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Short-term regional clearance of an inhaled submicrometric aerosol in pulmonary fibrosis.

Regional clearance of submicrometric aerosol during 5 days was studied in control hamsters and in those with diffuse interstitial pulmonary fibrosis. Fibrosis was induced by treatment with bleomycin (1.6 U/kg) and oxygen (70% for 72 h) 80 days earlier. Diseased and control animals were exposed for 30 min to an insoluble colloidal 198Au aerosol (AMAD, 0.62 micron; sigma g, 1.35). Five diseased and 6 control animals were killed immediately (Day 0); 6 diseased and 6 control animals were killed 5 days later (Day 5). All lungs were excised, dried at TLC, sliced into 1-mm sections, and dissected into pieces. When compared with deposition in Day 0 control lungs, 26.3% of the particles had been cleared 5 days after exposure from the control lungs. Diseased animals cleared 44.6% of the particles (p less than 0.05, compared with Day 0 diseased animals). Examination of regional clearance on the basis of lobar differences, apex to base levels, and presence of airways also reflected increased clearance in the fibrotic animals. The parenchymal distribution of particle retention at Day 0 was less uniform in the fibrotic animals than in the control animals and was not significantly altered after 5 days of clearance in either group. Particle clearance may be greater in diseased lungs because of accelerated alveolar-bronchiolar transport of particles or particle-containing macrophages.

Aerosols↗

Quantification of idiopathic pulmonary fibrosis using computed tomography and histology.

We used computed tomography (CT) and histologic analysis to quantify lung structure in idiopathic pulmonary fibrosis (IPF). CT scans were obtained from IPF and control patients and lung volumes were estimated from measurements of voxel size, and X-ray attenuation values of each voxel. Quantitative estimates of lung structure were obtained from biopsies obtained from diseased and normal CT regions using stereologic methods. CT density was used to calculate the proportion of tissue and air, and this value was used to correct the biopsy specimens to the level of inflation during the CT scan. The data show that IPF is associated with a reduction in airspace volume with no change in tissue volume or weight compared with control lungs. Lung surface area decreased two-thirds (p < 0.001) and mean parenchymal thickness increased tenfold (p < 0.001). An exudate of fluid and cells was present in the airspace of the diseased lung regions and the number of inflammatory cells, collagen, and proteoglycans was increased per 100 g of tissue in IPF. We conclude that IPF reorganized lung tissue content causing a loss of airspace and surface area without increasing the total lung tissue.

Aged↗

Utility of a lung biopsy for the diagnosis of idiopathic pulmonary fibrosis.

It is not known if a surgical lung biopsy is necessary in all patients for the diagnosis of idiopathic pulmonary fibrosis (IPF). We conducted a blinded, prospective study at eight referring centers. Initially, cases were evaluated by clinical history and examination, transbronchial biopsy, and high-resolution lung computed tomography scans. Pulmonologists at the referring centers then assessed their certainty of the diagnosis of IPF and provided an overall diagnosis, before surgical lung biopsy. The lung biopsies were reviewed by a pathology core and 54 of 91 patients received a pathologic diagnosis of IPF. The positive predictive value of a confident (certain) clinical diagnosis of IPF by the referring centers was 80%. The positive predictive value of a confident clinical diagnosis was higher, when the cases were reviewed by a core of pulmonologists (87%) or radiologists (96%). Lung biopsy was most important for diagnosis in those patients with an uncertain diagnosis and those thought unlikely to have IPF. These studies suggest that clinical and radiologic data that result in a confident diagnosis of IPF by an experienced pulmonologist or radiologist are sufficient to obviate the need for a lung biopsy. Lung biopsy is most helpful when clinical and radiologic data result in an uncertain diagnosis or when patients are thought not to have IPF.

Biopsy↗

[Clinical presentation and medical management in patients with idiopathic pulmonary fibrosis before diagnosis].

UNLABELLED: The aim of the study was to find factors that may influence diagnostic process of idiopathic pulmonary fibrosis (IPF). Clinical presentation and medical management in the period before the diagnosis of IPF were assessed in 57 patients. There were 25 females and 32 males in the study group; mean age was 61.4 +/- 10.9 years. Mean duration of symptoms in the whole group was 18.4 +/- 16.0 months. The most common symptoms were dyspnea on exertion (96.5% of cases) and cough (84.2% of cases). 56 out of 57 patients (98.2% of cases) had crackles on auscultation of the lungs. In one third of the patients clubbing of the fingers was found. Mean FVC% of predicted was 77.2 +/- 19.8%, and mean DLCO% of predicted was 61.6 +/- 16.8%. The most common associated disease was ischemic heart disease, found in 43.9% of patients. Duration of symptoms in patients with ischemic heart disease was 25.7 +/- 18.8 months and was as twice long as in the rest of the patients, 12.8 +/- 10.5 months (p < 0.005). Prior the diagnosis of IPF 22 patients (38.6% of cases) did not any receive treatment for symptoms of interstitial lung disease. 31 patients (54.4% of cases) received antibacterial treatment (29 antibiotics and 2 anti-Tb drugs), although there were no clear signs of infection. CONCLUSIONS: 1. Associated ischemic heart disease may cause delay in establishing the diagnosis of IPF; 2. In the period before diagnosis of IPF over half of the patients were given antibacterial treatment without appropriate indications.

Adult↗

Herpesvirus DNA is consistently detected in lungs of patients with idiopathic pulmonary fibrosis.

On the basis of earlier reports associating Epstein-Barr Virus (EBV) with half of the cases of idiopathic pulmonary fibrosis (IPF), we hypothesized that chronic infection with EBV or a closely related herpesvirus would be detected in all cases of IPF. We tested lung specimens from 33 IPF patients (8 patients with familial IPF and 25 patients with sporadic IPF) and 25 patients with other diseases as controls for the presence of eight herpesviruses using PCR-based techniques. One or more of four herpesviruses (cytomegalovirus [CMV], EBV, human herpesvirus 7 [HHV-7], and HHV-8) were detected in 32 of 33 (97%) subjects with IPF and in 9 of 25 (36%) controls (P < 0.0001). CMV, EBV, and HHV-8 were found more frequently in IPF patients than in controls (P < 0.05, P < 0.001, and P < 0.01 respectively). Two or more herpesviruses were detected in 19 of 33 (57%) IPF patients and in 2 of 25 (8%) controls (P < 0.001). Two or more herpesviruses and HHV-8 were found more frequently in patients with sporadic IPF than in patients with familial IPF (P < 0.05 for both comparisons), and CMV was found less frequently in patients with sporadic IPF than in patients with familial IPF (P < 0.05). Immunohistochemistry for EBV or HHV-8 antigen showed viral antigen primarily in airway epithelial cells. These data support the concept that a herpesvirus could be a source of chronic antigenic stimulation in IPF.

Adult↗

Autoantibodies to IL-1 alpha in sera from rapidly progressive idiopathic pulmonary fibrosis.

To clarify the clinical significance of autoantibodies to interleukin-1 alpha (IL-1 alpha autoantibodies) in rapidly progressive idiopathic pulmonary fibrosis (IPF), we measured the level of IL-1 alpha autoantibodies in serum of 11 patients on the first hospital day, when patients were admitted due to severe symptoms, and on the 21st hospital day. IL-1 alpha autoantibodies in serum were measured using radioimmunoassay, and the limitation of this assay for IL-1 alpha autoantibodies was 5 ng/ml. These antibodies were detected in 5 of 11 patients on the first hospital day. On the 21st hospital day, these antibodies were detected in all patients, and its level was increased compared with that on the first hospital day. IL-1 alpha autoantibodies that appeared in patients corresponded to that of IgG. The half life of exogenous autoantibodies was investigated following administration of autoantibody rich plasma obtained from healthy blood donors to 6 control patients (CP) and 6 progressive IPF patients. These autoantibody levels in their serum were less than 5 ng/ml before administration. Serum was obtained at the indicated time after administration of IL-1 alpha autoantibodies and the level of these autoantibodies in serum was measured, then the half life was calculated. Half life of exogenous IL-1 alpha autoantibodies in progressive IPF patients was significantly shorter than that in CP (71.3 +/- 31.8 hr vs 352.0 +/- 98.3 hr, p < 0.01). These findings suggested that IL-1 alpha autoantibodies were generated in response to the inflammatory process of rapidly progressive IPF and may act as a regulatory factor for IL-1 alpha.

Aged↗

Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double-blind, randomized, placebo-controlled clinical trial.

Twenty-seven newly diagnosed patients with idiopathic pulmonary fibrosis (IPF) who were previously untreated for IPF were enrolled in a prospective, double-blind, randomized, placebo-controlled study to compare the therapeutic effect of combined prednisone/azathioprine (n = 14) with prednisone plus placebo (n = 13). Prednisone was started at 1.5 mg/kg/day (not to exceed 100 mg/day) for the first 2 wk followed by a biweekly taper to a maintenance dose of 20 mg/day. Azathioprine was administered at a daily dose of 3 mg/kg (not to exceed 200 mg/day). The patients tolerated the use of azathioprine well with few associated side effects. Changes in lung function at 1 yr, as measured by resting alveolar-arterial oxygen difference P[A-a]O2, FVC, and single breath diffusing capacity for carbon monoxide (DLCOSB), were all somewhat better in the azathioprine/prednisone group compared with the prednisone alone group, although none of these comparisons were statistically significant. Six of 14 (43%) patients randomized to prednisone plus azathioprine died during the 9-yr follow-up period, compared with 10 of 13 (77%) patients randomized to prednisone plus placebo. A Cox model survival analysis shows a nonsignificant but potentially large survival advantage for azathioprine/prednisone (hazard ratio 0.48, with 95% confidence interval increasing from 0.17 to 1.38). When adjusted for age, the survival advantage of azathioprine/prednisone becomes marginally significant (hazard ratio 0.26, with 95% confidence interval increasing from 0.08 to 0.88; p = 0.02 by large sample approximation, p = 0.05 by randomization test). We conclude that combined prednisone and azathioprine is a safe and possibly effective regimen for the treatment of IPF.(ABSTRACT TRUNCATED AT 250 WORDS)

Azathioprine↗

[The control of respiration in pulmonary fibrosis. The effect of O2 and CO2].

We have studied the mode of ventilation and chemosentivity in 10 patients suffering from pulmonary fibrosis. The total lung capacity was on average 63.5 +/- 8% of the predicted. Their static compliance was 0.078 +/- 0.05 l.cm of water. The patients were studied in the prone position breathing ambient air then on hyperoxia. The response to CO2 was assessed according to the rebreathing method of Read. The results of these patients were compared with those of 11 normal subjects. The ventilation at rest was normal, with a shortened respiratory time and a Ti/Ttot ratio which was lowered. The occlusion pressure (P0.1) was very much higher than that in normal subjects. This rise was correlated with an increase in pulmonary elastance and a reduction in vital capacity. The correction of hypoxia was without effect on the respiratory parameters. In relation to normal subjects the ventilatory response to carbon dioxide in fibrotics was decreased whilst the response of the P0.1 was increased expressing central hyperactivity. In conclusion, fibrotic patients have normal ventilation in spite of an increase in inspiratory work. This normal ventilation results from hyperactivity of the respiratory centre, as in the hyperventilation induced by carbon dioxide when at rest.

Adult↗

[A case of Hand-Schüller-Christian disease with pulmonary fibrosis].

A 42-year-old man was admitted with dyspnea and abnormal shadows on chest roentgenogram, which showed bilateral reticulonodular shadows, multiple pulmonary cysts, and pleural effusion. A month after admission, he developed severe respiratory failure and chest X-ray revealed exacerbation of reticulonodular shadows. Steroid pulse therapy improved the symptoms and chest X-ray. He had atrophy of the mandible. Bone scintigram revealed multiple hot lesions. Bone biopsy of the right tibia showed lipogranuloma, and the diagnosis of Hand-Schüller-Christian disease (HSC) was made. The percentage of OKT6-positive cells (Langerhans cells) found by immunofluorescence was 16.1% of all cells in bronchoalveolar lavage fluid, indicating pulmonary involvement due to HSC. This is a rare case of Hand-Schüller-Christian disease with pulmonary fibrosis.

Adult↗

[Pulmonary fibrosis after endotoxin-induced permeability edema].

To know the pathogenesis of the lung fibrosis after ARDS, we investigated the role of PMN-elastase after endotoxin-induced pulmonary edema in awake sheep with chronic lung lymph fistulas. The permeability of the pulmonary circulation increased 2 hours after endotoxin injection. Four hours after endotoxin injection, WBC migrated to the lung interstitium and the number of WBC in BALF increased. Endotoxin increased PMN-elastase in plasma and lymph whereas the level of alpha-1-protease inhibitor (alpha-1-PI) did not change. The activity of alpha-1-PI measured by trypsin inhibitory capacity was zero in the exudative phase. The level of PMN-elastase in lymph was significantly higher 1 week after endotoxin injection than baseline levels. Histologically, pulmonary fibrosis developed 1 week after endotoxin injection. These results suggest that inflammatory mediators released from PMN play an important part in progress to the fibrotic phase after ARDS.

Animals↗

Cutaneous alternariosis in a patient with idiopathic pulmonary fibrosis.

A 78-year-old farmer presented with symptomless skin lesions for evaluation. Two years prior, he had developed idiopathic pulmonary fibrosis (IPF) and had been treated thereafter with oral prednisolone 20 mg/day and occasionally with colchicine 1 mg/day. On examination, erythematoviolaceous, slightly infiltrated plaques, measuring approximately 5 x 9 cm, rubbery in consistency, intermingled with pustules, sometimes eroded, with distinctive borders, were noted on the dorsum of both hands and on the extensor surface of both forearms. The lesions had developed over a 20-day period. The skin of these areas was atrophic or eroded with multiple ecchymoses (Fig. 1). The abnormal laboratory findings included an elevated white blood cell count of 17,100/mm3, with 79% neutrophils, 16% lymphocytes, and 5% monocytes, C-reactive protein of 33.15 mg/dL (normal, <0.8 mg/dL), and immunoglobulin G of 598 mg/dL (normal, 701-1545 mg/dL). Other blood and urine tests performed were within normal limits. The diagnosis of IPF was reconfirmed through radiology, high-resolution computed tomography, and spirometry, as well as bronchoscopy and bronchoalveolar lavage fluid analysis. Coexistence of presumptive pulmonary alternariosis was excluded. Hematoxylin and eosin stained sections of the excised cutaneous specimen showed focal ulceration of the epidermis adjacent to a mainly intradermal abscess cavity. Within the latter, remnants of a partly destroyed hair follicle were seen amongst degenerating polymorphonuclear leukocytes, as well as many histiocytes and a few Langhans-type multinucleated giant cells. Minute collections of polymorphonuclear leukocytes were seen in the adjacent epidermis. Periodic acid-Schiff (PAS) and Gomori's silver methenamine stains showed a multitude of broad branching fungal hyphae and large spores within the aforementioned cavity, both free and within the cytoplasm of giant cells (Fig. 2). Immunohistochemistry was performed by means of the alkaline phosphatase anti-alkaline phosphatase (APAAP) method. Sections showed that the infiltrate consisted of an almost equal number of B and T lymphocytes, whereas histiocytes and the few giant cells were labeled with anti-CD68 antibodies. Skin smears and biopsy specimens taken twice from all lesions were used for mycologic examination. Wet mounts revealed numerous, brownish, septate hyphae and ovoid Skin smears and biopsy specimens taken twice from all lesions were used for mycologic examination. Wet mounts revealed numerous, brownish, septate hyphae and ovoid structures. Biopsy material was plated on Sabourand's dextrose agar with cloramphenicol (0.05 mg/mL). After 7 days at 27 degrees C, dark, gray-white colonies with a dark brown underside appeared. Microscopic examination of the colonies revealed hyphae with typical conidia having transverse and longitudinal septa. Based on macroscopic and microscopic examination, the isolates were identified as Alternaria alternata (Fig. 3). Treatment with prednisolone was reduced to 10 mg/day and the patient received oral itraconazole (200 mg/day). This resulted in progressive improvement of alternariosis, and the lesions healed completely within 3 months, when treatment was interrupted. Two years later, there is no evidence of recurrence.

Aged↗

Progressive worsening of idiopathic pulmonary fibrosis. High resolution computed tomography (HRCT) study with functional correlations.

PURPOSE: To evaluate the usefulness of the high-resolution computed tomography (HRCT) visual score in idiopathic pulmonary fibrosis (IPF) and its correlation with respiratory function tests. MATERIAL AND METHODS: We studied the pulmonary function tests and HRCT scans of 42 IPF patients, at presentation (T0) and follow-up (T1: mean 13.7 months post-diagnosis). Of the 42 patients, 21 had been treated with steroid and immunosuppresion therapy. The pulmonary function tests considered were vital capacity (VC), diffusion lung capacity for carbon monoxide (D(L)CO) and arterial blood oxygen partial pressure (PaO(2)). The main HRCT parameters were type of lesion, and site and extent, the latter calculated by means of the visual score. RESULTS: Between T0 and T1, both mean HRCT score (from 43.57% to 50.64%) and lung function tests worsened (VC from 68.43% to 64.18%; D(L)CO from 36.31% to 28.97%; PaO(2) from 76.31 to 68.89 mmHg), without considerable differences between treated and untreated patients. At presentation (T0), the HRCT visual score had a significant correlation with lung function tests and these correlated with one another. Similar correlations were found at T1, but not for HRCT score and D(L)CO. In the interval between T0 and T1 the variations correlated significantly with each other, with two exceptions: HRCT score and D(L)CO, and D(L)CO and PaO(2). DISCUSSION AND CONCLUSIONS: IPF exhibited a progressive deterioration both in HRCT extent of disease and lung function impairment. There is a significant correlation between HRCT visual score and lung function tests both at diagnosis and at follow-up. The HRCT study is able to identify and quantify anatomic IPF and also to evaluate the progression of the disease. In clinical practice, the HRCT visual score of disease extent can be used in association with function tests to monitor IPF evolution, and to evaluate prognosis and therapy. In the future, helical CT with 3D model construction will provide a more precise IPF quantification with automatic score.

Aged↗

Microsatellite instability in transforming growth factor-beta 1 type II receptor gene in alveolar lining epithelial cells of idiopathic pulmonary fibrosis.

It has been reported that transforming growth factor (TGF)-beta, which plays an integral role in the pathogenesis of idiopathic pulmonary fibrosis (IPF), suppresses proliferation of alveolar epithelial cells in vitro. Although hyperplastic lesions of alveolar lining epithelial cells (ALECs) are characteristic pathologic features of IPF, the mechanism of their involvement in the pathogenesis has not yet been extensively studied. On the assumption that the hyperplastic ALECs have escaped from the growth-inhibitory effects of TGF-beta, we searched for mutations in the microsatellite of the TGF-beta receptor type II (T beta RII) gene. To detect a deletion in the polyadenine tract in exon 3 of the T beta RII gene, cells were isolated by microdissection from lung sections of IPF patients, and DNA was extracted from these cells and amplified by high-fidelity polymerase chain reaction. A total of 121 sites of hyperplastic ALECs from 11 IPF patients were analyzed, and a one-base-pair deletion was detected in nine sites from five patients. The mutation was also detected in smooth muscle-like cells of the thickened pulmonary artery. In some tissue areas where the deletion was detected, low T beta RII expression was confirmed by immunohistochemical staining. These data suggest that microsatellite instability in the T beta RII gene occurred in some lesions of hyperplastic ALECs in IPF, although at a low incidence, and that this genetic disorder might play a partial role in the pathologic changes of IPF.

Adult↗

[Diffuse familial interstitial pulmonary fibrosis. Study of a family].

A study of the genealogy of a 53 year old lady (A.M...) suffering from diffuse interstitial pulmonary fibrosis (FID) has revealed several cases of FID in her forbears and relations. Two brothers of A.M... died of histologically proven FID; FID was also discovered in one of their daughters. A sister died young of some unclassified respiratory problem. Two cousins died likewise at a young age of acute FID proven histologically. The level of spontaneous pneumothorax was particularly elevated in this family which represented a clinical peculiarity when compared to sporadic FID. The most probable mode of transmission of familial FID is autosomal dominant with variable penetrance. The HLA group seen in A.M... showed the A2 and B12 alleles. The B12 allele was also present in the niece of A.M...

Bronchi↗

[Tracheal intubation in a case of idiopathic pulmonary fibrosis using remifentanil and propofol without muscle relaxants].

The anesthetic management of a 58 year-old-male suffering from idiopathic pulmonary fibrosis associated with a previous experience of altered dose-response relationship to muscle relaxants is reported. He underwent a gastroendoscopic surgical procedure. After intravenous atropine, remifentanil 3.0 microg kg(-1) was injected over 90 sec. Sixty seconds after the start of remifentanil bolus dose, propofol 2.0 mg kg(-1) was injected and intubation was performed 1 min after the administration of propofol. Anesthesia was maintained by N(2)O, oxygen, sevoflurane (0.5-0.8%) and remifentanil titrated infusion (mean dose of 0.15 mg kg(-1) min(-1)) under spontaneous respiration or assisted ventilation, if the patient was apnoic. The intubating conditions were good, a 30 per cent reduction in MAP was observed after propofol administration. The patient regained consciousness 5 minutes after the end of remifentanil administration and his trachea was extubated without any troubles. Recovery was uneventful without the need of long-term intensive therapy.

Anesthetics, Intravenous↗