 10.13 (9.21-11.05). There was no significant difference in change in ppFEV1 for studies treating for 10-12 days; 8.85 (7.47-10.23), vs 13-15 days; 10.68 (9.53-11.82). Similar changes in CRP and WBC were seen irrespective of treatment duration. CONCLUSION: This systematic review provides evidence that shorter durations of treatment may be associated with similar changes in FEV1, CRP and WBC compared with longer durations.
Asunto(s)
Fibrosis Quística , Administración Intravenosa , Antibacterianos , Fibrosis Quística/complicaciones , Fibrosis Quística/diagnóstico , Fibrosis Quística/tratamiento farmacológico , Volumen Espiratorio Forzado , HumanosRESUMEN
Rationale: The etiology of cystic fibrosis (CF) pulmonary exacerbations (PEx) is likely multifactorial with viral, bacterial, and non-infectious pathways contributing. Objectives: To determine whether viral infection status and CRP (C-reactive protein) can classify subphenotypes of PEx that differ in outcomes and biomarker profiles. Methods: Patients were recruited at time of admission for a PEx. Nasal swabs and sputum samples were collected and processed using the respiratory panel of the FilmArray multiplex polymerase chain reaction (PCR). Serum and plasma biomarkers were measured. PEx were classified using serum CRP and viral PCR: "pauci-inflammatory" if CRP < 5 mg/L, "non-viral with systemic inflammation" if CRP ⩾ 5 mg/L and no viral infection detected by PCR and "viral with systemic inflammation" if CRP ⩾ 5 mg/L and viral infection detected by PCR. Results: Discovery cohort (n = 59) subphenotype frequencies were 1) pauci-inflammatory (37%); 2) non-viral with systemic inflammation (41%); and 3) viral with systemic inflammation (22%). Immunoglobulin G, immunoglobulin M, interleukin-10, interleukin-13, serum calprotectin, and CRP levels differed across phenotypes. Reduction from baseline in forced expiratory volume in 1 second as percent predicted (FEV1pp) at onset of exacerbation differed between non-viral with systemic inflammation and viral with systemic inflammation (-6.73 ± 1.78 vs. -13.5 ± 2.32%; P = 0.025). Non-viral with systemic inflammation PEx had a trend toward longer duration of intravenous antibiotics versus pauci-inflammation (18.1 ± 1.17 vs. 14.8 ± 1.19 days, P = 0.057). There were no differences in percent with lung function recovery to <10% of baseline FEV1pp. Similar results were seen in local and external validation cohorts comparing a pauci-inflammatory to viral/non-viral inflammatory exacerbation phenotypes. Conclusions: Subphenotypes of CF PEx exist with differences in biomarker profile, clinical presentation, and outcomes.
Asunto(s)
Fibrosis Quística , Humanos , Pulmón , Proteína C-Reactiva/metabolismo , Antibacterianos/uso terapéutico , Biomarcadores , Inflamación/tratamiento farmacológico , Fenotipo , Progresión de la EnfermedadRESUMEN
RATIONALE: Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease resulting in respiratory failure and death. Use of noninvasive ventilation (NIV) improves survival. However, use of volume-assured pressure support (VAPS) has not been extensively studied in ALS. OBJECTIVES: To explore the clinical usefulness of a detailed evaluation of device-recorded NIV data in the management of chronic respiratory failure in ALS, and to determine whether there are differences in efficacy between patients using VAPS or PS. METHODS: We performed a retrospective chart review of 271 patients with ALS using either PS or VAPS, along with an evaluation of device-recorded data to explore differences in attainment of goal tidal volumes (Vt) and ratio of respiratory rate to tidal volume (f/Vt), in addition to triggering and cycling ability. RESULTS: Two hundred and fifteen patients were using PS, while 56 were using VAPS. There were no significant differences in demographic data, symptoms, pulmonary function, or patient compliance. Compared with VAPS, achieved Vt was significantly lower for PS while f/Vt was significantly higher. Percent spontaneous triggering was relatively preserved in both cohorts, whereas percent spontaneous cycling was considerably decreased in both. Furthermore, there was no association found between spontaneous triggering or cycling, and pulmonary function, indicating the presence of low spontaneous breath cycling or triggering ability is difficult to predict. CONCLUSIONS: Examination of device data for exhaled tidal volumes and f/Vt may be of use in evaluating efficacy of NIV in ALS. VAPS provides more reliable goal Vt than does PS, and is associated with decreased f/Vt. Spontaneous cycling is decreased in ALS despite preservation of triggering ability. Although a set backup rate may address decreased triggering, perhaps more importantly, setting a sufficient fixed inspiratory time would address the issue of decreased cycling.
Asunto(s)
Esclerosis Amiotrófica Lateral/fisiopatología , Respiración , Volumen de Ventilación Pulmonar/fisiología , Esclerosis Amiotrófica Lateral/complicaciones , Esclerosis Amiotrófica Lateral/terapia , Humanos , Ventilación no Invasiva , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/terapia , Estudios RetrospectivosRESUMEN
Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of monocyte-derived alveolar macrophages after their recruitment to the lung ameliorated lung fibrosis, whereas tissue-resident alveolar macrophages did not contribute to fibrosis. Using transcriptomic profiling of flow-sorted cells, we found that monocyte to alveolar macrophage differentiation unfolds continuously over the course of fibrosis and its resolution. During the fibrotic phase, monocyte-derived alveolar macrophages differ significantly from tissue-resident alveolar macrophages in their expression of profibrotic genes. A population of monocyte-derived alveolar macrophages persisted in the lung for one year after the resolution of fibrosis, where they became increasingly similar to tissue-resident alveolar macrophages. Human homologues of profibrotic genes expressed by mouse monocyte-derived alveolar macrophages during fibrosis were up-regulated in human alveolar macrophages from fibrotic compared with normal lungs. Our findings suggest that selectively targeting alveolar macrophage differentiation within the lung may ameliorate fibrosis without the adverse consequences associated with global monocyte or tissue-resident alveolar macrophage depletion.
Asunto(s)
Pulmón/patología , Macrófagos Alveolares/patología , Animales , Diferenciación Celular , Fibrosis , Humanos , Pulmón/citología , Ratones , Monocitos/patologíaRESUMEN
Patients with chronic lung disease may have mild hypoxemia at sea level. Some of these cases may go unrecognized, and even among those who are known to be hypoxemic, some do not use supplemental oxygen. During air travel in a hypobaric hypoxic environment, compensatory pulmonary mechanisms may be inadequate in patients with lung disease despite normal sea-level oxygen requirements. In addition, compensatory cardiovascular mechanisms may be less effective in some patients who are unable to increase cardiac output. Air travel also presents an increased risk of venous thromboembolism. Patients with cystic lung disease may also be at increased risk of pneumothorax. Although overall this risk appears to be relatively low, should a pneumothorax occur, it could present a significant challenge to the patient with chronic lung disease, particularly if hypoxemia is already present. As such, a thorough assessment of patients with chronic lung disease and cardiac disease who are contemplating air travel should be performed. The duration of the planned flight, the anticipated levels of activity, comorbid illnesses, and the presence of risk factors for venous thromboembolism are important considerations. Hypobaric hypoxic challenge testing reproduces an environment most similar to that encountered during actual air travel; however, it is not widely available. Assessment for hypoxia is otherwise best performed using a normobaric hypoxic challenge test. Patients in need of supplemental oxygen need to contact the airline and request this accommodation during flight. They should also be advised on arranging portable oxygen concentrators before air travel, and a discussion of the potential risks of travel should take place.
Asunto(s)
Medicina Aeroespacial/métodos , Aeronaves , Hipoxia/etiología , Enfermedades Pulmonares/terapia , Oxígeno/metabolismo , Aptitud Física , Viaje , Presión del Aire , Humanos , Hipoxia/metabolismo , Hipoxia/terapia , Enfermedades Pulmonares/complicaciones , Enfermedades Pulmonares/fisiopatología , Factores de RiesgoRESUMEN
RATIONALE: During the recent H1N1 outbreak, obese patients had worsened lung injury and increased mortality. We used a murine model of influenza A pneumonia to test the hypothesis that leptin receptor deficiency might explain the enhanced mortality in obese patients. METHODS: We infected wild-type, obese mice globally deficient in the leptin receptor (db/db) and non-obese mice with tissue specific deletion of the leptin receptor in the lung epithelium (SPC-Cre/LepR fl/fl) or macrophages and alveolar type II cells (LysM-Cre/Lepr fl/fl) with influenza A virus (A/WSN/33 [H1N1]) (500 and 1500 pfu/mouse) and measured mortality, viral clearance and several markers of lung injury severity. RESULTS: The clearance of influenza A virus from the lungs of mice was impaired in obese mice globally deficient in the leptin receptor (db/db) compared to normal weight wild-type mice. In contrast, non-obese, SP-C-Cre+/+/LepR fl/fl and LysM-Cre+/+/LepR fl/fl had improved viral clearance after influenza A infection. In obese mice, mortality was increased compared with wild-type mice, while the SP-C-Cre+/+/LepR fl/fl and LysM-Cre+/+/LepR fl/fl mice exhibited improved survival. CONCLUSIONS: Global loss of the leptin receptor results in reduced viral clearance and worse outcomes following influenza A infection. These findings are not the result of the loss of leptin signaling in lung epithelial cells or macrophages. Our results suggest that factors associated with obesity or with leptin signaling in non-myeloid populations such as natural killer and T cells may be associated with worsened outcomes following influenza A infection.
Asunto(s)
Células Epiteliales Alveolares/fisiología , Subtipo H1N1 del Virus de la Influenza A/inmunología , Leptina/fisiología , Macrófagos Alveolares/virología , Infecciones por Orthomyxoviridae/inmunología , Células Epiteliales Alveolares/virología , Animales , Perros , Pulmón/inmunología , Pulmón/patología , Pulmón/virología , Macrófagos Alveolares/fisiología , Células de Riñón Canino Madin Darby , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Obesos , Neutrófilos/inmunología , Neutrófilos/virología , Infecciones por Orthomyxoviridae/metabolismo , Infecciones por Orthomyxoviridae/virología , Receptores de Leptina/genética , Receptores de Leptina/metabolismoRESUMEN
BACKGROUND: To determine whether the serum osmolarity, calculated at the time of an emergency medical presentation, alone or combined with other predictors, could identify patients at low and high risks of an inpatient death by day 30. METHODS: A retrospective analysis of all emergency medical patients admitted to St. James's Hospital (SJH), Dublin between the 1st of January 2002 and the 31st of December 2009, using the hospital in-patient enquiry (HIPE) system, linked to the patient administration system, and laboratory datasets. Hospital inpatient mortality (30 days) was obtained from a database of deaths over the same period. Multivariate logistic regression was used to derive the best predictive model, with goodness of fit and Area Under the Receiver Operator Curves (AUROC) assessing the predictive accuracy. RESULTS: Univariate analysis identified two quantiles of <10% and >75% of the osmolarity distribution as being at an increased mortality risk. Their respective mortality rates were 13.7% and 15.7% respectively, with unadjusted odds rate that were 1.66 (1.47, 1.88): p<0.0001 and 3.14 (2.87, 3.43): p<0.0001. After adjustment for other outcome predictors, a significant association with increased mortality remained, with OR=1.82 (1.61, 2.06), p<0.0001. Although the calculated osmolarity alone was not sufficiently predictive with AUROC=0.74 (95% CI: 0.73, 0.76), when combined with other predictors, the AUROC increased to 0.86 (95% CI: 0.84, 0.88). CONCLUSION: Admission osmolarity, a simple calculation, is associated with the risk of mortality in acutely ill medical patients; deviations outside the normal range are relevant. A useful clinical predictive algorithm requires the incorporation of additional predictors.
Asunto(s)
Servicio de Urgencia en Hospital/estadística & datos numéricos , Admisión del Paciente/estadística & datos numéricos , Suero/química , Adulto , Anciano , Femenino , Mortalidad Hospitalaria/tendencias , Humanos , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Concentración Osmolar , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: The implementation of workplace smoking bans has contributed to a significant reduction in the incidence of acute coronary syndrome admissions, but their influence on adult acute pulmonary disease admissions is unclear. We sought to assess the impact of a national smoking ban on nationwide admissions of individuals of working age with acute pulmonary illness. METHODS: Data relating to emergency hospital admissions of subjects aged 20 to 70 years preceding and succeeding the implementation of the Irish smoking ban were obtained from a central registry. Population, weather, pollution, and influenza data were obtained from the relevant authorities. Poisson regression analysis was used to assess adjusted risk of emergency hospital admission following implementation of the smoking ban. RESULTS: Overall admissions with pulmonary illness decreased from 439 per 100,000 population per annum to 396 per 100,000 population per annum following the ban (unadjusted relative risk [RR], 0.91; 95% CI, 0.83-0.99; P = .048). This persisted following adjustment for confounding factors (adjusted RR, 0.85; 95% CI, 0.72-0.99; P = .04) and was most marked among younger age groups and in admissions due to asthma (adjusted RR, 0.60; 95% CI, 0.39-0.91; P = .016). Admissions with acute coronary syndromes (adjusted RR, 0.82; 95% CI, 0.70-0.97; P = .02), but not stroke (adjusted RR, 0.93; 95% CI, 0.73-1.20; P = .60), were also reduced. CONCLUSIONS: The implementation of a nationwide workplace smoking ban is associated with a decline in admissions with acute pulmonary disease among specific age groups and an overall reduction in asthma admissions. This may result from reduced exposure of vulnerable individuals to environmental tobacco smoke, emphasizing the potential benefit of legislation reducing second-hand smoke exposure.