Evidence Of Lung Disease Research Articles

Mutation of SFTPC in infantile pulmonary alveolar proteinosis with or without fibrosing lung disease

Pulmonary surfactant protein C (SP-C) is a highly hydrophobic peptide produced by type-II alveolar cells through the processing of a high-molecular weight precursor (pro-SP-C), that enhances surface tension and facilitates the recycling of pulmonary surfactant in vitro. Recently, two seemingly dominant-negative mutations of the pro-SP-C-encoding gene (SFTPC, MIM 178620), were reported in families with vertically-inherited interstitial lung disease (Nogee et al. [2001: N Engl J Med 344:573-579]; Thomas et al. [2002: Am J Respir Crit Care Med 165:1322-1328]). We have examined the SP-C protein and its precursor as well as the encoding gene, in a cohort of 34 sporadic or familial cases with unexplained respiratory distress (URD) in which surfactant protein B (SP-B) deficiency related to SFTPB mutation had been ruled out. One patient with complete SP-C deficiency had no detectable mutation of SFTPC. Of the 10 patients with abnormal pro-SP-C processing, as suggested from analysis of broncho-alveolar lavage (BAL) fluid, two distinct heterozygous SFTPC missense mutations were identified. The first, g.1286T > C (p.I73T), was de novo and resulted in progressive respiratory failure with intra-alveolar storage of a granular, protein- and lipid-rich, periodic acid Schiff (PAS)-positive material (pulmonary alveolar proteinosis (PAP)), and interstitial lung disease. The second, g.2125G > A (p.R167Q), was found in two PAP patients from the endogamous white settler population of Réunion Island in which URD has an unexpectedly high prevalence. Since this mutation was diagnosed in subjects from this subpopulation who did not have evidence for lung disease, we propose environmental exposures or modifier genes to play a role in the phenotype, as suggested from murine models lacking the SP-C protein, although we cannot rule out a rare polymorphism, hitherto restricted to that subpopulation. Most remarkably, these observations extend the phenotypic spectrum related to SFTPC mutation from interstitial lung disease to PAP. Notably, the reported mutations do not appear to be dominant negatives. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299/suppmat/index.html.

Bronchoalveolar lavage in children with chronic diffuse parenchymal lung disease.

The aim of the present study was to compare cellular and noncellular components of bronchoalveolar lavage fluid (BAL) in a group of children with a diagnosis of chronic diffuse parenchymal lung disease (cDPLD) and a group of children without parenchymal lung disease undergoing BAL for various clinical indications (control group). We evaluated cellular and non-cellular components (total proteins, albumin, hyaluronic acid, and fibronectin) in BAL fluid from 14 children (7 boys and 7 girls; mean age 9.2 years, range 5 months to 18.4 years) fulfilling the clinical and radiological diagnosis of chronic cDPLD, and in 19 controls without evidence of lung disease. The 14 patients were assigned to two study groups: early-stage cDPLD (6 patients; age range 5 months to 5.2 years; duration of illness, 5-7 months) and long-standing cDPLD (8 patients; age range 9.6-18.4 years; duration of illness, 1.2-17.6 years). Ninety-three percent of the patients with cDPLD had at least two BAL constituents outside normal limits, with high numbers of cells, including all types of alveolar cells, but especially lymphocytes and foamy macrophages. These findings indicate a mixed, predominantly lymphocytic alveolitis. Our patients also had a significant increase in two noncellular BAL components, namely fibronectin and hyaluronic acid. BAL samples from children with long-standing cDPLD contained increased numbers of lymphocytes, whereas samples from children with early-stage cDPLD contained increased percentages and numbers of foamy macrophages and increased concentrations of fibronectin, hyaluronic acid, and albumin. In conclusion, we clearly identified an abnormal BAL profile in our group of cDPLD patients. Moreover, BAL findings differentiated younger cDPLD patients in the early stages of their illness from old patients with long-standing disease.

Systemic sclerosis: using high-resolution CT to detect lung disease in children.

The purpose of this study was to determine the prevalence of interstitial lung disease and the severity of disease in children with systemic sclerosis using high-resolution CT (HRCT). Eleven children (mean age, 11 years) with scleroderma underwent HRCT, chest radiography, and pulmonary function testing. Eight of these 11 patients also underwent follow-up HRCT. HRCT studies were assessed by two observers for ground-glass attenuation, honeycombing, and other abnormalities. Profusion scores for ground-glass attenuation and honeycombing were determined by multiplying severity of disease by the percentage of lung involvement. Chest radiographs predicted interstitial lung disease in only two patients, whereas HRCT showed interstitial lung disease in eight patients (p = .05). On HRCT, ground-glass attenuation was found in eight patients (73%), honeycombing in five patients (45%), linear opacities in six patients (55%), and subpleural micronodules in seven patients (64%). By the end of the study, 10 patients (91%) had evidence of interstitial lung disease on HRCT. Overall, profusion scores for these 10 patients showed four patients with mild, one with moderate, and five with severe disease. Also, HRCT revealed worsening disease in three of eight patients. We found no correlation between duration of scleroderma and severity of interstitial lung disease (p > .02). Seven patients with evidence of lung disease on HRCT had abnormal results on pulmonary function tests; patients with the highest scores for ground-glass attenuation had the most abnormal results on pulmonary function tests (p < .01). HRCT shows significant pulmonary disease in children with systemic sclerosis, revealing abnormalities in 91% of our patients. Pulmonary disease should be suspected in children with scleroderma, even if the chest radiograph has normal findings.

Clinical utility of chest auscultation in common pulmonary diseases.

In this investigation we applied the techniques of lung sound mapping and time-expanded wave-form analysis to four common diseases that involve the lung: interstitial pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), and pneumonia (Pn). Twenty subjects were studied in each group. We also studied 15 subjects without evidence of lung disease. Differences in timing, character, and location were observed, which allowed separation among these groups. Multiple logistic regression models were created and tested by the bootstrap method. Regression models correctly classified 68 and 79% of subjects. Area under the receiver operating curve ranged from 0.96 for IPF and CHF to 0.80 for COPD. We conclude that auscultatory differences exist among common pulmonary conditions and that statistical models based on auscultatory data perform well in predicting diagnostic categories.

Pathophysiologic correlations in lymphoid interstitial pneumonia.

Effective alveolar volume, diffusing capacity for carbon monoxide (DCOsb), volume-corrected diffusing capacity (D/VA), static lung compliance (Cst), and lung distensibility were measured in 16 sheep seropositive for maedi-visna virus (MVV) immediately before they were killed. Lungs were inflation-fixed, and the left lung was randomly sampled for morphometric analysis. The total lung weight, total fixed lung volume, volume densities of tissue (Vvt) and air (Vva), and the alveolar surface density were measured and correlated with the physiologic measurements. The density of surface forces could not account for the variation in the distensibility of the lungs, indicating that tissue-related forces may be important in determining lung distensibility in lymphoid interstitial pneumonia (LIP) associated with MVV infection. Possible sources of tissue-related forces are the contractile tissue associated with lung parenchyma, airways, or vasculature. When DCOsb was corrected for volume, a strong negative correlation with Vvt was noted, indicating that factors distinct from lung-volume reduction are important in limiting gas exchange in LIP associated with MVV infection. More sheep demonstrated abnormal D/VA values than any other physiologic measurement, with reduced values being apparent even in sheep considered clinically normal and with little or no morphometric evidence of lung disease. Measurements of diffusing capacity are thus considered the most sensitive functional index of disease progression.

Raised serum soluble interleukin-2 receptor concentrations in cystic fibrosis patients with and without evidence of lung disease.

Soluble interleukin-2 receptor (sIL-2R-CD25) concentrations were measured in the sera of 115 children with cystic fibrosis and 45 aged matched controls. Above the age of 4 years children with cystic fibrosis had significantly raised concentrations irrespective of disease status as judged by Shwachman score, lung function, or evidence of pseudomonas colonisation. It is believed that these data indicate that T lymphocyte activation can be detected before there is clinical evidence of lung inflammation due to infection in cystic fibrosis. They support the notion that early use of anti-inflammatory (immunosuppressive) drugs may have a role in delaying the progress of lung damage in cystic fibrosis.

Effects of Hemodialysis and Anemia on Pulmonary Diffusing Capacity, Membrane Diffusing Capacity and Capillary Blood Volume in Uremic Patients

The study aimed at investigating pulmonary function in uremic patients, emphasizing the lung diffusing capacity for CO (DLCO) and its membrane and pulmonary capillary blood volume (Vc) components. The study sample comprised 25 uremic patients without clinical/radiological evidence of lung disease. They were enrolled in a chronic hemodialysis (HD) program and had anemia requiring transfusions. The subjects were tested for their lung function before and after both a first HD and a HD with blood transfusion (BT) that followed a few days later. After HD-induced removal of body fluid, and increase in pre-HD reduced forced vital capacity, alveolar volume and mid-expiratory flow rate (FEF25-75%) was observed. HD-induced DLCO decrease (p less than 0.005) was observed and was related to decreased Vc. The second HD with BT increased DLCO, due to partially normalized Hb. On average, a 7.2% DLCO increase corresponded to each 10-g/l Hb rise. In conclusion, (1) the beneficial effect of HD in uremic patients reverts the small-airway obstruction; (2) the lower values of DLCO in these patients are due to reduced Hb and HD causes further DLCO reduction via decrease of Vc, and (3) HD with BT still increases DLCO because improvement of Hb predominates.

Diagnostic significance of flow cytometric DNA analysis applied for the detection of cancer cells in bronchial washing fluid : Deinlein E, Sander U, Greiner C, Homstein OP. Department of Dermatology, University of Erlangen-Numberg, D-8520 Erlangen. Anal Nal Quant Cytol Histol 1988;10:360-4

Since both DNA aneuploidy and increased proliferative activity are important characteristics of malignant neoplasms, flow cytometric (FCM) analysis was used to examine the cell content in bronchial washing samples obtained via fiberoptic bronchoscopy from 73 patients. The results were compared with the results of histology and conventional cytology. The patients included 30 with bronchial carcinomas, 12 with bronchopneumonia and 31 with no evidence of lung disease. Of the 30 patients with histologically confirmed lung cancers, 25 showed either aneuploid stem lines (19 cases) or high levels of proliferation (6 cases) as determined by analysis of cell-cycle stages. The same rate of cancer cell detection was obtained by cytology. In the 43 cases with neither histologic nor clinical evidence of malignancy, FCM data yielded 5 false-positive results, as compared to 4 erroneous suspicions of cancer by cytology. From these data, it is concluded that FCM measurements of both DNA ploidy and proliferative activity may complement conventional cytology in the recognition of bronchial carcinomas.

Activated alveolar macrophages in subclinical pulmonary inflammation in collagen vascular diseases.

A study was initiated to determine whether alveolar macrophages from patients with collagen vascular diseases but free of pulmonary symptoms were spontaneously activated and whether they released various mediators related to the pathogenesis of pulmonary fibrosis. Alveolar macrophages obtained by bronchoalveolar lavage from 32 patients with proved collagen vascular disease but no evidence of lung disease were compared with those from 10 patients with collagen vascular disease with interstitial lung disease (CVD-ILD) and from 10 healthy controls. The total number of alveolar macrophages did not differ between patients with collagen vascular disease and controls but were substantially increased in the CVD-ILD group. Alveolar macrophages from 31 of the 32 patients with collagen vascular disease and from all 10 in the CVD-ILD group had at least one criterion of activation. Neutrophil chemotactic activity was detected in supernatants from alveolar macrophage culture in 23 of the 32 patients with collagen vascular disease and from nine of the 10 in the CVD-ILD group; fibronectin secretion by alveolar macrophages was increased in 12 of the 32 patients with collagen vascular disease and in nine of the 10 in the CVD-ILD group. Furthermore, alveolar macrophages from 20 of the 32 patients with collagen vascular disease and four of the 10 CVD-ILD patients spontaneously released increased amounts of superoxide anion. Thus alveolar macrophages were spontaneously activated in a high proportion of patients with collagen vascular disease.

Bleomycin-Associated Pulmonary Fibrosis: Rapidly Fatal Progression Without Chest Radiotherapy

Two patients with carcinoma of the tonsil were treated with bleomycin (396 and 224 units, respectively) but not with radiotherapy. Respiratory insufficiency led to death 45 and 52 days, respectively, after onset of therapy. Chest radiographs before bleomycin therapy revealed no evidence for lung disease. Postmortem examinations showed severe interstitial and intraalveolar pulmonary fibrosis. Comparably rapid progression from radiographically normal pulmonary parenchyma to fatal fibrosis has been documented previously only in patients with thoracic neoplasia as well as, in all but one instance, either prior or concurrent chest radiotherapy. These two cases indicate that chest radiotherapy is not a necessary cofactor for the development of rapidly progressive, fatal, diffuse interstitial pulmonary fibrosis after bleomycin therapy.

Diaphragmatic work of breathing in premature human infants.

Present methods of assessing the work of breathing in human infants do not account for the added load when intercostal muscle activity is lost and rib cage distortion occurs. We have developed a technique for assessing diaphragmatic work in this circumstance utilizing measurements of transdiaphragmatic pressure and abdominal volume displacement. Eleven preterm infants without evidence of lung disease were studied. During periods of minimal rib cage distortion, inspiratory diaphragmatic work averaged 5.9 g X cm X ml-1, increasing to an average of 12.4 g X cm X ml-1 with periods of paradoxical rib cage motion (P less than 0.01). Inspiratory work was strongly correlated with the electrical activity of the diaphragm as measured from its moving time average (P less than 0.05). Assuming a mechanical efficiency of 4% in these infants, the caloric cost of diaphragmatic work may reach 10% of their basal metabolic rate in periods with rib cage distortion. When lung disease is superimposed, the increased metabolic demands of the diaphragm may predispose preterm infants to fatigue and may contribute to a failure to grow.

Neutrophil collagenase in rheumatoid interstitial lung disease.

Ten patients with rheumatoid arthritis were evaluated by bronchoalveolar lavage. Five patients (group I) had interstitial lung disease by physiological and radiographic criteria, whereas five (group II) had no evidence of lung disease. Lavage fluid from four of the five group I patients contained an active collagenase which by inhibitory profile and substrate specificity appeared to be of neutrophil origin. None of the group II patients demonstrated lavage fluid collagenase. Treatment of lavage fluid with trypsin failed to uncover latent collagenase activity in either group, suggesting that the collagenase is present entirely in an active form. These findings parallel those observed in idiopathic pulmonary fibrosis and suggest a potential pathogenetic role for collagenase in rheumatoid interstitial lung disease.

Distortion of chest wall and work of diaphragm in preterm infants.

Chest wall distortion is common in infants and is especially visible in preterm infants. It has been suggested that this distortion increases the volume displacement of the diaphragm during inspiration, which may be associated with muscular fatigue and apnea. We studied 10 preterm infants who had no evidence of lung disease, investigating the effect of chest wall distortion on the volume displacement and work of the diaphragm. The volume changes of the respiratory system were partitioned using an inductance plethysmograph. The minute volume displacement and the work of the diaphragm were calculated using the partitioned abdominal volume change and the gastric and esophageal pressures. The paradoxical movement of the chest wall lasted an average of 36% of inspiration. The minute volume displacement of the diaphragm ranged from 72 to 176% of the minute pulmonary ventilation, and diaphragmatic work ranged from 94 to 793% of that performed on the lungs. The amount of chest wall distortion, as reflected by the duration of the paradoxical chest wall movement, the minute volume excursion, or work of the diaphragm, was not related to the mechanical properties of the lungs. This estimated work load may represent a significant expenditure of calories in these infants and may contribute to the development of diaphragmatic fatigue, apnea, and a prolonged need for mechanical ventilation.

Altered factor VIII in acute respiratory failure.

Acute respiratory failure is characterized by pulmonary vascular injury and increased endothelial permeability. Since endothelial cells synthesize or release factor VIII, we studied factor VIII:antigen, factor VIII:von Willebrand's factor, and factor VIII:coagulant activity in 100 patients with acute respiratory failure, in 29 critically ill patients without evidence of lung disease, and in 60 normal subjects. As a group, patients with respiratory failure had factor VIII:antigen levels that were five times normal, whereas their factor VIII:coagulant and von Willebrand's activities were normal or above normal. However, there was a remarkable disproportion between the levels of factor VIII:antigen and those of factor VIII:coagulant and von Willebrand's factor. In the other ill patients and in the normal group, these levels were in close proportion. In patients with respiratory failure, both slowly and rapidly migrating components of factor VIII:antigen had abnormal electrophoretic patterns; in moderate and severe cases, there was a marked increase in the fast component. Patients who recovered from acute respiratory failure had electrophoretic patterns that returned toward normal. Factor VIII:antigen may be a sensitive circulating indicator of pulmonary endothelial injury and repair.

Immunocytochemical diagnosis of alpha-1-antitrypsin deficiency Review of eight cases

Eight cases of liver disease associated with alpha-1-antitrypsin deficiency are described. Six of the cases, including the only childhood case, showed no evidence of lung disease. An occult but variable clinical course is defined in this disorder. A spectrum in the severity of tissue change was noted, and in some instances, extensive liver disease was correlated with relatively minor derangement in liver function. While this form of liver disease is uncommon, it should be included in the differential diagnosis of adult liver disease. Screening for alpha-1-antitrypsin globules in periodic acid-Schiff stained liver tissue sections should be considered in certain cases of cryptogenic liver disease in adults, particularly when advanced disease presents suddenly, where micronodular (portal) cirrhosis is unrelated to excessive alcohol use, or where tissue changes exceed those anticipated from serum biochemical abnormalities. In most of these cases, tissue findings from liver biopsy or autopsy, rather than clinical suspicion, led to the diagnosis. The availability of a simple and reliable immunoperoxidase technique, applicable to routinely processed tissue samples, allowed for rapid and specific diagnosis in all cases. This immunocytochemical method has proven its usefulness in the prospective and retrospective tissue diagnosis of alpha-1-antitrypsin deficiency and associated liver disease.

Chest X-ray film not needed during antituberculosis chemoprophylaxis.

To the Editor.— Among those given isoniazid (INH) chemoprophylaxis are many persons who have no lung disease but who are, nonetheless, at great risk from pulmonary tuberculosis. They are close contacts of newly discovered cases of tuberculosis, persons known to have recently become tuberculous infected (converted from negative to positive tuberculin reaction), and tuberculin reactors through the age of 20 years. 1 Many are children; some are women of childbearing age. Their exposure to ionizing radiation, even to the small dosages associated with chest roentgenograms, should be commensurate with the results achieved. 2 We conducted the following study to determine whether these tuberculin-positive persons need periodic chest roentgenograms while they take prophylactic treatment with INH. Material and Methods.— The population studied (Fig 1 and 2) consisted of 552 men, women, and children who had no evidence of lung disease when they accepted antituberculosis chemoprophylaxis at the New Orleans Tuberculosis Clinic

The bronchial arteries in chronic obstructive pulmonary disease

Selective catheterization and visualization of the right bronchial artery was carried out in twenty patients. Five patients either had no evidence of lung disease or a minimal degree of chronic obstructive pulmonary disease (COPD); in all five the bronchial arteries were normal. Fifteen patients had chronic obstructive pulmonary disease which varied from mild to severe. In these fifteen patients the bronchial arteries were enlarged; however, there was no correlation between the size of these arteries and the changes in pulmonary vessels observed on angiograms, impairment in pulmonary function, cough and dyspnea. Nine of the fifteen patients had no evidence of lung disease other than chronic obstructive pulmonary disease. Four patients had bullous emphysema, one patient had severe bronchiolectasis and one patient had severe bronchiectasis in addition to chronic obstructive pulmonary disease. The bronchial arteries in patients with bullae and the patient with bronchiolectasis were similar to those with chronic obstructive pulmonary disease; however, in the patient with bronchiectasis this artery was markedly enlarged.

Bronchial mucus gland hypertrophy: Its relation to symptoms and environment

Major bronchi from a series of 644 consecutive autopsies were examined for mucus gland hypertrophy and cellular infiltration. The findings were related to environmental histories, obtained before death from the patients themselves if possible, or after death from the relatives. The two measurements made to assess mucus gland hypertrophy were reasonably reproducible for any one case, but they were not closely related to each other, suggesting that they reflected different aspects of bronchitic change. In males smoking seemed to be the dominant factor in producing mucus gland hypertrophy. No significant effect of place of residence was seen, but the area in which the survey was carried out did not include any region of really heavy air pollution. The smoking habit seemed to be largely responsible for the increased incidence of mucus gland hypertrophy in men in the older age-groups. Pipe-smokers and ex-cigarette-smokers had almost as high an incidence of mucus gland hypertrophy as cigarette-smokers. The clinical symptoms of chronic cough and expectoration were associated with mucus gland hypertrophy. The incidence of mucus gland hypertrophy was higher in the various lung diseases studied than in patients with no evidence of lung disease. There was little difference in incidence between the various lung diseases. No consistent association between inflammatory cell infiltration in the bronchus and mucus gland hypertrophy was seen.