Diagnosis and management of pulmonary arterial hypertension: Implications for respiratory care

Pulmonary arterial hypertension (PAH) is a pathological condition of the small pulmonary arteries. PAH is characterized histopathologically by vasoconstriction, vascular proliferation, in situ thrombosis, and remodeling of all 3 levels of the vascular walls. These pathologic changes result in progressive increases in the mean pulmonary-artery pressure and pulmonary vascular resistance, which, if untreated, leads to right-ventricular failure and death. PAH can be associated with multiple conditions or risk factors (eg, collagen vascular diseases, liver disease, human immunodeficiency virus, congenital heart disease, or ingestion of certain medications or toxins) or it can be idiopathic. Up to 10% of the idiopathic cases are familial. Regardless of the etiology, the clinical presentation, histopathologic lesions, and response to therapy are all similar. Early in the disease process, the signs and symptoms of PAH are often subtle and nonspecific, making diagnosis challenging. Patients most often present with progressively worsening dyspnea and fatigue. An extensive evaluation is indicated to diagnose PAH, decipher its etiology, and determine long-term treatment goals. Transthoracic echocardiogram is an excellent screening tool to evaluate PAH, but every patient requires a right-side heart catheterization to help stage the disease and guide therapy. Prior to a decade ago, clinicians were only able to offer symptomatic therapy to this challenging group of patients. Earlier diagnosis, rapidly advancing understanding of the pathogenesis, and an increasing number of treatment options have changed the course of PAH, which was once thought to be invariably fatal.     

Palliative and end-of-life care for patients with idiopathic pulmonary fibrosis: challenges and dilemmas

Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening interstitial lung disease of unknown aetiology and with limited proven treatment options. As it is predominantly a disease of older age, a growing elderly population will increase its incidence. IPF has a poor prognosis, with a median survival of 3-5 years after diagnosis and a 5-year survival rate of 10-15%. Patients may suffer gradual decline but acute and unpredictable episodes of respiratory failure may result in death. Further research is needed to ascertain the worth of potential prognostic indicators such as age, respiratory hospitalisations, percentage of predicted forced vital capacity (FVC), and 24-week change in FVC. Integration of palliative care principles into IPF treatment is essential, including advance care planning, relief of physical and psychological burden, and patient and carer education. It is unknown whether pulmonary rehabilitation is of benefit but it may improve fatigue and functional capacity.     

Pharmacologic therapies for idiopathic pulmonary fibrosis,past and future

Valve replacement is the only long-term effective treatment for calcific aortic valve stenosis. However, this treatment is aimed only at patients with advanced leaflet disease and symptoms of left ventricular obstruction. Over the past 15 years, our understanding of the pathogenesis of calcific aortic stenosis has changed significantly: away from a passive degenerative disease to an active process involving endothelial dysfunction, lipid accumulation, an inflammatory infiltrate, and a regulated process of calcification. Since many of the same processes are characteristic of atherosclerosis, trials have been undertaken to test whether medical therapy (statins, renin-angiotensin inhibition) can prevent or alter the disease course. Although retrospective and non-randomized studies suggested a positive effect with statins, benefit has not been seen in perspective randomized controlled trials, although two major studies are still in progress. Inhibition of renin-angiotensin has shown discordant results in retrospective studies with no randomized controlled data published. In the future, we need to consider other medical therapies that might target different pathways in this disease process. In addition, we need to define the optimal timing and duration of therapy for this chronic slowly progressive disease; treatments aimed at the early disease process may be ineffective with end-stage tissue changes.     

Dyspnea in idiopathic pulmonary fibrosis: a systematic review

ContextLittle is known about the treatment and correlates of dyspnea in idiopathic pulmonary fibrosis (IPF).ObjectivesThe objective of this systematic review was to summarize the literature regarding the treatment and correlates of dyspnea in IPF.MethodsMEDLINE, EMBASE, and all Evidence-Based Medicine Reviews were searched for publications that evaluated treatment or correlates of dyspnea in IPF. Reference lists and recent review articles also were searched.ResultsThe heterogeneity of included studies did not permit meta-analysis. Dyspnea improved in studies of sildenafil, pulmonary rehabilitation, and prednisone with colchicine. Additional studies of these three treatments, however, found discordant results. One study suggested that assisted ventilation delivered by facemask improved exertional dyspnea. Oxygen and opioids improve dyspnea in other chronic lung diseases, but data in IPF are limited. Correlates of dyspnea included functional and physiological measures and comorbid diseases.ConclusionSildenafil and pulmonary rehabilitation should be considered as potential therapies for dyspnea in selected patients with IPF. Supplemental oxygen and opioids may be additional potential therapies; however, the evidence supporting their use is weak. Additional research should focus on the management of functional status and comorbidities as potential treatments for dyspnea.     

细胞因子治疗特发性肺纤维化

目的:总结并分析细胞因子在特发性肺纤维化发病机制与治疗中的作用,特别是致炎细胞因子在特发性肺纤维化治疗中的应用。资料来源:应用计算机检索Pubmed1996-01/2006-05有关细胞因子治疗特发性肺纤维化应用及研究的文献,检索词“idiopathic pulmonary fibrosis,cytokines,biologic agent therapy,gene therapy”,并限定文献语言种类为English。资料选择:对资料进行整理,并查看每篇文献后的引文,选取针对性强的文章,同一领域的文献则选择近期发表或权威杂志的文章。纳入标准:关于特发性肺纤维化的概念、分类、发病机制和治疗方法及细胞因子在特发性肺纤维化发病机制和治疗方法中的作用。排除标准:重复性研究。资料提炼:共检索到54篇符合要求的相关文献,其中研究内容相似的,以近3年内发表的文章优先。对符合标准的30篇文献进行分析。纳入的文章主要涉及细胞因子在特发性肺纤维化的发病机制和治疗方法中的作用。资料综合:目前,特发性肺纤维化的传统药物疗法仍然存在争议。随着对特发性肺纤维化发病机制认识的逐渐深入,各种新的治疗策略相继出现。而最近的临床和动物试验研究均提出针对调节促纤维化细胞因子的治疗是比较有前途的治疗策略。促纤维化细胞因子的释放导致纤维细胞增殖并迁移到肺组织的不同部位,接着分化为不同的成纤维细胞亚型,而这种纤维细胞的分化可能是特发性肺纤维化慢性进程的关键原因。针对细胞因子治疗包括生物制剂治疗和基因治疗两大领域已经成为特发性肺纤维化治疗研究的热点和主要方向。本文从细胞因子在特发性肺纤维化治疗中的应用方面进行综述。结论:细胞因子在特发性肺纤维化发病中起到了促纤维化的关键性作用,针对细胞因子包括生物制剂治疗和基因治疗两大领域已经成为治疗特发性肺纤维化最有前景的手段之一。     

Noninvasive ventilation in the event of acute respiratory failure in patients with idiopathic pulmonary fibrosis

Background

Some patients with idiopathic pulmonary fibrosis (IPF) develop severe acute respiratory failure (ARF) requiring admission to an intensive care unit (ICU) and ventilatory support. A limited number of observational studies have reported that noninvasive ventilation (NIV) can be an effective treatment to support breathing and to prevent use of invasive mechanical ventilation in these patients. This study aimed to retrospectively investigate the clinical status and outcomes in IPF patients receiving NIV for ARF and to identify those clinical and laboratory characteristics, which could be considered risk factors for its failure.

Methods

This is a retrospective analysis of short-term outcomes in 18 IPF patients being administered NIV for ARF. This study was conducted in a 4-bed respiratory ICU (RICU) in a university hospital. Eighteen IPF patients who were administered NIV between January 1, 2005, and April 30, 2013, were included. The outcome measures are the need for endotracheal intubation despite NIV treatment and mortality rate during their RICU stay. The length of the patients' stay in the RICU and their survival rate following RICU admission were also evaluated.

Results

Noninvasive ventilation was successful in 8 patients and unsuccessful in 10 who required endotracheal intubation. All the patients in the NIV failure group died within 20.2 ± 15.3 days of intubation. The patients in the NIV success group spent fewer days in the RICU (11.6 ± 4.5 vs 24.6 ± 13.7; P = .0146). The median survival time was significantly shorter for the patients in the NIV failure with respect to the success group (18.0 [95% confidence interval {CI}, 9.0-25.0] vs 90.0 [95% CI, 65.0-305.0] days; P < .0001); the survival rate at 90 days was, likewise, lower in the NIV failure group (0% vs 34% ± 19.5%). At admission, the patients in the failure group had significantly higher respiratory rate values (36.9 ± 7.8 vs 30.5 ± 3.3 breaths/min; P = .036), plasma N-terminal fragment of the prohormone of B-type natriuretic peptide (NT-proBNP) levels (4528.8 ± 4012.8 vs 634.6 ± 808.0 pg/mL; P = .023) and serum C-reactive protein values (72.0 ± 50.0 vs 20.7 ± 24.0 μg/mL; P = .0289) with respect to those in the success group. Noninvasive ventilation failure was correlated to the plasma NT-proBNP levels at RICU admission (P = .0326) with an odds ratio of 12.2 (95% CI, 1.2 to infinity) in the patients with abnormally high values (>900 pg/mL).

Conclusions

The outcome of IPF patients who were administered NIV was quite poor. The use of NIV was, nevertheless, found to be associated with clinical benefits in selected IPF patients, preventing the need for intubation and reducing the rate of complications/death. Elevated plasma NT-proBNP levels at the time of ICU admission is a simple clinical marker for poor NIV outcome.     

Caveolin-1: a critical regulator of lung fibrosis in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive chronic disorder characterized by activation of fibroblasts and overproduction of extracellular matrix (ECM). Caveolin-1 (cav-1), a principal component of caveolae, has been implicated in the regulation of numerous signaling pathways and biological processes. We observed marked reduction of cav-1 expression in lung tissues and in primary pulmonary fibroblasts from IPF patients compared with controls. We also demonstrated that cav-1 markedly ameliorated bleomycin (BLM)-induced pulmonary fibrosis, as indicated by histological analysis, hydroxyproline content, and immunoblot analysis. Additionally, transforming growth factor beta1 (TGF-beta1), the well-known profibrotic cytokine, decreased cav-1 expression in human pulmonary fibroblasts. cav-1 was able to suppress TGF-beta1-induced ECM production in cultured fibroblasts through the regulation of the c-Jun N-terminal kinase (JNK) pathway. Interestingly, highly activated JNK was detected in IPF- and BLM-instilled lung tissue samples, which was dramatically suppressed by ad-cav-1 infection. Moreover, JNK1-null fibroblasts showed reduced smad signaling cascades, mimicking the effects of cav-1. This study indicates a pivotal role for cav-1 in ECM regulation and suggests a novel therapeutic target for patients with pulmonary fibrosis.     

Primary pulmonary carcinoma in patients with idiopathic pulmonary fibrosis

OBJECTIVE: To identify distinguishing characteristics between patients with idiopathic pulmonary fibrosis (IPF) and primary lung carcinoma and patients with either IPF or carcinoma alone. PATIENTS AND METHODS: The study group consisted of 24 patients with histologically proven usual interstitial pneumonia and lung carcinoma identified through a search of the Rochester Mayo Clinic database for 1990 to 1998. Medical records, radiographs, and histological slides were reviewed. Several variables including survival were compared in 2 control groups, IPF only and carcinoma only, by using various statistical methods. RESULTS: Our study group included 21 men and 3 women (mean age, 72.3 years). Twenty-two were past or current smokers. Approximately half of the lung carcinomas were incidental findings. Of the 14 patients with preoperative computed tomographic scans, 12 had peripheral tumors situated in areas of fibrosis. Squamous cell carcinoma was the most common histological type, accounting for 16 cases. Almost all patients underwent surgical treatment; nearly 40% developed postoperative complications, and 3 died within 30 days of surgery. The ratio of men to women in patients with IPF and carcinoma was 7:1 compared with 1:1 in patients with IPF only (P=.003). Patients with IPF and carcinoma were also older, with a mean age of 72.3 years compared with 64.4 years (P=.001), and were more often smokers (P=.002). Carcinomas involved the lower lobes in 42% of patients with IPF and carcinoma compared with 29% of patients with carcinoma only (P=.004) and were mainly composed of squamous cell carcinoma (P=.004). Mean survival in patients with IPF and lung carcinoma was 2.3 years after the diagnosis of IPF and 1.6 years after that of carcinoma. This finding did not differ significantly from survival of patients with either IPF or carcinoma alone. However, statistical power was limited. CONCLUSION: Carcinoma in patients with IPF arises in older male smokers and usually presents as peripheral squamous cell carcinoma. The prognosis is poor.     

乙酰半胱氨酸联合泼尼松治疗特发性肺间质纤维化患者疗效

目的：观察乙酰半胱氨酸联合泼尼松治疗特发性肺间质纤维化（IPF）患者的治疗效果。方法将45例IPF 患者随机分为3组,泼尼松组15例（A 组）,每日（理想体质量）0．5 mg／kg,口服4周,然后每日0．25 mg／kg,口服8周,继之减量至每日0．125 mg／kg 口服;小剂量乙酰半胱氨酸组15例（B 组）,在上述泼尼松治疗基础上加用乙酰半胱氨酸200 mg,每日3次;大剂量乙酰半胱氨酸组15例（C 组）,在上述泼尼松治疗基础上加用大剂量乙酰半胱氨酸600 mg,每日3次;疗程6个月。观察治疗前后各组患者肺活量（VC）、6分钟步行试验（6MWT）距离变化,评价总体疗效。结果3组治疗后 VC、6MWT 较治疗前均降低。C 组疗效好于 A 组和 B 组（P ＜0．05）。C 组 VC、6MWT 较其他治疗组下降缓慢（P ＜0．05）。结论大剂量乙酰半胱氨酸联合泼尼松能延缓特发性肺间质纤维化患者肺功能下降及6MWT 距离的减少。     

Interferon-gamma 1b for the treatment of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) represents a particularly aggressive disease, the aetiology of which still remains unknown. The natural history of the disease often leads to respiratory failure and death, with a mortality rate greater than some cancers. To date, no management approach has proven to be efficacious for the treatment of this disease. IPF has been characterised as an 'epithelial-fibroblastic disorder', characterised by abnormal wound healing with excessive fibrosis and minimal inflammation. These emerging data have focused attention on antifibrotic drugs. Interferon-gamma1b (IFN-gamma1b) has recently been proposed as a promising candidate for the treatment of IPF. The reason for this is that IFN-gamma1b has the ability to modulate the Th1/Th2 imbalance and to suppress fibroblast activation. The view that IPF is untreatable at present requires reconsideration, as improved survival has been suggested in three controlled trials of IFN-gamma1b in IPF therapy.     

Cystic fibrosis: current trends in respiratory care

Cystic fibrosis is a genetic disease that typically produces malnutrition and chronic respiratory infections. Prolonged bronchial obstruction, infection, and inflammation result in bronchiectstasis and permanent lung damage. Most cystic fibrosis patients die because of this progressive respiratory disease. Thus, in the absence of a cure, effective respiratory therapy is the primary means to extend and improve the quality of life for the cystic fibrosis patient. Aerosol therapy, airway clearance techniques, and noninvasive ventilation can all improve quality of life and possibly extend survival. Close patient monitoring with pulmonary function testing, chest radiography, and induced sputum can result in earlier treatment, potentially reducing permanent lung damage. Earlier diagnosis has prevented serious complications through early initiation of preventive therapies such as improved nutrition.     

Interferon gamma-1b therapy for advanced idiopathic pulmonary fibrosis

OBJECTIVE: To report on observations made in a group of patients with idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP) who were treated with interferon gamma-1b. PATIENTS AND METHODS: We reviewed the clinical records, radiological studies, and pulmonary function data of all patients treated with interferon gamma-1b between January 2000 and March 2002 at the Mayo Clinic in Rochester, Minn. RESULTS: Twenty-one patients (mean age, 68 years; range, 52-80 years) were treated with interferon gamma-1b for a mean duration of 82 months (range, 3-21 months). All patients had been diagnosed previously as having IPF/UIP based on clinical, pulmonary function, and chest high-resolution computed tomographic scan criteria; 12 patients had also undergone video-assisted thoracoscopic surgical lung biopsy. Baseline pulmonary function data (mean +/- SEM percent predicted) were as follows: total lung capacity, 57.3 +/- 2.5; vital capacity, 55.0 +/- 3.3; diffusing capacity of lung for carbon monoxide, 39.7 +/- 2.8; and forced expiratory volume in 1 second, 58.1 +/- 3.6. Only 1 patient showed symptomatic and functional improvement, and 7 discontinued treatment because of a perceived lack of benefit. Eleven patients (52%) died after a mean of 6.4 months of treatment, and follow-up pulmonary function data suggested continued worsening in all but 1 patient. CONCLUSION: These observations do not support the use of interferon gamma-lb therapy for patients with advanced IPF/UIP.     

特发性肺纤维化药物治疗进展

本文就特发性肺纤维化糖皮质激素／细胞毒药物及抗纤维化药物治疗方面的研究进展进行综述。     

两种细胞因子与特发性肺纤维化的关系

目的：观察转化生长因子(TGF—β)及血小板衍生生长因子(PDGF)在特发性肺纤维化(IPF)经纤维支气管镜(纤支镜)肺活检标本中的表达，探索其在IPF发病中的作用。方法：用免疫组织化学技术检测IPF患者纤支镜活检肺组织中TGF—β及PDGF的表达。结果：IPF组TGF—β主要分布在细支气管上皮细胞、Ⅱ型肺泡上皮细胞及肺泡巨噬细胞，与对照组比较，P＜0．01。IPF组PDGF主要位于血管周围成纤维样细胞、间质细胞及细支气管上皮细胞、肺泡巨噬细胞及Ⅱ型肺泡上皮细胞，与对照组比较，P＜0．01。结论：TGF—β、PDGF通过与肺组织细胞相互作用，参与肺纤维化形成。     

阿奇霉素对特发性肺间质纤维化干预作用的临床研究

目的探讨阿奇霉素治疗特发性肺间质纤维化（IPF）的临床疗效。方法IPF患者34例，随机分为阿奇霉素组20例（阿奇霉素0．5g/次，1次／d，静脉滴注；症状好转后改为片剂，0125g／次，1次／d，口服）和泼尼松组14例（泼尼松30mg／次，1次／d，口服；4周后减为15mg／次，1次／d，口服；8周后改为隔日1次，口服）；两组疗程均为3个月。观察两组患者临床表现、肺功能改变情况及副作用。结果两组患者的临床表现、肺功能均有不同程度的改善，但差异无显著性（P〉0．05），阿奇霉素组副作用显著少于泼尼松组（P〈0．05）。结论阿奇霉素治疗IPF具有与口服泼尼松相当的疗效且副作用少．临床值得推广。     

Collagen polymorphism in idiopathic chronic pulmonary fibrosis.

Collagens in normal human lung and in idiopathic chronic fibrosis were investigated in terms of their covalent structure and compared for possible alterations in the diseased state. Collagens were solubilized by limited digestion with pepsin under nondenaturing conditions, and after purification they, were fractionated into types I and III. Carboxymethylcellulose and agarose chromatography of both types I and III collagens, and amino acid and carbohydrate analyses of the resulting alpha-chains indicated that the alpha 1 (I), alpha 2, and alpha 1 (III) chains of normal human lung were identical with the human skin alpha-chains in all respects examined except that the normal lung chains contained higher levels of hydroxylysine. Examination of collagens obtained from the diseased lung revealed that the content of hydroxylysine of the alpha 1 (I) and the alpha 1 (III) chains appeared to be diminished as compared to the normal lung chains. The values, expressed as residues per 1,000 residues, are 7.1 and 8.3 for the alpha 1 (I) and the alpha 1 (III) chains, respectively, as compared to 10.0 and 11.1 for the alpha-chains from the normal tissue. The chromatographic properties and amino acid and carbohydrate composition of the alpha-chains from the diseased tissue were otherwise indistinguishable from those of normal lung. In addition, isolation and characterization of the CNBr peptides of alpha 1 (I), alpha 2 and alpha 1 (III) from the diseased lung revealed no significant differences from the CNBr peptides from other human tissues reported previously. Normal and diseased lungs were also digested with CNBr, and the resultant alpha 1 (I) and alpha 1 (III) peptides were separated chromatographically. The relative quantities of these peptides indicate that type III collagen constitutes 33% of the total collagen in normal human lung, with the remainder being type I, whereas in idiopathic chronic pulmonary fibrosis, the relative content of type III collagen is markedly diminished, ranging from 12 to 24% in different patients. These results indicate that an alteration in tissue collagen polymorphism as well as subtle variations in the collagen structure accompany the fibrotic process in the diseased state, and suggest that these alterations may have possible pathogenetic implications.     

Platelet-derived growth factor in idiopathic pulmonary fibrosis.

Fibrosis is a complex process involving an inflammatory reaction, fibroblast proliferation, and abnormal accumulation of interstitial collagens. Mononuclear cells are usually present in lung fibrosis. Activated monocytes and macrophages in culture have been shown to produce several growth factors including platelet-derived growth factor (PDGF). PDGF is a potent mitogen and chemoattractant for fibroblasts and smooth muscle cells and a stimulator of collagen synthesis. We have studied the expression of c-sis/PDGF-2 mRNA in lung tissues derived from five patients with idiopathic pulmonary fibrosis (IPF) and from four control individuals without IPF. Northern blot analysis of specimens obtained from four patients with IPF revealed the expression of the c-sis/PDGF-2 protooncogene. A control lung tissue without IPF did not express the c-sis protooncogene. In situ hybridization extended these studies demonstrating the expression of the c-sis mRNA in the five specimens with IPF but not in the four control specimens without IPF. The expression of c-sis mRNA was localized primarily in the epithelial cells. Invading alveolar macrophages also expressed c-sis mRNA. The expression of c-sis mRNA was accompanied by the expression of PDGF-like proteins in lung specimens with IPF but not in control lung specimens. These findings demonstrate the in vivo expression of the c-sis/PDGF-2 protooncogene and the production of PDGF-like proteins in the epithelial cells and macrophages of the fibrotic tissue. This localized and sustained production of PDGF-like mitogen may constitute an important contributing factor in the abnormal fibroblast proliferation and collagen production, events associated with pulmonary fibrosis.