Contribution of pathology to diagnosis of fibrosing lung diseases

The main criteria for the morphologic diagnosis of fibrosing lung disease are the type of inflammation, the localization of the lesion within the lung, and the microtopographic pattern of inflammation and fibrosis. Among the microtopographic patterns six types (perilobular, intraalveolar, alveoloseptal, bronchiolitic, vasculitic, bronchiolectatic), all corresponding to pathogenetic mechanisms can be recognized. Mainly one of these basic patterns is realized in sarcoidosis, histiocytosis X and shock lung. In other diseases a combination of two or more patterns may occur. The microtopographic pattern can be shown best in open biopsies after unfolding of the lung tissue. The findings in bronchoalveolar lavage do not reflect the real composition of the inflammatory infiltration of the lung tissue, and especially T-lymphocytes are usually overrepresented.     

Mechanical ventilation for acute exacerbation of fibrosing interstitial lung diseases

BackgroundAcute exacerbation of fibrosing interstitial lung diseases, including idiopathic pulmonary fibrosis, is associated with poor prognosis. Accordingly, tracheal intubation and invasive mechanical ventilation are generally avoided in such patients. However, the efficacy of invasive mechanical ventilation for acute exacerbation of fibrosing interstitial lung diseases remains unclear. Therefore, we aimed to investigate the clinical course of patients with acute exacerbation of fibrosing interstitial lung diseases who were treated with invasive mechanical ventilation.MethodsWe retrospectively analyzed 28 patients with acute exacerbation of fibrosing interstitial lung diseases who underwent invasive mechanical ventilation at our hospital.ResultsOf the 28 included patients (20 men, 8 women; mean age, 70.6 years), 13 (46.4%) were discharged alive and 15 died. Ten patients (35.7%) had idiopathic pulmonary fibrosis. Univariate analysis revealed that longer survival was significantly associated with lower partial pressure of arterial carbon dioxide (hazard ratio [HR] 1.04 [1.01–1.07]; p = 0.002) and higher pH (HR 0.0002 [0–0.02] levels; p = 0.0003) and less severe general status according to the Acute Physiology and Chronic Health Evaluation II score (HR 1.13 [1.03–1.22]; p = 0.006) at the time of mechanical ventilation initiation. In addition, the univariate analysis indicated that patients without long-term oxygen therapy use had significantly longer survival (HR 4.35 [1.51–12.52]; p = 0.006).ConclusionsInvasive mechanical ventilation may effectively treat acute exacerbation of fibrosing interstitial lung diseases if good ventilation and general conditions can be maintained.     

Progressive fibrosing interstitial lung disease associated with systemic autoimmune diseases

Clinical Rheumatology - Interstitial lung disease (ILD) is a common manifestation of systemic autoimmune diseases and a leading cause of death in these patients. A proportion of patients with...     

Genetics of hepatobiliary diseases.

With the recent publication of the first human map of genetic variation (ie, Human Haplotype Map), genomic-based discoveries will likely affect not only the research bench but also the bedside. These advances will improve the understanding of the genetics of hepatobiliary diseases, resulting in better prevention measures and diagnosis as well as more effective therapies. Currently, alcoholic liver disease, nonalcoholic fatty liver disease, and symptomatic gallbladder stones affect a sizable portion of the population. On the other hand, chronic cholestatic liver diseases, hepatocellular carcinoma, and polycystic liver disease, although rare, shorten life expectancy and diminish the quality of life of patients. In the genomic era, we have the opportunity to start dissecting the susceptibility genetic variants of liver diseases. We are now in a position to begin elucidating the complex genotype/phenotype relationships of liver diseases with the anticipation to understand disease pathogenesis better. These efforts will require the application of genomic-based approaches in large well-organized translational studies in the diseases of interest.     

HRCT of fibrosing lung disease

The use of high‐resolution computed tomography (HRCT) has brought increased diagnostic discrimination to the evaluation of lung disease, particularly fibrosing lung diseases. Once the presence of a predominantly fibrosing lung disease has been established on evaluation of a HRCT, a stepwise approach is proposed that can refine the potential HRCT diagnoses from a list of over 100 different interstitial lung diseases to one of only five fibrosing lung diseases. Within the category of the fibrosing lung diseases, the recognition of idiopathic pulmonary fibrosis (IPF) is key. IPF is the most prevalent idiopathic interstitial pneumonia and has a mortality greater than any of the other diffuse lung diseases. Several diagnostic dilemmas are explored including challenges with the recent IPF diagnosis and management guidelines (2011), as well as with the ‘difficult to characterize’ fibrosing diseases such as smoking‐related lung fibrosis, unclassifiable disease and acute exacerbations of fibrosing lung disease.     

纤维化性间质性肺疾病预后因素的前瞻性队列研究

目的 探讨纤维化性间质性肺疾病的临床特点和发展为进行性纤维化型及死亡的风险因素.方法 选择2019年5月至12月解放军总医院呼吸科收治的58例纤维化性间质性肺疾病患者为研究对象.收集临床资料,行肺CT、肺功能等检查,同时行6 min步行试验,应用加利福尼亚大学圣地亚哥分校呼吸困难问卷(SOBQ)进行呼吸困难评分,并随访...     

Crackles in interstitial lung disease. Comparison of sarcoidosis and fibrosing alveolitis

STUDY OBJECTIVE: Determine why crackles on chest auscultation are characteristic of most interstitial lung diseases, but may not be heard in sarcoidosis. DESIGN: All patients with sarcoidosis or cryptogenic fibrosing alveolitis seen during a four-week period were studied. In a second study to relate ausculatory findings to anatomy, patients with fibrotic changes on their chest roentgenogram were studied. SETTING: Patients were recruited from outpatient clinics. PATIENTS: In the first part, all patients seen over the course of one month were studied. In the second study, patients with pulmonary fibrosis seen on chest roentgenograms were studied. INTERVENTIONS: For the first study, two independent observers performed auscultation on five sites for crackles and reviewed four roentgenogram quadrants for changes. For the second study, patients underwent VC measurements, auscultation, and high resolution computer tomography scans. MEASUREMENTS AND RESULTS: For the first study, crackles were noted at greater than 2 sites in all 11 CFA patients, but only one of 17 SARC patients (p less than 0.001). Roentgenogram changes were seen in greater than 2 quadrants in nine of 11 CFA patients and eight of 17 SARC patients (p = ns). In the second study, the VC was similar in the two groups: SARC: 1.96 +/- .90 L (means +/- SD), 58 +/- 20.4 percent predicted; CFA: 1.81 +/- .33 L, 59 +/- 9.2 percent predicted). Only two of 14 SARC patients had crackles in greater than 1 area, while all 14 CFA patients had crackles at greater than 2 sites. The HRCT studies were read by a radiologist unaware of the diagnosis. The presence and degree (0 to 3 scale) of subpleural and peribronchial fibrosis were scored. Twelve SARC patients had peribronchial changes (mean score 1.9 +/- 1.08), while only eight had subpleural fibrosis (mean score .6 +/- .52). There was a significantly different pattern in the CFA patients, where eight had peribronchial fibrosis (mean score = .9 +/- .78, p less than 0.05) and all 14 had subpleural fibrosis (mean score = 1.6 +/- .73, p less than 0.01). CONCLUSIONS: We conclude that crackles are more frequent in fibrosing alveolitis than in sarcoidosis; this difference may be due to the distribution of parenchymal fibrosis.     

Clinical characteristics of non-idiopathic pulmonary fibrosis,progressive fibrosing interstitial lung diseases: A single-center retrospective study

Progressive fibrosing interstitial lung disease (PF-ILD) is a progressive phenotype of fibrosing ILDs with varying definitions and elusive clinical characteristics. We aimed to clarify the clinical features and prognosis of PF-ILD cases based on the deterioration of pulmonary function.Altogether, 91 consecutive ILD patients who underwent at least 2 pulmonary function tests (PFTs) with an interval of at least 24 months, as the screening period, between January 2009 and December 2015 were retrospectively reviewed. The deterioration of forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLco) was calculated based on PFT data and screening period. The definition of PF-ILD was

• 1.relative decline of 10% or more in FVC per 24 months or
• 2.relative decline in FVC of 5% or more with decline in DLco of 15% or more per 24 months.

Medical records of 34 patients with idiopathic pulmonary fibrosis (IPF), 11 patients with non-IPF, PF-ILD, and 46 patients with non-IPF, non-PF-ILD were retrospectively analyzed. Patient characteristics, pharmacologic or non-pharmacologic treatment status, and prognosis were compared between the IPF and non-IPF groups and between the non-IPF, PF-ILD and non-IPF, non-PF-ILD groups.Eleven patients (19.3%) showed a progressive phenotype in the non-IPF group. The pulmonary function data at the first PFT were worse in non-IPF, PF-ILD patients than in non-IPF, non-PF-ILD patients. There were no differences in the proportion of patients who were observed without pharmacologic treatment or of those receiving pharmacologic treatment between the non-IPF, PF-ILD and non-IPF, non-PF-ILD groups. Low %FVC at the first PFT and the usual interstitial pneumonia-like fibrotic pattern on high-resolution computed tomography were risk factors for PF-ILD in the non-IPF group. The mortality in the non-IPF, PF-ILD group was significantly worse than that of the non-IPF, non-PF-ILD group and was as poor as that of the IPF group. Multivariate logistic analysis showed that aging and low %DLco at the first PFT were risk factors for mortality within the non-IPF group.The prognosis of non-IPF, PF-ILD patients was as poor as that of IPF patients. Non-IPF, PF-ILD patients require more intensive treatment before disease progression.     

Cystic liver diseases. Genetics and cell biology

In 50% of cases, polycystic liver disease is associated with autosomal dominant polycystic kidney disease, which is caused by mutations in the PKD1 and PKD2 genes that encode polycystin-1 and -2, respectively. These proteins form a polycystin-1/2 complex on the plasma membrane, including that localized on the surface of primary cilia, where they act as mechanosensors. Polycystin-1 acts as a (mechano)receptor of environmental signals, and polycystin-2 as a calcium channel mediating intracellular transduction. Isolated autosomal dominant polycystic liver disease is caused by mutations in PRKCSH that encodes hepatocystin, a protein of the endoplasmic reticulum, which may participate in the N-glycosylation and maturation of proteins addressed to the cell surface. Congenital hepatic fibrosis whether it is accompanied by bile duct dilatations (Caroli's syndrome) or not, may be associated with autosomal recessive polycystic kidney disease, which is caused by mutations in PKHD1 that encodes fibrocystin, a protein of primary cilia. Genetic defects in fibrocystin cause ciliary dysfunction, presently considered as a major pathogenic event in cystogenesis. Excessive cell proliferation, a hallmark of cystic biliary epithelium, occurs in combination with deregulation of the epidermal growth factor (EGF) and probably also estrogen receptors. EGF receptor antagonists inhibit kidney and liver cyst development in animal models, and are currently under investigation in phase I and II clinical trials in patients with autosomal dominant polycystic kidney disease.     

Genetics in liver diseases

In recent years, few fields in medicine have witnessed discoveries as momentous as those pertaining to the liver. Dramatic advances have been made, particularly in the areas of molecular biology and genetics. A joint EASL/AASLD Monothematic Conference was held on June 23rd-24th, 2006, in Modena, Italy, to bring the latest breakthroughs in different fields of genetics to hepatologists. This article reports the highlights of the conference and summarizes the main conclusions and implications for clinical and experimental hepatology.     

Genetics of the complement system and rheumatic diseases.

The complement system, especially the early components of the classic pathway, are critically involved in immune complex processing. The deposition of clusters of complement component C3b on a target marks it for elimination, primarily through an interaction with complement receptors. Not surprisingly, total and partial deficiencies of certain complement components and C3b receptors are associated with rheumatic diseases, particularly systemic lupus erythematosus. This predisposition is explicable, based on the critical role complement plays in immune complex handling.     

Increased circulating levels of soluble Fas ligand are correlated with disease activity in patients with fibrosing lung diseases

OBJECTIVE: The Fas-Fas ligand (FasL) pathway is one of the important apoptosis-signalling molecule systems. We previously determined that this pathway may be involved in the pathogenesis of fibrosing lung diseases. In the present study, we evaluated the clinical significance of the levels of soluble forms of Fas (sFas) and FasL (sFasL) in serum from patients with fibrosing lung diseases. METHODOLOGY: We measured sFas, sFasL, KL-6 (a measure of alveolar type II cell damage), surfactant protein D (SP-D), and surfactant protein A (SP-A) levels in serum from 35 patients with idiopathic pulmonary fibrosis (IPF), 17 patients with interstitial pneumonia associated with collagen vascular diseases (CVD-IP), and 13 normal healthy controls using enzyme-linked immunosorbent assays (ELISA). RESULTS: The serum levels of sFasL were significantly increased in patients with active IPF and CVD-IP, compared with those with inactive disease and controls. There was no significant difference in sFasL levels between patients with inactive disease and controls. Serum sFasL levels were significantly correlated with lactate dehydrogenase and KL-6 levels in IPF. The decrease in sFasL levels following corticosteroid therapy was not correlated with the clinical course of IPF. There was no significant difference in serum sFas levels between IPF or CVD-IP patients and controls. CONCLUSIONS: Although further studies need to be performed on a large number of patients with histologically proven IPF or CVD-IP, it would seem that serum sFasL levels may reflect the activity of IPF and CVD-IP.     

Expiratory lung crackles in patients with fibrosing alveolitis

Inspiratory lung crackles are a diagnostic feature of interstitial pulmonary fibrosis, but expiratory crackles are not well documented. In a phonopneumographic study of 13 patients with fibrosing alveolitis, expiratory crackles were audible with the stethoscope in 12. Phonopneumographic analysis of these 12 patients showed the crackles to be fine with the initial wave deflection of the expiratory and inspiratory crackles in opposite directions. They were few in number, occurred predominantly in mid- and late expiration, and were not affected by varying the volume history or by breath holding maneuvers. These observations support the theory that some crackles are produced by vibration of the walls of peripheral airways. In addition, this group of patients showed a significant correlation between the number of expiratory crackles and the reduction in predicted transfer factor, suggesting that expiratory crackles may be a clinical indicator of the severity of disease in fibrosing alveolitis.     

Pulmonary involvement in systemic scleroderma. Part I. Chronic fibrosing interstitial lung disease

INTRODUCTION: Chronic pulmonary interstitial fibrosis is the most frequent respiratory manifestation in systemic sclerosis, occurring in 80% of cases. It remains a severe complication of the disease and is the primary cause of mortality related to respiratory insufficiency in 20 to 60% of cases. CURRENT KNOWLEDGE AND KEY POINTS: The date of onset of interstitial lung disease remains undetermined, and only in rare cases does it reveal the presence of systemic sclerosis. The clinical signs are only observable at a later stage, when at least 50% of the lung parenchyma is affected. The methods of choice adopted for early diagnosis of this disease are high resolution computed tomography and pulmonary functional investigations; they should be carried out during the preliminary investigation and at follow-up once a year. Moreover, high resolution computed tomography also provides prognostic data, for there is a correlation between the type of lesion and its severity as determined by high resolution computed tomography and by histological findings. The value of other methods of investigation, in particular bronchoalveolar lavage, has not yet been clearly established. The association of cyclophosphamide and corticoids is currently being evaluated (indications, administration modalities, duration), and this combination may be the most effective treatment. FUTURE PROSPECTS AND PROJECTS: Interstitial lung disease is one of the major causes of morbidity and mortality in systemic sclerosis. Early diagnosis and management of this disease is therefore of utmost importance.     

Effect of single lung transplantation on pulmonary hypertension in patients with end stage fibrosing lung disease.

OBJECTIVE--To investigate the effect of successful single lung transplantation on pulmonary haemodynamic variables and right ventricular function. DESIGN--Pulmonary haemodynamic variables and right ventricular function were measured at right heart catheterisation after single lung transplantation. The results were compared with the preoperative pulmonary haemodynamic variables measured at the time of assessment for transplantation. SETTING--A tertiary referral centre. PATIENTS--Five survivors of single lung transplantation performed for end stage lung disease. INTERVENTIONS--Cardiac catheterisation in all five patients at a mean of 18 months postoperatively. Preoperative catheter data were available for comparison in four. Right heart pressures and cardiac output were measured and right ventricular angiography was performed. Perfusion scans performed for clinical reasons were used to assess the percentage of cardiac output passing through each lung. MAIN OUTCOME MEASURES--Right heart pressures, cardiac output, right ventricular function, percentage perfusion to lungs. RESULTS--After operation mean peak right ventricular pressure fell from 53 mm Hg to 33 mm Hg, mean pulmonary artery pressure from 33 mm Hg to 18 mm Hg, total pulmonary resistance from 11.2 U x m2 to 5.8 U x m2, and pulmonary arteriolar resistance from 8.9 U x m2 to 3.6 U x m2. Pulmonary artery wedge pressure and cardiac index were unchanged. Right ventricular function improved in all patients. The transplanted lung received most of the cardiac output. CONCLUSION--In patients with moderate pulmonary hypertension and right ventricular dysfunction secondary to end stage fibrosing lung disease single lung transplantation was followed by an improvement in pulmonary haemodynamic variables and right ventricular function.     

Effect of single lung transplantation on pulmonary hypertension in patients with end stage fibrosing lung disease.

OBJECTIVE--To investigate the effect of successful single lung transplantation on pulmonary haemodynamic variables and right ventricular function. DESIGN--Pulmonary haemodynamic variables and right ventricular function were measured at right heart catheterisation after single lung transplantation. The results were compared with the preoperative pulmonary haemodynamic variables measured at the time of assessment for transplantation. SETTING--A tertiary referral centre. PATIENTS--Five survivors of single lung transplantation performed for end stage lung disease. INTERVENTIONS--Cardiac catheterisation in all five patients at a mean of 18 months postoperatively. Preoperative catheter data were available for comparison in four. Right heart pressures and cardiac output were measured and right ventricular angiography was performed. Perfusion scans performed for clinical reasons were used to assess the percentage of cardiac output passing through each lung. MAIN OUTCOME MEASURES--Right heart pressures, cardiac output, right ventricular function, percentage perfusion to lungs. RESULTS--After operation mean peak right ventricular pressure fell from 53 mm Hg to 33 mm Hg, mean pulmonary artery pressure from 33 mm Hg to 18 mm Hg, total pulmonary resistance from 11.2 U x m2 to 5.8 U x m2, and pulmonary arteriolar resistance from 8.9 U x m2 to 3.6 U x m2. Pulmonary artery wedge pressure and cardiac index were unchanged. Right ventricular function improved in all patients. The transplanted lung received most of the cardiac output. CONCLUSION--In patients with moderate pulmonary hypertension and right ventricular dysfunction secondary to end stage fibrosing lung disease single lung transplantation was followed by an improvement in pulmonary haemodynamic variables and right ventricular function.