Elevation of Anti-cytokeratin 19 Antibody in Sera of the Patients With Idiopathic Pulmonary Fibrosis and Pulmonary Fibrosis Associated With Collagen Vascular Disorders

It has been suggested that cytokeratin 19 is expressed in regenerated bronchoepithelial cells in patients with pulmonary fibrosis, and serum cytokeratin 19 fragment is elevated in patients with pulmonary fibrosis. We hypothesized that serum antibodies to cytokeratin 19 may be formed in patients with pulmonary fibrosis. To prove the existence of anti-cytokeratin 19 antibodies in patients' sera, human recombinant cytokeratin 19 was stained with patients' sera by a Western immunoblot. Then, we tried to establish an enzyme-linked immunosorbent assay to quantitate anti-cytokeratin 19 antibody in the sera of patients with idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis associated with collagen vascular disorders (PF-CVD). We demonstrated the anti-cytokeratin 19 antibody in patient' sera by a Western immunoblot. In patients with IPF and PF-CVD, significantly high anti-cytokeratin 19 antibody was demonstrated compared with normal volunteers, patients with chronic bronchitis, and patients with pneumonia. These results suggest that anti-cytokeratin 19 antibody may have played a role in the process of lung injury in pulmonary fibrosis. Accepted for publication: 27 May 1999     

Sleep-Related Breathing Disorders in Patients with Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic and usually fatal lung disease of unknown etiology. The aim of this study was to describe clinical and polysomnographic features of sleep-related breathing disorders (SRBD) and to identify predictors of obstructive sleep apnea (OSA) in IPF patients. Eight hundred fifty-seven patients with IPF were admitted to the Cleveland Clinic from 2001 to 2005. An all-night polysomnogram (PSG) was performed in 18 of them to investigate complaints suggestive of sleep-disordered breathing. OSA was confirmed in 11 of the 18 IPF patients with complaints suggestive of sleep apnea, while the remain 7 patients had a diagnosis of primary snoring or upper airway resistance syndrome (UARS). All patients showed a reduction in sleep efficiency, REM sleep, and slow wave sleep. The apnea-hypopnea index (AHI) was positively correlated with body mass index (p < 0.0001, r = 0.80). The REM AHI and overall AHI were negatively correlated with FEV₁ (p = 0.008, r = −0.59 and p = 0.04, r = −0.49, respectively) and FVC percentages (p = 0.03, r = −0.50 and p = 0.08, r = −0.42, respectively). Our study is the first describing SRBD in IPF patients. An increased BMI and a significant impairment in pulmonary function testing may be predictors of OSA in this population. In the absence of effective treatments for IPF, the diagnosis and treatment of comorbid SRBD may lead to improvements in quality of life.     

Patterns of Proteinuria and Circulating Immune Complexes in Febrile Patients

ABSTRACT. Circulating immune complexes (CIC) were detected in 8 of 15 patients with fever due to non-renal infections. Elevated urinary albumin and β-2-microglobulin excretion rates were found during the febrile period compared to the levels two days after normalization of the temperature. No relationship could be demonstrated between CIC and the excretion rates of albumin and β-2-microglobulin or the albumin/β-2-microgIobulin ratio. Thus we have not been able to confirm the hypothesis that the glomerular type of proteinuria is caused by immune complexes.     

应用单克隆抗体ELISA检测包虫病人循环免疫复合物的研究

应用抗包虫单克隆抗体F1建立了检测包虫病人循环免疫复合物和解离抗原的ELISA法。102例包虫病人中CIC阳性率为50％(51/102),其中手术前检出率为62.62％(33/53),手术后检出率为36.73％(18/49)。二者差异显著(P<0.005)。用PEG沉淀的免疫复合物经尿素解离后检测包虫抗原的阳性率为58.82％(60/102)。CIC与解离抗原二者累积阳性率达到86.27％(88/102)。表明在包虫病人中CIC的存在是普遍的。F1单克隆抗体ELISA法在检测包虫病人CIC和解离抗原上有极高的敏感性,因而证明F1单克隆抗体所识别的抗原表位是形成CIC的主要抗原成分。在IgG型CIC阳性的血清中解离抗原的检出率仅为48.1％(23/51)。可能是由于IgG抗体的高度亲和力,由其形成的CIC解离效率低。在IgG-CIC阴性血清中,检出解离抗原的阳性率高达72.5％(37/51),证明了在相当部分包虫病人血清中可能存在着IgE和IgM型CIC。解离抗原阳性率高表明这类CIC容易解离。在17例特异性IgG抗体阴性的包虫病人中CIC阳性者10例(58.82％),解离抗原阳性者9例(52.94％),二者累积阳性率为76.47％(13/17)。说明CIC与解离抗原的检测在IgG抗体阴性的包虫病人诊断上有实际意义。     

Lymphocyte Subsets in Lung Tissues of Non-specific Interstitial Pneumonia and Pulmonary Fibrosis Associated with Collagen Vascular Disorders: Correlation with CD4/CD8 Ratio in Bronchoalveolar Lavage

This study was designed to evaluate the distribution of lymphocyte subsets in lung specimens that were obtained by open-lung biopsy from 8 patients with idiopathic nonspecific interstitial pneumonia/fibrosis (NSIP) and 10 patients with pulmonary fibrosis associated with collagen vascular disorders (PF-CVD). Distributions of B lymphocytes, CD4-positive T lymphocytes, and CD8-positive T lymphocytes were evaluated immunohistochemically and compared with the cell composition in BALF. Correlation between CD4/CD8 ratios in bronchoalveolar lavage fluids (BALF) and CD4/CD8 ratios in lung tissues was also examined. B lymphocytes were mostly restricted in lymphoid follicles. CD4-positive T lymphocytes were observed inside and around lymphoid follicles and in the thick fibrotic wall of reconstructed alveoli with fibrosis. In contrast, CD8-positive T lymphocytes were diffusely distributed, especially in relatively thin alveoli. Correlation was weak between CD4/CD8 ratios in lung tissue and CD4/CD8 ratios in BALF. However, even in patients with very low CD4/CD8 ratios in BALF, many CD4 lymphocytes were observed in lung tissues, suggesting that CD8-positive lymphocytes diffusely distributed in thin alveolar architecture were more easily recovered in BALF than CD4-positive lymphocytes. Therefore, a low CD4/CD8 ratio in BALF may indicate that the alveolar structure was not severely reconstructed by fibrosis. This is the first report that compared lymphocyte subsets in lung tissues and in BALF. Accepted for publication: 14 November 2000     

Latin American Registry of Idiopathic Pulmonary Fibrosis (REFIPI): Clinical Characteristics,Evolution and Treatment

IntroductionIdiopathic pulmonary fibrosis (IPF) is a progressive, irreversible and frequently fatal disease. Currently there are national and multinational registries in Europe, United States, Australia and China to better understand the magnitude of the problem and the characteristics of the IPF patients. However, there are no national or regional registries in Latin America, so the objective of this study was to carry out a Latin American registry that would allow the identification of IPF patients in our region.MethodologyA system consisting of 3 levels of control was designed, ensuring that patients met the diagnostic criteria for IPF according to international guidelines ATS/ERS/ALAT/JRS 2011. Demographic, clinical, serological, functional, tomographic, histological and treatment variables were recorded through a digital platform.Results761 IPF patients from 14 Latin American countries were included for analysis, 74.7% were male, with a mean age of 71.9 + 8.3 years. In general there was a long period of symptoms before definitive diagnosis (median 1 year). In functional tests, an average reduction of FVC (70.9%) and DLCO (53.7%) was detected. 72% received at least one antifibrotic drug (pirfenidone or nintedanib) and 11.2% of the patients had an acute exacerbation, of which 38 (45.2%) died from this cause.ConclusionsLike other registries, we found that there is difficulty in the recognition and excessive delay in the diagnosis of IPF in Latin America. Most of the patients in REFIPI received antifibrotics; these were well tolerated and associated with fewer adverse events than those reported in clinical trials.     

Heterogeneous Remodeling of Lung Vessels in Idiopathic Pulmonary Fibrosis

Recently, several reports suggest differences in the vascularization of the various histopathologic patterns of parenchymal remodeling seen in usual interstitial pneumonia (UIP). In this study, we sought to validate the importance of vascular remodeling in patients with idiopathic pulmonary fibrosis (IPF) and to examine the relationship between vascular remodeling and parenchymal remodeling or pulmonary function. Open lung biopsies were performed in 57 patients with IPF, and vascular changes in alternating areas of parenchymal remodeling (UIP histologic patterns) were studied. Quantitative analysis of the internal area, internal perimeter, wall thickness, and surrounding cellularity of medium or large pulmonary arteries, as well as their distribution according to air/parenchymal ratios, was performed. Semiquantitative analysis also was used to determine the grade of vascular occlusion. An inverse association was found between vascularization and UIP parenchymal remodeling (p < 0.05); that is, the decreased internal luminal area and perimeter as well as the increased wall thickness run in parallel with progression from alveolar collapse toward severe mural-organizing fibrosis with honeycombing. Vascular regression (diminished internal area and perimeter of vessels) was also associated with higher FEV₁, FVC, and RV values (r = 0.48, p< 0.05), reflecting a tight relationship between vascular remodeling and pulmonary function. A progressive regression of vascularization, reflected by different degrees of luminal occlusion after vascular remodeling, coincided with parenchymal remodeling (alveolar collapse, mural-organizing fibrosis, and honeycombing). This vascular regression may be responsible for the impaired wound healing and progressive fibroproliferation found in patients with IPF. Further studies are needed to determine whether this relationship is causal or consequential.     

Effect of Terbutaline on Exercise Capacity and Pulmonary Function in Patients with Chronic Obstructive Pulmonary Disease

The objective of this study was to investigate the effects of a single dose of a β₂-agonist, terbutaline (Bricanyl Turbuhaler?), on resting lung function and exercise capacity in patients with chronic obstructive lung disease. Using a double-blind, placebo-controlled, randomized crossover study and outpatients from a department of pulmonary medicine at a major inner-city hospital, we examined 26 individuals with chronic obstructive lung disease who met the criteria of 40% ≤ FEV₁≤ 70% of predicted, FEV₁/FVC ≤ 70%, and ΔFEV₁≤ 200 ml 20 min after inhalation of 1 mg of terbutaline. The patients inhaled 2.5 mg of terbutaline and matched placebo. At rest, terbutaline caused significant increases in D_LCO, MVV_12sec, and all spirometric indices derived from the flow-volume loop, the increases also being significantly larger than those after inhalation of 1 mg of terbutaline for FEV₁, FVC, and PEF. The peak work rate was unchanged after terbutaline. Oxygen uptake, ventilation, and tidal volume at peak work rate increased significantly, whereas carbon dioxide elimination increased insignificantly. Cumulative oxygen uptake and carbon dioxide elimination during progressive exercise to exhaustion and 10 min of recovery were significantly higher after terbutaline. We concluded that despite significant improvements in resting lung function, inhalation of 2.5 mg of terbutaline did not increase exercise capacity, but it increased cumulative oxygen uptake and carbon dioxide elimination during exercise and recovery, presumably because of a thermogenic effect of terbutaline. Accepted for publication: 29 April 1999     

肝硬化 肝癌患者血清循环免疫复合物的研究

采用一种简单、敏感的放射免疫法测定了101例肝病患者(25例肝癌,17例肝硬化,26例慢迁肝,33例乙肝病毒携带着)的血清循环免疫复合物,并观察了各组肝功能的变化以及HBV标志.结果表明:肝癌组的IgG-CIC含量及γ-GT含量明显高于其它各组.IgG-CIC 5.21(PHC),3.43(LC),2.41(CPH)及1.92(ASC),P<0.01.γ-GT 262(PHC).63.1(LC),44.7(CPH)以及18.7(ASC),P<0.01.伴有HBV感染的肝癌组中有80%可检出IgG-CIC,而CPH及ASC组中仅有50%可检出IgG-CIC.研究结果还表明:肝癌组中,IgG-CIC含量随着AFP含量的升高而上升.但在AFP过度升高时,IgG-GIC反而降低.这可能提示:随着肿瘤的生长,IgG-CIC升高,AFP值随肿瘤恶化逐渐上升,致使IgG-CIC从结合补体转变成非结合补体,导致IgG-CIC的下降.根据结果提示:HBV感染与肝癌发生有着密切关系.     

Cytokeratin Fragment 19 (CYFRA 21-1) and Carcinoembryonic Antigen for Early Prediction of Recurrence of Lung Adenocarcinoma

Fifty patients with adenocarcinoma of the lung were enrolled in this study, including 20 patients with recurrence and 30 patients without recurrence 1 year after surgery. Serial serum levels of cytokeratin fragment 19 (CYFRA 21-1) and carcinoembryonic antigen (CEA) were measured before the operation and 1 week, 1 month, 3 months, 6 months, 9 months, and 12 months after surgery for the early detection of recurrence. The results revealed that the mean serum values of either CYFRA 21-1 or CEA were significantly higher until 9 and 12 months after surgery in the 20 patients with recurrent adenocarcinoma compared with the 30 patients without recurrent adenocarcinoma. We conclude that CYFRA 21-1 is not a better marker than CEA for early prediction of adenocarcinoma. We conclude that CYFRA 21-1 is not a better marker than CEA for early prediction of adenocarcinoma recurrence in lung. Accepted for publication: 7 July 1999     

The Relation of Fat-free Mass to Maximum Exercise Performance in Patients with Chronic Obstructive Pulmonary Disease

To assess the factors determining maximum exercise performance in patients with chronic obstructive pulmonary disease (COPD), we examined nutritional status with special reference to body composition and pulmonary function in 50 stable COPD patients. Nutritional status was evaluated by body weight and body composition, including fat mass (FM) and fat-free mass (FFM) assessed by bioelectrical impedance analysis (BIA). Exercise performance was evaluated by maximum oxygen uptake (Vo _2max) on a cycle ergometer. A total of 50 patients (FEV₁= 0.98 L) was divided randomly into either a study group (group A, n= 25) or validation group (group B, n= 25). Stepwise regression analysis was performed in group A to determine the best predictors of Vo _2max from measurements of pulmonary function and nutritional status. Stepwise regression analysis revealed that Vo _2max was predicted best by the following equation in group A: Vo _2max (mL/min) = 10.223 × FFM (kg) + 4.188 × MVV (L/min) + 9.952 × DL_co (mL/min/mmHg) − 127.9 (r= 0.84, p < 0.001). This equation was then cross-validated in group B: Measured Vo _2max (mL/min) = 1.554 × Predicted Vo _2max (mL/min) − 324.0 (r= 0.87, p < 0.001). We conclude that FFM is an important factor in determining maximum exercise performance, along with pulmonary function parameters, in patients with COPD. Accepted for publication 15 February 2000     

Health-Related Quality of Life in Long Term Oxygen-Treated Chronic Obstructive Pulmonary Disease Patients

Chronic obstructive pulmonary disease (COPD) induces changes in daily activities and mood. Health-related quality of life (HRQL) measures are of particular relevance in the management of such patients, but predictors of HRQL have rarely been investigated. The aim of this study was to seek factors predicting HRQL in severe COPD patients under long term oxygen therapy (LTOT). The pulmonary function parameters at the start of LTOT were studied as potential predictors of future HRQL. HRQL was assessed after an average of 40 months follow-up by the Duke Health Profile (Duke) and by the St. George Respiratory Questionnaire (SGRQ). Sixty-one patients (47 males and 14 females) with a mean age of 66 years were included in the study. Stepwise multiple regression analyses conducted in each HRQL dimension identified few significantly predictive factors. By the Duke, higher Self-esteem scores were associated with higher Pao ₂ (p < 0.01) and with older age (p < 0.05); higher Social Health scores were associated with older age (p < 0.005), and higher Pain scores were associated with a higher FEV₁/FVC ratio (p < 0.05). By the SGRQ, the Activity score correlated with FEV₁/FVC (p < 0.05). The proportion of the variance in each score accounted for by covariates in the model did not exceed 10%. No other significant regression models could be identified using the other HRQL dimensions. Our findings demonstrated weak relations between lung function at the start of LTOT and some dimensions of HRQL measured by the Duke and the SGRQ at the end of follow-up. Accepted for publication: 9 July 1996     

Pneumonia in Stroke Patients: A Retrospective Study

This is a retrospective study of 378 consecutive stroke patients who were referred between June 1994 and June 1997 for videofluorographic study of oropharyngeal swallow. Patients who had radiation therapy, brain tumor, brain surgery, head and/or spinal cord trauma, oral–pharyngeal disease or surgery, or other neurologic diseases in addition to the stroke were excluded from the study. Patients were assigned to two groups: one with pneumonia and one without pneumonia. One hundred one patients were included in the pneumonia group, and 277 patients were included in the nonpneumonia group. Within the pneumonia group, patients were assigned to an acute pneumonia group (pneumonia within 6 months poststroke) and a chronic pneumonia group (pneumonia more than 6 months poststroke). Variables examined in the study included patients' medical history and the findings from the videofluorographic studies. Pearson chi-square analysis was used to identify those variables that were significantly different between the pneumonia and nonpneumonia patient groups and between the acute and chronic pneumonia groups. Results showed that stroke patients who developed pneumonia had a significantly higher incidence of multiple-location and unspecified lesion strokes, chronic airway disease in their medical history, and aspiration during the videofluorographic studies when compared with patients who did not develop pneumonia. Within the pneumonia group, the acute pneumonia group was found to have a significantly higher incidence of hypertension and diabetes in their medical history and a significantly higher incidence of aspiration and reduced laryngeal elevation during the videofluorographic studies. Between 48% and 55% of all stroke patients in the study aspirated. Patients who suffered multiple strokes, brainstem stroke, or subcortical stroke had the greatest frequency of aspiration.     

Effects of Physostigmine on Swallowing and Oral Motor Functions in Patients with Progressive Supranuclear Palsy: A Pilot Study

The purpose of this pilot study was to investigate whether cholinergic stimulation reduces swallowing and oral motor disturbances in patients with progressive supranuclear palsy (PSP). A controlled, double-blind crossover trial of physostigmine, a centrally active cholinesterase inhibitor, and placebo was conducted. Patients were randomized to a 10-day crossover placebo-controlled double-blind trial of physostigmine at their previously determined best dose administered orally every 2 hr, six times per day. Patients were evaluated with ultrasound imaging of the oropharynx and an oral motor examination at baseline and during the third or fourth days of each study phase (placebo and drug). Under the double-blind placebo-controlled conditions, patients showed no statistically significant improvement in oral motor functions or swallow durations. Because patients with PSP have increased sensitivity to cholinergic blockade compared with control subjects, studies with newer, more potent cholinergic stimulating agents need further exploration. Suggestions for future research include the evaluation of newer direct cholinergic agonists in the treatment of the less-impaired PSP patients who may have a greater number of cholinergic neurons preserved and the evaluation of combined therapies.     

Gradual Onset of Dysphagia: A Study of Patients with Oculopharyngeal Muscular Dystrophy

This study describes five patients with slowly developing dysphagia secondary to oculopharyngeal muscular dystrophy (OPMD), a progressive neurological disorder characterized by gradual onset of dysphagia, ptosis, and facial and trunk limb weakness. OPMD is a genetic disorder that affects formerly healthy adults who typically begin to experience symptoms in the fourth or fifth decade of life. Despite the debilitating nature of the disease, it is common for affected individuals to live to old age. Because of the gradual progression of dysphagia, as well as the deterioration of articulation, resonance, and breath support, patients with OPMD may come to the attention of physicians, nurses, and speech pathologists before a diagnosis is made. We hope to heighten awareness of how these subjects developed strategies to cope with their swallowing problems without medical intevention until the disease was producing marked symptoms. Patients with suspected dysphagia should be questioned about overt problems with eating and swallowing, but also about their adaptations and compensatory strategies. A Clinical Interview Questionnaire is included that may yield additional information about hidden dysphagia.     

Prevalence of Aspiration and Laryngeal Penetration in Patients with Unilateral Vocal Fold Motion Impairment

The adverse consequences of aspiration in regard to patient health and quality of life are well documented. It is generally accepted that the probability of aspiration is increased in patients with unilateral vocal fold motion impairment, however, the incidence and proposed mechanism of aspiration vary depending on the reported series. We reviewed the cine or video pharyngoesophagographic findings in patients with documented unilateral vocal fold motion impairment, identified through the Johns Hopkins Hospital Swallowing Center database, to determine the prevalence and cause of aspiration and laryngeal penetration. Aspiration and laryngeal penetration were identified in 38% and 12% of patients, respectively. Aspiration resulted from impaired airway protection, not from esophageal obstruction with laryngeal ``spill-over.' The number and degree of impairments directly correlated with probability of aspiration. Obstruction potentiated the likelihood of aspiration. Video pharyngoesophagography accurately identifies patients at risk for aspiration.     

Kinematic Analysis of Laryngeal Movements in Patients with Neurogenic Dysphagia before and after Swallowing Rehabilitation

To examine whether kinematic analysis of laryngeal movements (which are closely linked to pharyngeal swallowing) can differentiate between normal and disturbed swallowing, we used a three-dimensional ultrasound movement recording system to measure the movements of the larynx during swallowing in 32 patients with neurogenic dysphagia caused by central nervous system lesions and in 32 age- and sex-matched healthy individuals. At the beginning of an inpatient rehabilitation swallowing program, laryngeal movements in 24 patients were highly disturbed in terms of velocity curve irregularities. After rehabilitation, the majority of patients with hitherto irregular velocity profiles exhibited laryngeal kinematics that were indistinguishable from those of 32 healthy subjects. Kinematic analysis of laryngeal movements, therefore, is suitable for monitoring motor recovery of swallowing disturbances in patients with neurogenic dysphagia while undergoing swallowing rehabilitation.