RESUMO
Pulmonary fibrosis has been identified as a main factor leading to pulmonary dysfunction and poor quality of life in post-recovery Severe Acute Respiratory Syndrome (SARS) survivor's consequent to SARS-Cov-2 infection. Thus there is an urgent medical need for identification of readily available biomarkers that in patients with SARS-Cov-2 infection are able to; (1) identify patients in most need of medical care prior to admittance to an intensive care unit (ICU), and; (2) identify patients post-infection at risk of developing persistent fibrosis of lungs with subsequent impaired quality of life and increased morbidity and mortality. An intense amount of research have focused on wound healing and Extracellular Matrix (ECM) remodelling of the lungs related to lung function decline in pulmonary fibrosis (PF). A range of non-invasive serological biomarkers, reflecting tissue remodelling, and fibrosis have been shown to predict risk of acute exacerbations, lung function decline and mortality in PF and other interstitial lung diseases (Sand et al. in Respir Res 19:82, 2018). We suggest that lessons learned from such PF studies of the pathological processes leading to lung function decline could be used to better identify patients infected with SARS-Co-V2 at most risk of acute deterioration or persistent fibrotic damage of the lung and could consequently be used to guide treatment decisions.
Assuntos
COVID-19/metabolismo , Matriz Extracelular/metabolismo , Fibrose Pulmonar/metabolismo , Cicatrização/fisiologia , Animais , Biomarcadores/metabolismo , COVID-19/diagnóstico , Humanos , Pulmão/metabolismo , Fibrose Pulmonar/diagnósticoRESUMO
The Department of Health is promoting the generation of specialist networks to manage long term ventilatory weaning and domiciliary non-invasive ventilation patients. Currently the availability of these services in England is not known. We performed a short survey to establish the prevalence of sleep and ventilation diagnostic and treatment services. The survey focussed on diagnostic services and Home Mechanical Ventilation (HMV) provision, and was divided into (a) availability of diagnostics, (b) funding, and (c) patient groups. This survey has confirmed that the majority of Home Mechanical Ventilation set-ups are currently for Obesity Related Respiratory Failure and Chronic Obstructive Pulmonary Disease. We have found that there is variable provision of diagnostic services, with the majority of units offering overnight oximetry (95%) but only 55% of responders providing a home mechanical ventilation service. Even more interestingly, less than two thirds of units charged their primary care trust for this service. These data may assist in the development of regional networks and specialist home mechanical ventilation centres.
Assuntos
Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Polissonografia/estatística & dados numéricos , Doença Pulmonar Obstrutiva Crônica/terapia , Respiração Artificial/estatística & dados numéricos , Monitorização Transcutânea dos Gases Sanguíneos/economia , Monitorização Transcutânea dos Gases Sanguíneos/estatística & dados numéricos , Eletroencefalografia/estatística & dados numéricos , Eletromiografia/estatística & dados numéricos , Inglaterra , Pesquisas sobre Atenção à Saúde , Serviços de Assistência Domiciliar , Humanos , Obesidade/complicações , Polissonografia/economia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Respiração Artificial/economiaRESUMO
In idiopathic interstitial pneumonia (IIP), the significance of connective tissue disease (CTD) features in the absence of a specific CTD diagnosis remains unclear. We studied the clinical and prognostic utility of a diagnosis of undifferentiated CTD (UCTD) in patients with biopsy-proven IIP. IIP patients undergoing surgical lung biopsy (1979-2005) were studied (nonspecific interstitial pneumonia (NSIP), n = 45; idiopathic pulmonary fibrosis, n = 56). UCTD was considered present when serum autoantibodies were present and symptoms or signs suggested CTD. The relationship between UCTD and NSIP histology was evaluated. A clinical algorithm that best predicted NSIP histology was constructed using a priori variables. The prognostic utility of UCTD, and of this algorithm, was evaluated. UCTD was present in 14 (31%) NSIP and seven (13%) IPF patients. UCTD was not associated with a survival benefit. The algorithm predictive of NSIP (OR 10.4, 95% CI 3.21-33.67; p<0.0001) consisted of the absence of typical high-resolution computed tomography (HRCT) features for IPF and 1) a compatible demographic profile (females aged <50 yrs) or 2) Raynaud's phenomenon. In patients with an HRCT scan not typical for IPF, this algorithm predicted improved survival (hazard ratio 0.35, 95% CI 0.14-0.85; p = 0.02) independent of IIP severity. UCTD is associated with NSIP histology. However, the diagnostic and prognostic significance of UCTD in IIP patients remains unclear.
Assuntos
Doenças do Tecido Conjuntivo/mortalidade , Pneumonias Intersticiais Idiopáticas/mortalidade , Adulto , Idoso , Algoritmos , Autoanticorpos/sangue , Biópsia , Doenças do Tecido Conjuntivo/sangue , Doenças do Tecido Conjuntivo/diagnóstico por imagem , Doenças do Tecido Conjuntivo/patologia , Feminino , Humanos , Pneumonias Intersticiais Idiopáticas/diagnóstico por imagem , Pneumonias Intersticiais Idiopáticas/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Doença de Raynaud/diagnóstico por imagem , Doença de Raynaud/mortalidade , Doença de Raynaud/patologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Sobrevida , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Nocturnal desaturation may contribute to long-term pulmonary vascular stress in interstitial lung disease (ILD). We study the prevalence, severity and prognostic utility of nocturnal desaturation across ILD. METHODS: ILD patients with overnight oximetry (June 2006-August 2008) were reviewed (n = 134). Significant nocturnal desaturation was considered as > 10% of sleep with SpO2 < 90%. Desaturation index (DI) was defined as the number of desaturation events > 4%/hr. Covariates, including indices of nocturnal desaturation, were evaluated against mortality. RESULTS: Nocturnal desaturation was present in 49 (37%) patients. 31% of patients had pulmonary hypertension (PH) on echocardiography. Increased DI was associated with higher mortality independent of age, gender and BMI (HR 1.04; 95% CI 1.00, 1.06; p = 0.009). In separate models, DI and a) elevated brain natriuretic peptide (BNP; HR 1.04; 95% CI 1.00, 1.08; p = 0.04); b) moderate-severe PH on echocardiography (HR 3.15; 95% CI 1.24, 8.00; p = 0.02); and c) daytime resting SpO2 (HR 0.92; 95% CI 0.85, 0.99; p = 0.04) independently predicted mortality following adjustment for age, gender and BMI. CONCLUSION: Nocturnal desaturation is common and may be severe in ILD. Elevated nocturnal DI predicts higher mortality across ILD, independent of other vascular parameters. This finding may have important implications for the pathogenesis of PH in IPF.
Assuntos
Ritmo Circadiano , Hipertensão Pulmonar/epidemiologia , Hipóxia/epidemiologia , Doenças Pulmonares Intersticiais/epidemiologia , Oxigênio/sangue , Idoso , Biomarcadores/sangue , Ecocardiografia , Teste de Esforço , Feminino , Humanos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/mortalidade , Hipóxia/sangue , Hipóxia/diagnóstico , Hipóxia/mortalidade , Londres/epidemiologia , Doenças Pulmonares Intersticiais/sangue , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Oximetria , Valor Preditivo dos Testes , Prevalência , Prognóstico , Modelos de Riscos Proporcionais , Testes de Função Respiratória , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Regulação para CimaRESUMO
BACKGROUND AND AIM: Acoustic lung imaging offers a unique method for visualising the lung. This study was designed to demonstrate reproducibility of acoustic lung images recorded from healthy individuals at different time points and to assess intra- and inter-rater agreement in the assessment of dynamically represented acoustic lung images. METHODS: Recordings from 29 healthy volunteers were made on three separate occasions using vibration response imaging. Reproducibility was measured using quantitative, computerised assessment of vibration energy. Dynamically represented acoustic lung images were scored by six blinded raters. RESULTS: Quantitative measurement of acoustic recordings was highly reproducible with an intraclass correlation score of 0.86 (very good agreement). Intraclass correlations for inter-rater agreement and reproducibility were 0.61 (good agreement) and 0.86 (very good agreement), respectively. There was no significant difference found between the six raters at any time point. Raters ranged from 88% to 95% in their ability to identically evaluate the different features of the same image presented to them blinded on two separate occasions. CONCLUSION: Acoustic lung imaging is reproducible in healthy individuals. Graphic representation of lung images can be interpreted with a high degree of accuracy by the same and by different reviewers.
Assuntos
Pulmão/anatomia & histologia , Som , Adulto , Feminino , Humanos , Masculino , Variações Dependentes do Observador , Reprodutibilidade dos TestesRESUMO
BACKGROUND: International guidelines recommend nintedanib (OFEV®) as an option for the treatment of idiopathic pulmonary fibrosis (IPF). OBJECTIVE: The objective of this study was to assess the cost effectiveness of nintedanib versus pirfenidone, N-acetylcysteine and best supportive care (BSC) for the treatment of IPF from a UK payer's perspective. METHODS: A Markov model was designed to capture the changes in the condition of adults with IPF. Efficacy outcomes included mortality, lung function decline and acute exacerbations. Treatment safety (serious adverse events) and tolerability (overall discontinuation) were also considered. The baseline risk of these events was derived from patient-level data from the placebo arms of nintedanib clinical trials (TOMORROW, INPULSIS-1, INPULSIS-2). A network meta-analysis (NMA) was conducted to estimate the relative effectiveness of the comparator treatments. Quality of life and healthcare resource use data from the clinical trials were also incorporated in the economic model. RESULTS: Nintedanib showed statistically significant differences against placebo on acute exacerbation events avoided and lung function decline. In the cost-effectiveness analysis, the results were split between two treatments with relative low costs and modest effectiveness (BSC and N-acetylcysteine) and two that showed improved effectiveness (lung function) and higher costs (nintedanib and pirfenidone). All comparators were assumed to have similar projected survival and the difference in quality-adjusted life-years (QALYs) was driven by the acute exacerbations and lung function estimates. In the base-case deterministic pairwise comparison with pirfenidone, nintedanib was found to have fewer acute exacerbations and resulted in less costs and more QALYs gained. CONCLUSIONS: Compared with BSC (placebo), nintedanib and pirfenidone were the only treatments to show statistical significance in the efficacy parameters. We found substantial uncertainty in the overall cost-effectiveness results between nintedanib and pirfenidone. N-Acetylcysteine was largely similar to BSC but with a worse survival profile. INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.
Assuntos
Acetilcisteína/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis/uso terapêutico , Piridonas/uso terapêutico , Acetilcisteína/efeitos adversos , Acetilcisteína/economia , Adulto , Análise Custo-Benefício , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/economia , Inibidores Enzimáticos/uso terapêutico , Humanos , Fibrose Pulmonar Idiopática/economia , Fibrose Pulmonar Idiopática/mortalidade , Indóis/efeitos adversos , Indóis/economia , Cadeias de Markov , Modelos Econômicos , Piridonas/efeitos adversos , Piridonas/economia , Qualidade de Vida , Anos de Vida Ajustados por Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Reino UnidoRESUMO
Idiopathic pulmonary fibrosis (IPF) conveys a median survival of 3 years and until recently has lacked effective therapies. Nintedanib, an orally available, small-molecule tyrosine kinase inhibitor with selectivity for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) receptors has recently been shown, in two pivotal phase III studies, to effectively slow IPF disease progression. Consequently, nintedanib was given accelerated approval by the FDA in October 2014 for the treatment of IPF. This monograph explores the preclinical rationale for the antifibrotic role of nintedanib and provides an overview of the available data on pharmacokinetics, efficacy and safety.
Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Ensaios Clínicos como Assunto , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Indóis/administração & dosagem , Indóis/efeitos adversos , Indóis/farmacocinética , Estrutura Molecular , Fator de Crescimento Derivado de Plaquetas/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/antagonistas & inibidores , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Idiopathic pulmonary fibrosis (IPF) is the most common and lethal of the idiopathic interstitial pneumonias with an estimated 5-year survival of approximately 20%. In the last two decades our understanding of disease pathogenesis has substantially evolved and novel compounds have been developed consequent to the increasing knowledge of the mechanisms underlying disease pathobiology. The disease appears to be driven - following chronic injury - by abnormal/dysfunctional alveolar epithelial cells that promote fibroblast recruitment and proliferation, resulting in scarring of the lung and irreversible loss of function. With very few exceptions, clinical trials evaluating novel potential therapies have provided disappointing results. More recently, pirfenidone and nintedanib, two compounds with pleiotropic mechanisms of action, have proven effective in slowing functional decline and disease progression in IPF patients with mild to moderate functional impairment, highlighting the importance of timely diagnosis and administration of treatment in early stages of disease. However, due to the complexity and uncertainties intrinsic to IPF, it is essential that each therapeutic strategy be tailored to the individual patient, after evaluation of potential benefits and risks. This article provides an overview of the most recent clinical trials in IPF and discusses how their results are going to change the clinical and clinical research landscape in IPF. A number of agents with high potential are currently being tested and many more are ready for clinical trials. Their completion is critical for achieving the ultimate goal of curing patients with IPF.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis/uso terapêutico , Piridonas/uso terapêutico , Animais , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodosRESUMO
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a dismal prognosis for which, until recently, there were no effective treatments. Pirfenidone (5-methyl-1-phenylpyridin-2[1H]-one) is a novel antifibrotic agent that has been demonstrated to slow disease progression in patients with IPF. In vitro and in vivo animal models of pulmonary fibrosis have shown that pirfenidone exerts its effect by reducing inflammatory cytokines such as TNF-α, by downregulating the transcription of key profibrotic growth factors including TGF-ß, and through reductions in lipid peroxidation and oxidative stress. In three of four multicenter, randomized, placebo-controlled trials in patients with IPF, pirfenidone has been shown to slow disease progression as measured by decline in forced vital capacity over 36-72 weeks. In general, in these clinical trials, pirfenidone was safe and well tolerated. Reported adverse effects include nausea, anorexia and photosensitivity dermatitis. A number of questions remain concerning the long-term efficacy and safety of pirfenidone and whether slowing of lung function decline will translate into improved survival for patients with IPF. These questions notwithstanding, pirfenidone represents an important development in the treatment of IPF and is a much needed addition to the previously inadequate therapeutic armamentarium for this devastating disease.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/efeitos dos fármacos , Piridonas/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacocinética , Ensaios Clínicos como Assunto/métodos , Modelos Animais de Doenças , Medicina Baseada em Evidências , Humanos , Fibrose Pulmonar Idiopática/imunologia , Fibrose Pulmonar Idiopática/fisiopatologia , Pulmão/imunologia , Pulmão/fisiopatologia , Piridonas/efeitos adversos , Piridonas/farmacocinética , Projetos de Pesquisa , Resultado do TratamentoRESUMO
Idiopathic pulmonary fibrosis (IPF) is a devastating condition that carries a prognosis worse than that of many cancers. A recent classification of the idiopathic interstitial pneumonias has redefined the diagnostic criteria necessary to determine a diagnosis of IPF. The present authors believe that this redefinition is incorrect, relying as it does on subtle histological differences for the definition of separate disease categories. A further issue affecting IPF research is the polarisation of views around two competing pathogenetic hypotheses. One argues for the primacy of inflammation as the trigger that initiates fibrosis, and the other proposes that fibrosis arises as a consequence of chronic epithelial injury and failure of repair due to aberrant epithelial-mesenchymal interactions. The present authors believe that this schism is hampering understanding of IPF and skewing research priorities. It is argued here, instead, that abnormalities in multiple pathways involved in wound healing and inflammation lead to the development of idiopathic pulmonary fibrosis, and it is suggested that a new rationale for clinical classification and pathogenesis may be more productive in driving the search for novel therapies in the future.
Assuntos
Fibrose Pulmonar/etiologia , Fibrose Pulmonar/fisiopatologia , Animais , Humanos , Prognóstico , Fibrose Pulmonar/classificação , Fibrose Pulmonar/terapiaRESUMO
AIM: This study aimed to determine whether patients with stage 1 testicular non seminomatous germ cell tumours (NSGCT) with high vascular density have a greater risk of disease recurrence than those with a low vascular density. METHODS AND RESULTS: Orchidectomy specimens from 42 patients with stage 1 NSGCT, treated by orchidectomy and surveillance alone, were studied. Vessel density was counted in tumour sections immunohistochemically stained for CD34. The mean of the three highest counts (x250, field size 0.67 mm2) for each tumour was used. Tumour vessel density was very similar for relapsing and non relapsing patients. Vascular invasion was the only variable significantly predictive of disease recurrence at 2 years post-orchidectomy (P = 0.025). There was wide variation of vessel counts between different blocks of a tumour, compared with interobserver variation. The tumour tissue type in the area of highest vessel density was embryonal carcinoma in 50% and teratoma (mature or immature) in 38%. CONCLUSIONS: We confirmed the value of vascular invasion as a prognostic marker in stage 1 NSGCT. Tumour vessel density was of no prognostic value. Two factors may contribute to this. First, there was wide variation of vessel density between different blocks of a tumour. Second, the most vascular area in a tumour was frequently in low-grade tumour.