A multicenter pilot study of a bronchial valve for the treatment of severe emphysema.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) affects millions of people and has limited treatment options. Surgical treatments for severe COPD with emphysema are effective for highly selected patients. A minimally invasive method for treating emphysema could decrease morbidity and increase acceptance by patients. OBJECTIVE: To study the safety and effectiveness of the IBV(R) Valve for the treatment of severe emphysema. METHODS: A multicenter study treated 91 patients with severe obstruction, hyperinflation and upper lobe (UL)-predominant emphysema with 609 bronchial valves placed bilaterally into ULs. RESULTS: Valves were placed in desired airways with 99.7% technical success and no migration or erosion. There were no procedure-related deaths and 30-day morbidity and mortality were 5.5 and 1.1%, respectively. Pneumothorax was the most frequent serious device-related complication and primarily occurred when all segments of a lobe, especially the left UL, were occluded. Highly significant health-related quality of life (HRQL) improvement (-8.2 +/- 16.2, mean +/- SD change at 6 months) was observed. HRQL improvement was associated with a decreased volume (mean -294 +/- 427 ml, p = 0.007) in the treated lobes without visible atelectasis. FEV(1), exercise tests, and total lung volume were not changed but there was a proportional shift, a redirection of inspired volume to the untreated lobes. Combined with perfusion scan changes, this suggests that there is improved ventilation and perfusion matching in non-UL lung parenchyma. CONCLUSION: Bronchial valve treatment of emphysema has multiple mechanisms of action and acceptable safety, and significantly improves quality of life for the majority of patients.

Computed tomography assessment of lung volume changes after bronchial valve treatment.

The aim of the present study was to correlate clinical outcome measures following treatment with bronchial valves with regional lung volume. Computed tomography (CT) scan data from 57 subjects with severe emphysema were obtained from nine North American clinical trial sites. IBV(R) Valves (Spiration, Inc., Redmond, WA, USA) were placed to occlude segmental and subsegmental bronchi in right and left upper lobes using a flexible bronchoscope. Subjects completed a St George's Respiratory Questionnaire (SGRQ), pulmonary function test (PFT) and exercise capacity test. CT scans were analysed at baseline and at 1, 3 or 6 months after treatment to measure total and lobar lung density, volume and mass. Total lung volumes measured using CT were strongly correlated with PFT and did not change with treatment. However, the treated upper lobes significantly decreased in volume in 88% of the observations, by mean+/-sd 335+/-444 mL, or a decrease of 10.2% in the 6 month data. The untreated lobes had an 11.6% increase in volume. Changes in regional lung volume were associated with clinically meaningful improvements in SGRQ (-8.95+/-16.22), but not clinically meaningful PFT changes. The significant health status improvements reported by subjects following bilateral bronchial valve treatment are associated with regional lung volume changes and interlobar shift measured using computed tomography.

The diagnosis of ventilator-associated pneumonia: a comparison of histologic, microbiologic, and clinical criteria.

STUDY OBJECTIVE: To evaluate histologic, microbiological, and clinical criteria in the recognition of ventilator-associated pneumonia (VAP) in patients who died while mechanically ventilated. METHODS: The study group consisted of 39 patients who died after a mean of 14 days of mechanical ventilation. Postmortem fiberoptic bronchoscopy (FOB) and open lung biopsy were performed with collection of specimens initiated <1 h after death. The microbiological specimens included suction catheter aspirate of tracheal secretions, FOB-guided protected specimen brush (PSB) of tracheal secretions, blindly placed PSB in a distal airway, FOB-guided PSB in a distal airway, and FOB-guided BAL fluid (BALF) in a distal airway. Qualitative bacteriologic study was performed on all specimens, and quantitative bacteriologic study was performed on all but the suction catheter aspirate of the trachea. A biopsy specimen of peripheral lung parenchyma from the same region sampled by FOB was sent for quantitative culture and histologic analysis. The BALF was analyzed for cell population and percent of neutrophils containing intracellular organisms. The clinical criteria selected for comparison with histologic and microbiological results included a temperature > or =38.5 degrees C during the 48 h prior to death, a WBC count > or =15,000/mm3 in the 48 h prior to death, presence of a bacterial or fungal pathogen on the last sputum culture, radiographic worsening in the week prior to death, and worsening gas exchange defined as a 15% decrease in the PaO2/fraction of inspired oxygen ratio in the 72 h prior to death. RESULTS: None of the quantitative cultures had a reliable positive predictive value for histologic pneumonia. None of the five clinical criteria tested showed agreement with the presence or absence of histologic pneumonia. There was a significant correlation between qualitative and quantitative microbiological results from the distal airway/FOB-guided PSB, distal airway/BALF, and quantitative culture of the lung parenchyma. Also, suction catheter aspirate of the trachea had a sensitivity of 87% in recognizing the bacterial species simultaneously present in lung parenchyma. None of the patients with histologic pneumonia had <50% neutrophils in the BALF. CONCLUSIONS: Neither the bacterial, density from the four airway quantitative cultures, nor the bacterial density from quantitative culture of lung parenchyma accurately separated the histologic pneumonia and nonpneumonia groups. No clinical criteria or combination of clinical criteria correlated with the presence or absence of histologic pneumonia. A BALF with <50% neutrophils had a 100% negative predictive value for histologic pneumonia. A BALF quantitative culture had a sensitivity of 63%, specificity of 96%, and positive predictive value of 91% in recognizing sterile lung parenchyma. Thus, BALF may have a role in excluding pneumonia/infection in the ventilated patient. Antibiotic choice for the empiric therapy of VAP can be accurately guided by the microbial population recognized through culture of a tracheal suction catheter aspirate.

TCR expression and clonality analysis in pulmonary sarcoidosis.

Pulmonary sarcoidosis is a granulomatous disease characterized by the accumulation of activated T cells in the lower respiratory tract. To evaluate the hypothesis that sarcoidosis is characterized by a selective activation and expansion of a limited repertoire of T cell receptor (TCR)-specific T cells, we analyzed TCRAV and TCRBV gene expression in bronchoalveolar lavage (BAL) T cells from sarcoidosis patients and, for comparison, from patients with other pulmonary diseases where lymphocyte accumulation is not observed. Increased expression of TCRAV9 and TCRAV14 in BAL T cells was observed in sarcoidosis patients compared to these controls. To ascertain whether the accumulation of AV9 and AV14 expressing BAL T cells in sarcoidosis was the result of clonal expansion, the lengths of the CDR3 regions in AV9 and AV14 transcripts were determined. Some individual patient samples showed evidence of oligoclonality. However, in most cases, the data were consistent with the presence of many different clones. These data suggest that the bulk of BAL T cells in sarcoid patients are either nonspecifically recruited or are responding to a complex mixture of antigens.

A clinical profile of chronic bacterial pneumonia. Report of 115 cases.

OBJECTIVE: To review the clinical presentation, radiology, microbiology, and response to therapy of patients with chronic bacterial pneumonia. DESIGN: A retrospective analysis. SETTING: An urban tertiary care medical center. PARTICIPANTS: One hundred fifteen patients with pulmonary and/or constitutional symptoms of at least 1 month's duration with 4,000 or more colony-forming units (CFUs) of a single bacterial species identified by quantitative culture obtained via fiberoptic bronchoscopy. MEASUREMENTS: Charts were analyzed for presence or absence of any predisposing illness, symptoms at presentation, roentgenographic abnormalities, microbiologic results, findings at fiberoptic bronchoscopy, and results of therapeutic intervention. RESULTS: Sixty-five percent of patients with chronic bacterial pneumonia had a predisposing disease, 35 percent were "normal." Cough, fatigue, dyspnea, and weight loss were predominant symptoms in both groups. Bronchogenic carcinoma was newly diagnosed in 16 patients (14 percent). Haemophilus influenzae or alpha-hemolytic streptococcus was isolated in 68 percent of patients. Risk of recurrence of infection was inversely associated with duration of therapy in both groups. CONCLUSIONS: Chronic bacterial pneumonia is more common than previously recognized. It occurs in patients with and without a predisposing illness. Clinical presentation, roentgenographic appearance, and bacteriology are similar between the two groups. Cure requires prolonged antibiotic therapy.

Fractional analysis of the 120-ml bronchoalveolar lavage. Determination of the best specimen for diagnosis of sarcoidosis.

STUDY DESIGN: Bronchoalveolar lavage with seven 20-ml aliquots was performed on 9 patients with sarcoidosis and 11 patients with idiopathic pulmonary fibrosis (IPF). The returns from the first 20-ml aliquot (volume 1), the next 100 ml of bronchoalveolar lavage fluid (volume 2), and the last 20 ml of lavage fluid (volume 3) were analyzed separately for cell content and differential cell counts. The cell content was calculated four different ways, including absolute number of cells per milliliter of return and as a differential cell count using three different denominators. The denominators used were (1) neutrophils, lymphocytes, eosinophils, macrophages, and epithelial cells; (2) neutrophils, lymphocytes, eosinophils, and macrophages; and (3) neutrophils, lymphocytes and eosinophils. The data were analyzed to see what volume and arithmetic expression of cell content provided the best means of distinguishing sarcoidosis from IPF. RESULTS: The results confirmed a proximal distribution of the first 20-ml aliquot with more bronchial epithelial cells and neutrophils than volumes 2 and 3. There were more macrophages and lymphocytes in volumes 2 and 3 than in volume 1. Volumes 2 and 3 had similar cell content. Sequential fractional analysis showed that the cells in volume 2 and 3 more clearly distinguished sarcoidosis from IPF than the cell content of volume 1. CONCLUSION: The presence of lymphocytes, and especially a predominance of lymphocytes with the relative absence of neutrophils, correlated best with sarcoidosis. The percentages of differential cell counts proved superior to both the absolute number of neutrophils and of lymphocytes per milliliter of return in distinguishing sarcoidosis from IPF. A percentage differential cell count with a denominator of neutrophils+lymphocytes+eosinophils provided the best means of distinguishing between sarcoidosis and IPF.

Bronchoalveolar lavage cell populations in the diagnosis of sarcoidosis.

STUDY DESIGN: Between February 1, 1984, and February 1, 1989, fiberoptic bronchoscopy was performed on 2,692 patients, 592 of whom had bronchoalveolar lavage (BAL). One hundred twenty-eight patients with 16 percent or more lymphocytes in BAL fluid (BALF) were selected for further study. The group included 27 patients with sarcoidosis, 28 with nonsarcoidosis interstitial lung disease (ILD), 22 with lung infection (organism isolated), 31 with inflammation (presumed infection, no organism isolated), 14 with neoplasm, and 6 with bronchial hyperreactivity. METHODS: The percentages of lymphocytes, B lymphocytes, and T lymphocytes, the CD4/CD8 ratio and the percentages of neutrophils and eosinophils were analyzed individually and in combination for discrimination between the sarcoidosis and nonsarcoidosis patients and compared with the diagnostic accuracy of multiple noncaseating granuloma (MNG) on a simultaneous transbronchial biopsy (Tbbx). RESULTS: Neither the percentages of lymphocytes, T lymphocytes, or B lymphocytes discriminated sarcoidosis from nonsarcoidosis patients. Sarcoidosis patients had higher CD4/CD8 ratios, fewer neutrophils, and 1 percent or less eosinophils in the BAL cell populations. An analysis of CD4/CD8 ratios, and percentages of neutrophils and eosinophils individually revealed that a CD4/CD8 ratio of 4:1 or greater had a positive predictive value of 94 percent in distinguishing sarcoidosis from other ILD but a sensitivity of only 59 percent. The positive predictive value of CD4/CD8 ratio of 4:1 or greater fell to 50 percent in separating sarcoidosis from all other diseases. A CD4/CD8 ratio of less than 1:1 has a 100 percent negative predictive value to exclude the diagnosis of sarcoidosis. Finding 1 percent or less neutrophils in BAL had an 80 percent positive predictive value in distinguishing sarcoidosis from nonsarcoidosis ILD and 51 percent for distinguishing sarcoidosis from all other disease groups. The CD4/CD8 ratio and the percentages of neutrophils and eosinophils also were combined and analyzed for the diagnosis of sarcoidosis. CONCLUSIONS: Results showed a BALF with a CD4/CD8 ratio of 2:1 or greater, 1 percent or less neutrophils, and 1 percent or less eosinophils has essentially the same specificity and positive predictive value as MNG on Tbbx in distinguishing sarcoidosis from nonsarcoidosis disease. The combination of finding MNG in a Tbbx specimen plus a BALF CD4/CD8 ratio of 4:1 or greater had a 100 percent positive predictive value in separating sarcoidosis from other ILD and an 81 percent value in separating sarcoidosis from all other disease. Finding MNG in a Tbbx specimen plus a BALF with a CD4/CD8 ratio of 2:1 or greater, 1 percent or less neutrophils, and 1 percent or less eosinophils had a 93 percent positive predictive value in distinguishing sarcoidosis from both nonsarcoidosis ILD and all other diseases.

Chronic dyspnea unexplained by history, physical examination, chest roentgenogram, and spirometry. Analysis of a seven-year experience.

The purpose of this article is to describe the spectrum and frequency of diseases presenting as unexplained dyspnea and to develop a logical diagnostic approach to such patients. Seventy-two consecutive physician-referred patients had dyspnea greater than one-month duration unexplained by the initial history, physical examination, chest roentgenogram, and spirometry. Patients underwent a standard diagnostic evaluation. A definite cause for dyspnea was recognized in 58 patients, and no answer was found in 14. Twenty-two diseases were recognized in the patient group. Dyspnea was due to pulmonary disease in 26 (36 percent) patients, cardiac disease in ten (14 percent) patients, hyperventilation in 14 (19 percent) patients, and only 3 patients had extrathoracic disease causing dyspnea. Age younger than 40 years, intermittent dyspnea, and normal alveolar-arterial oxygen pressure difference (P[A-a]O2) at rest breathing room air was strongly predictive of bronchial hyperreactivity or hyperventilation. No patient diagnosed as having disease of the lung parenchyma or vasculature had a P(A-a)O2 less than or equal to 20 mm Hg. The differential diagnosis to explain dyspnea in patients with nondirective histories, normal findings from physical examinations, normal chest roentgenograms, and normal spirograms is extensive. The patient's age and measurement of gas exchange at rest help to formulate a diagnostic approach.

Oral antibiotics for pneumonia.

The majority of patients presenting with community-acquired pneumonia can be treated with oral antibiotics and can be managed successfully as outpatients. Oral-antibiotic selection requires a knowledge of the classes of antibiotics available, utility of diagnostic testing, epidemiology of pneumonia, and a rational approach to empiric therapy when a cause cannot be immediately identified. These topics are reviewed, with the goal improved therapeutic efficacy in the oral treatment of pneumonia.

Use of bronchoalveolar lavage to diagnose acute diffuse pneumonia in the immunocompromised host.

We compared the diagnostic information obtained by bronchoscopy and needle aspiration of the lung with information obtained concurrently by open-lung biopsy in 15 marrow transplant recipients. Bronchoscopy included a wash, brush, and bronchoalveolar lavage. Laboratory evaluation included standard histological and cytological methods, specific immunofluorescence with monoclonal antibodies, and DNA hybridization to detect cytomegalovirus (CMV). Bronchoscopy permitted diagnosis of five of six patients with CMV pneumonia, whereas needle aspiration alone permitted diagnosis of only one of six. Bronchoalveolar lavage alone provided the diagnosis in four of six patients. Bronchoscopy also identified the bacterial component of a combined infection and identified one case of primary lung hemorrhage. Immunofluorescent staining and hybridization studies each diagnosed one case of CMV pneumonia not identified by standard techniques. The diagnostic sensitivity of the bronchoscopy was 89%, as compared with 17% for needle aspiration, and there were no complications.

Occurrence of the adult respiratory distress syndrome in neutropenic patients.

Neutrophils are believed to play an essential role in the pathogenesis of the adult respiratory distress syndrome (ARDS). This concept is largely based on the observation that neutrophil depletion protects against altered pulmonary vascular permeability in several models of acute lung injury produced in laboratory animals. Four patients who developed ARDS during periods of profound neutropenia are presented. These patients met commonly accepted clinical and roentgenographic criteria for the syndrome, and each had the characteristic findings of diffuse alveolar damage by lung histologic examination. The failure of this degree of neutropenia to protect against ARDS in humans raises questions about whether neutrophils or neutrophil products are essential in the pathogenesis of the syndrome.

The effects of chronic bronchitis and chronic air-flow obstruction on lung cell populations recovered by bronchoalveolar lavage.

Bronchoalveolar lavage is used to evaluate parenchymal inflammation in patients with diffuse lung disease. Normal values for lavage cell counts and proteins are derived primarily from young subjects who are free from lung disease; however, older patients who undergo bronchoalveolar lavage often have used cigarettes for long periods of time and have developed variable degrees of chronic bronchitis and/or chronic air-flow obstruction. Therefore, we evaluated the effects of cigarette use, chronic bronchitis, and chronic air-flow obstruction on lavage cell populations by performing bronchoalveolar lavage in 48 male patients who were undergoing diagnostic fiberoptic bronchoscopy. Sixteen patients (33%) had elevated percentages of neutrophils (greater than or equal to 10%) in lavage fluid. Fourteen of these (87.5%) had chronic cough and/or phlegm production, but only 9 (64.3%) met criteria for definite chronic bronchitis. Patients with moderate or severe air-flow obstruction, defined spirometrically, had significantly greater percentages of lavage neutrophils and lower percentages of macrophages than did patients with mild or no air-flow obstruction. The first lavage aliquot contained the greatest proportion of neutrophils and the smallest proportion of macrophages. The percentage of neutrophils declined and the percentage of macrophages increased in sequential aliquots. The data indicate that patients with chronic cough and/or phlegm production and chronic air-flow obstruction may have increased proportions of neutrophils in bronchoalveolar lavage fluid in the absence of diffuse parenchymal lung disease or infections. These variables must be taken into account when interpreting lavage cellular analyses.(ABSTRACT TRUNCATED AT 250 WORDS)

Factors related to the appearance of alveolar macrophages in the developing lung.

The numbers of alveolar macrophages (AM) are known to be low in utero and to increase rapidly after birth. This study analyzed factors related to the appearance of AM in the lungs of term and preterm monkeys (Macaca nemestrina). We found that the numbers of AM were greater at birth in term than in preterm monkeys (p less than 0.01) and that they increased with postnatal age in term animals (r = 0.86) and in preterm animals without hyaline membrane disease (HMD) (r = 0.79). In contrast, the numbers of AM did not increase with postnatal age in preterm animals with HMD (r = 0.17). By multivariant analysis, AM numbers correlated most strongly with a combination of 2 variables: lavage fluid phospholipid and absence of HMD (r = 0.996). Preparations of alveolar surface-active material from newborn monkeys and to a lesser degree from adult monkeys were found to stimulate migration and polarization of monkey AM and blood monocytes in vitro. The migration-stimulating factor(s) in alveolar surface-active material had an apparent molecular weight greater than 10,000 and appeared not to be a lipoxygenase product of arachidonic acid metabolism. These data indicate a correlation between factors regulating lung pressure-volume stability and AM numbers and are consistent with a potential role for components of alveolar surface-active material in regulating the perinatal increase in AM.

Pulmonary function of marrow transplant patients. I. Effects of marrow infusion, acute graft-versus-host disease, and interstitial pneumonitis.

The pulmonary function of patients receiving marrow transplants was studied during a two-year period. The 81 patients studied before transplantation showed a slight reduction in average lung volumes and diffusing capacity (DLCO). Studies were repeated within 48 h after marrow infusion to look for evidence of fat embolism syndrome. There was no change in the DLCO, but there was a 4% decrease in the lung volumes. Sixty-three patients (20 with aplastic anemia, 43 with hematologic malignancies) completed studies on admission and every other week during hospitalization (mean of six studies per patient). When categorized by diagnosis or conditioning regimen (including with and without total body irradiation), no differences were seen. The patients developing interstitial pneumonitis (IP) had restrictive ventilatory changes and decreases in the DLCO. The patients not developing IP remained unchanged. The patients developing IP averaged a 20% decrease in the DLCO before the clinical diagnosis of pneumonia, but a decrease in the DLCO lacked specificity for predicting occurrence of IP. Among 18 patients developing graft-versus-host disease, there was no evidence of air-flow obstruction. We conclude that patients developing IP have restrictive ventilatory changes, but in the absence of complicating IP, the marrow transplant regimen (including marrow infusion and total body irradiation) leaves pulmonary function largely unchanged.

Energy expenditure estimation in recipients of marrow transplants.

The resting metabolic expenditure of seven allogeneic marrow transplant patients supported by total parenteral nutrition was monitored by respiratory indirect calorimetry using a portable apparatus with a plexiglass canopy. The averaged measurements of resting metabolic expenditure using indirect calorimetry were highly correlated with calculated basal energy expenditures, ideal body weights, fat-free weights, and actual body weights. No consistent correlation was demonstrated between resting metabolic expenditure and body temperature. It is concluded that indirect calorimetry using a portable system is feasible and that measurements of energy expenditure so obtained correlate well with calculated estimates employing the basal energy expenditure equation.

Pulmonary bronchoalveolar cell and protein kinetics in dogs given total-body irradiation, autologous marrow grafts, and methotrexate.

Patients receiving allogeneic marrow transplantation for hematologic malignancies commonly are conditioned with total body irradiation (TBI) and given methotrexate (MTX) in an attempt to prevent graft-versus-host disease. To study the effects of TBI with or without MTX on bronchoalveolar cells and proteins, we performed sequential bronchoalveolar lavages in dogs before and after irradiation. Ten dogs received 9 Gy TBI followed by autologous marrow grafts. Six dogs were given no additional treatment and four also received MTX at 0.4 mg/kg on days 1, 3, 6, and 11- and then weekly until day 100. TBI alone resulted in a significant decrease in alveolar macrophages and lymphocytes with recovery after day 30. The addition of MTX resulted in a more profound and prolonged decrease in alveolar macrophages and lymphocytes. The addition of MTX was also associated with a significant increase in alveolar granulocytes with a concomitant rise in lavage protein content in one animal. Lavage fluid IgA levels remained constant. We conclude that the irradiation and chemotherapy used in marrow transplantation has significant pulmonary effects and may contribute to the pulmonary complications following marrow transplantation.

Rapidly progressive air-flow obstruction in marrow transplant recipients. Possible association between obliterative bronchiolitis and chronic graft-versus-host disease.

Severe obstructive airways disease developed in 4 young nonsmoking adults after marrow transplantation. They were free of respiratory disease until symptoms developed 277 to 600 days after transplant. Pulmonary function testing showed that the mean forced expiratory volume in one second was 35% of predicted (range, 23 to 49%). All patients had active or inactive extensive chronic graft-versus-host disease that included oral mucositis, esophagitis, sinusitis, and oral and ocular sicca. Three patients had subnormal serum IgA levels. Bronchitis was apparent during fiberoptic bronchoscopy in 3 patients. An open-lung biopsy specimen from 1 patient showed obliterative bronchiolitis. Treatment has included bronchodilators and corticosteroids without objective benefit. The disorder stabilized in all 4 patients, but a severe reduction in air flow persisted. Awareness of this complication may lead to earlier diagnosis and more effective treatment.

Pathophysiological patterns of resolution from acute oleic acid lung injury in the dog.

Lungs of mongrel dogs with permanent tracheostomies and implanted systemic pulmonary arterial catheters were injured by intravenous infusion of oleic acid (0.09 mg/kg). Injury resulted in extensive, multifocal, and nonrandomly distributed lung damage. Awake dogs were studied during a control period and 1, 4, and 7 days following injection of oleic acid. Standard gas exchange measurements, the inert gas elimination technique, and subsegmental bronchoalveolar lavage (BAL) were used. Five oleic acid dogs and two saline control dogs were killed after each study period for morphological evaluation. Control dogs did not develop significant gas exchange abnormalities but did have localized inflammatory reactions at the lavage site. The oleic acid dogs developed significant shunt at day 1 with resolution of shunt by day 7. The multifocal sites of oleic acid injury were virtually identical in appearance at a given time interval; they consisted of alveolar cell necrosis with varying amounts of hemorrhagic inflammatory exudation at day 1 followed by a proliferative reparative reaction resulting in substantial restoration of alveolar structure at day 7. BAL showed a suppurative inflammatory response with hemorrhage on day 1 and an increased number of macrophages by day 7. The oleic acid model of acute diffuse lung injury demonstrates several pathophysiological alterations that could be compared with pathomorphological changes during the acute injury phase and during the subsequent reparative phase.