The importance of leukotrienes in airway inflammation in a mouse model of asthma.

Inhalation of antigen in immunized mice induces an infiltration of eosinophils into the airways and increased bronchial hyperreactivity as are observed in human asthma. We employed a model of late-phase allergic pulmonary inflammation in mice to address the role of leukotrienes (LT) in mediating airway eosinophilia and hyperreactivity to methacholine. Allergen intranasal challenge in OVA-sensitized mice induced LTB4 and LTC4 release into the airspace, widespread mucus occlusion of the airways, leukocytic infiltration of the airway tissue and broncho-alveolar lavage fluid that was predominantly eosinophils, and bronchial hyperreactivity to methacholine. Specific inhibitors of 5-lipoxygenase and 5-lipoxygenase-activating protein (FLAP) blocked airway mucus release and infiltration by eosinophils indicating a key role for leukotrienes in these features of allergic pulmonary inflammation. The role of leukotrienes or eosinophils in mediating airway hyperresponsiveness to aeroallergen could not be established, however, in this murine model.

Increased surface tension favors pulmonary edema formation in anesthetized dogs' lungs.

The possibility that surface tension may affect the hydrostatic transmural pressure of pulmonary vessels and the development of pulmonary edema was studied in anesthetized, open-chested dogs. Isogravimetric pressure (the static intravascular pressure at which transmural osmotic and hydrostatic pressures are balanced such that net fluid flux is zero and lung weight is constant) was measured in nine animals under three conditions: (a) control, normal surface tension, at an alveolar pressure of 30 cm H2O with the apenic lung at room temperature; (b) after increasing surface tension by cooling and ventilating at a low functional residual capacity, at an alveolar pressure sufficient to produce the same lung volume present during control measurements; and (c) after restoring surface tension by rewarming while holding the lung at a high inflation volume, again at the control lung volume. Lung volumes were established from external dimensions and confirmed +/- 10% by deflation spirometry. The isogravimetric pressure (relative to alveolar pressure) was significantly less with increased surface tension than during either the initial control condition (P less than 0.01), or when the surface tension has been restored (P less than 0.01). Similar changes occurred in each of three additional studies performed with control alveolar pressures of 10 cm H2O. Thus, increased surface tension favors fluid leakage presumably because it increases the microvascular transmural pressure.

Blockade of CD49d (alpha4 integrin) on intrapulmonary but not circulating leukocytes inhibits airway inflammation and hyperresponsiveness in a mouse model of asthma.

Immunized mice after inhalation of specific antigen have the following characteristic features of human asthma: airway eosinophilia, mucus and Th2 cytokine release, and hyperresponsiveness to methacholine. A model of late-phase allergic pulmonary inflammation in ovalbumin-sensitized mice was used to address the role of the alpha4 integrin (CD49d) in mediating the airway inflammation and hyperresponsiveness. Local, intrapulmonary blockade of CD49d by intranasal administration of CD49d mAb inhibited all signs of lung inflammation, IL-4 and IL-5 release, and hyperresponsiveness to methacholine. In contrast, CD49d blockade on circulating leukocytes by intraperitoneal CD49d mAb treatment only prevented the airway eosinophilia. In this asthma model, a CD49d-positive intrapulmonary leukocyte distinct from the eosinophil is the key effector cell of allergen-induced pulmonary inflammation and hyperresponsiveness.

Efficacy of a 6-week prophylactic ganciclovir regimen and the role of serial cytomegalovirus antibody testing in lung transplant recipients.

CMV is a frequently occurring pathogen in recipients of solid organ transplants, and those receiving lung transplants seem to be affected more frequently and more severely. Because the duration of prophylactic ganciclovir may influence the incidence of CMV disease in solid organ transplant recipients, we evaluated the efficacy of a 6-week prophylactic regimen in lung transplant recipients. We also evaluated the ability of a fourfold rise in CMV antibody titer to predict the development of CMV disease. Twenty-one consecutive lung transplant recipients were enrolled: 15 were CMV antibody-positive at the time of transplantation, and six were CMV antibody-negative and received a lung transplant from CMV-positive donors. Mean +/- SD follow-up was 430 +/- 157 days (range 178-730 days, median 449 days). The 6-week ganciclovir regimen prevented neither CMV infection (which occurred in 17/21 patients, 81%) nor CMV disease (seen in 8/21 patients, 38%). A fourfold rise in CMV antibody titer only preceded the onset of CMV disease in 3/13 instances (23%). We conclude that a 6-week regimen of ganciclovir prophylaxis does not prevent CMV infection or disease in lung transplant recipients and that a rise in serially obtained CMV antibody titers rarely precedes the development of CMV disease.

Endobronchial tuberculosis progressing to bronchial stenosis. Fiberoptic bronchoscopic manifestations.

Severe stenosis of main-stem and segmental bronchi occurred in a 79-year-old woman with previously and adequately treated endobronchial tuberculosis. Symptoms and physiologic abnormalities did not occur until more than three years after diagnosis and initiation of therapy.

Dyspnea resulting from fibromyalgia.

Two patients with chronic, severe, episodic dyspnea underwent prolonged, extensive, and invasive evaluations without a diagnosis being made. Both were subsequently diagnosed with fibromyalgia, and therapy directed at this condition resulted in resolution of their symptoms. Fibromyalgia is rarely included in the differential diagnosis of dyspnea, and timely diagnosis and treatment may be delayed. However, this condition must be considered because it can only be established by seeking the appropriate history and physical findings.

The prognosis of patients with chronic obstructive pulmonary disease after hospitalization for acute respiratory failure.

We followed the course of 36 consecutive patients hospitalized with chronic obstructive pulmonary disease and acute respiratory failure due to exacerbation of chronic bronchitis in order to clarify the prognosis in this common group of patients. All of the patients had spirometric evidence of severe, poorly reversible airflow limitation and all had a similar cause of acute respiratory failure. In addition, all received similar treatment during hospitalization and follow-up. Patients wtih asthma and pneumonia were excluded by clinical, spirometric, and roentgenographic criteria. Hospital survival was 94 percent, and only one patient required intubation. Two-year survival was 72 percent, and none of the patients died during a readmission for acute respiratory failure. This prognosis is much better than commonly recognized and compares favorably to that of stable outpatients with similar degrees of airflow limitation. An episode of acute respiratory failure, triggered by an exacerbation of chronic bronchitis, does not necessarily alter the prognosis of patients with COPD.

Bronchiolitis obliterans caused by Legionella pneumophila.

A diabetic patient presented with symptoms and laboratory findings compatible with atypical pneumonia. Despite appropriate antibiotic therapy, his dyspnea, arterial oxygenation, and chest roentgenographic findings worsened. Because the patient had a history of homosexual contact, an open lung biopsy was obtained to morphologically define the tissue reaction and to search for a specific etiology. Histologic examination showed bronchiolitis obliterans but did not demonstrate a cause. Legionnaires' disease was subsequently diagnosed on the basis of a fourfold rise in indirect fluorescent antibody titer. This case report demonstrates that Legionella pneumophila may induce lung injury with bronchiolitis obliterans. Such patients may benefit from corticosteroid treatment.

Economic aspects of lung volume reduction surgery.

OBJECTIVE: To investigate the economics of lung volume reduction surgery. DESIGN: Medical center and physician charges obtained from billing records. SETTING: Academic health center. PATIENTS: Twenty-three consecutive patients undergoing lung volume reduction surgery at a single institution who were discharged from the hospital prior to November 1, 1995. OUTCOME MEASURES: Length of hospital stay, mortality, medical center charges and professional fees, and sponsor reimbursement. RESULTS: Median hospital stay was 8.0 days and there were no deaths. The median charge was $26,669 (range, $20,032 to $75,561) of which 73% was for medical center services and 27% was for physician services. Fees for medical center rooms and operating suite time accounted for 71% of medical center charges. Charges by surgeons and anesthesiologists accounted for 77% of professional fees. Total charges were directly related to length of stay (r2 = 0.95). Median reimbursement for medical center services was $22,264 (114%; range, $13,333 to $123,362) and for physician services was $2,783 (34%; range, $2,597 to $11,265), resulting in a median total reimbursement that represented 94% of total charges. The median reimbursement-to-cost ratio was 1.22, compared with 1.05 for all medical services in fiscal year 1995. CONCLUSIONS: These data must now be assessed relative to outcomes such as quality of life, patient function, and long-term survival to determine cost-effectiveness of lung volume reduction surgery.

Clinical experimentation. Lessons from lung volume reduction surgery.

Although the advancement of medical science can occur only with the systematic evaluation of new interventions, novel therapies continue to be introduced and accepted prior to thorough study. The recent development of lung volume reduction surgery for emphysema provides an illustration of the unwillingness or the inability of the medical community, unconstrained by legal or reimbursement limitations, to assure the safety and efficacy of a new procedure prior to widespread utilization. Medical practitioners must learn to recognize the experimental nature of new procedures independent of the courts and third-party payers. The nature of the informed consent that must be obtained for an experimental therapy is different from that which is required for standard medical practice and this difference can provide a test of whether a new treatment is experimental. A comparison between the introduction of lung volume reduction surgery and the rigorous scrutiny required of any pharmacologic interventions for emphysema underscores the double standard that exists for evaluating new surgical (and some medical) innovations. Such a double standard cannot be defended on ethical or scientific grounds. Specific changes in the way experimental therapies are introduced and disseminated are suggested. Until all new medical and surgical interventions are required to undergo a thorough evaluation prior to becoming standard of case, the promise of evidence-based medicine can never be fulfilled.

Estimated growth of lung volume reduction surgery among Medicare enrollees: 1994 to 1996.

OBJECTIVE: To estimate the number of lung volume reduction surgery procedures performed on Medicare enrollees from 1994 to 1996. DESIGN: Statistical analysis of national Medicare claims data. PATIENTS: All Medicare enrollees with emphysema hating claims records for pulmonary resection procedures from January 1, 1993, through December 31, 1996. MAIN OUTCOME MEASURE: Estimated number of lung volume reduction procedures performed per month from July 1994 through December 1996. RESULTS: An estimated 1,212 lung volume reduction procedures were performed on Medicare enrollees between July 1994 and December 1995 (95% confidence interval, 1,012 to 1,408). Nearly one half of these procedures were performed in the last 3 months of 1995. At the time Health Care Financing Administration announced that it would suspend reimbursement for the procedure (December 1995), lung volume reduction surgery was being performed in 37 states. The number of claims per month decreased from a peak of 169 in December 1995, to 11 in March 1996. Average Medicare reimbursement per procedure was $31,398. CONCLUSIONS: Lung volume reduction surgery for patients increased rapidly following its reintroduction in 1994. The growth of lung volume reduction surgery demonstrates that widespread adoption and utilization of a surgical procedure can occur in the absence of data from controlled clinical trials. Medicare expenditures for lung volume reduction surgery were an estimated $30 million to $50 million. Performing the surgery for all current Medicare patients who meet the appropriate clinical criteria would cost an estimated $1 billion.

Underestimation of mortality following lung volume reduction surgery resulting from incomplete follow-up.

STUDY OBJECTIVES: Incomplete follow-up can bias interpretation of data that are collected in longitudinal studies. We noted that many patients failed to return for follow-up in a study of effect of lung volume reduction surgery (LVRS) on quality of life (QOL). Accordingly, we designed this investigation to determine the reasons patients dropped out, and to assess differences between those who continued in the study (attendees) and those who did not (nonattendees). DESIGN: Telephone survey. SUBJECTS: Patients with advanced emphysema who had undergone LVRS and had previously agreed to participate in a longitudinal QOL study. RESULTS: No differences were found with regard to age, gender, preoperative pulmonary function, or oxygen use between attendees and nonattendees. Long-term mortality in nonattendees (27%) was considerably greater than that seen in attendees (3%, p < 0.05). Distance from the hospital, financial burden, and living out of the region were the most common reasons cited by surviving nonattendees for their failure to return for follow-up. CONCLUSIONS: Studies reporting the long-term mortality after LVRS can be biased in the direction of underestimating the true value if they are compromised by incomplete follow-up.

The cost-effectiveness of lung transplantation. A pilot study. University of Washington Medical Center Lung Transplant Study Group.

OBJECTIVE: Lung transplantation is one of the fastest-growing solid organ transplant procedures in the world, yet its cost-effectiveness is unknown. We compared the costs and outcomes of the first 25 patients who received lung transplants at the University of Washington with 24 patients currently on the lung transplant waiting list. DESIGN: Inpatient and outpatient charges were obtained from the hospital billing service and home health agencies. Quality-adjusted life year scores (QALYs) were computed from the following: (1) utility scores obtained through standard gamble interviews, and (2) published survival data from an international lung transplant registry and from studies of patients on lung transplant waiting lists. RESULTS: Transplantation charges averaged $164,989 (median, $152,071). Average monthly charges posttransplant were $11,917 in year 1 and $4,525 thereafter, vs $3,395 for waiting-list patients. Posttransplant utility scores were significantly higher than waiting-list scores (0.80 vs 0.68; p < 0.001). Life expectancy was not greater for lung transplant vs waiting-list patients (5.89 vs 5.32 years; p > 0.05), although quality-adjusted life expectancy did improve significantly. After converting charges to costs, the incremental cost per QALY gained for posttransplant compared with waiting-list patients was $176,817. CONCLUSIONS: Lung transplantation is very expensive, although it can substantially improve quality of life. Two-thirds of care costs are incurred after transplantation. The principal barriers to cost-effectiveness at present are the high cost of postrecovery care and marginal gains in life expectancy compared with conservative care.

Improvement in quality of life after lung transplantation: a preliminary study. The University of Washington Medical Center Lung Transplant Study Group.

BACKGROUND: Lung transplantation is an expensive therapeutic option for a number of endstage conditions. Improving health-related quality of life is an important objective of transplantation. METHODS: We report quality of life measurements in 21 waiting list patients and 23 patients after transplantation with seven different pulmonary conditions using two standardized instruments: the Sickness Impact Profile and the standard gamble. RESULTS AND CONCLUSIONS: This cross-sectional study indicates the following: (1) overall quality of life improves significantly after transplantation; (2) although most dimensions of functional disability improve after transplantation, some aspects may suffer; (3) quality of life gains after transplantation may not be equal for all pretransplantation conditions.

Continuity of arterial and venous extra-alveolar interstitium in excised rabbit lungs.

We studied the interdependence of arterial and venous extra-alveolar vessel (EAV) leakage on the rate of pulmonary vascular fluid filtration (measured as the change in lung weight over time). Edema was produced in continually weighed, excised rabbit lungs kept in zone 1 (alveolar pressure = 25 cmH2O) by increasing pulmonary arterial (Ppa) and/or venous (Ppv) pressure from 5 to 20 cmH2O (relative to the lung base) and continuing this hydrostatic stress for 3-5 h. Raising Ppa and Ppv simultaneously produced a lower filtration rate than the sum of the filtration rates obtained when Ppa and Ppv were raised separately, while the lung gained from 20 to 95% of its initial weight. When vascular pressure was elevated in either EAV segment, fluid filtration always decreased rapidly as the lung gained up to 30-45% of its initial weight. Filtration then decreased more slowly. The lungs became isogravimetric at 60 and 85% weight gain when the Ppa or Ppv was elevated, respectively; when Ppa and Ppv were raised simultaneously substantial fluid filtration continued even after 140% weight gain. We conclude that the arterial and venous EAV's share a common interstitium in the zone 1 condition, this interstitium cannot be represented as a single compartment with a fixed resistance and compliance, and arterial and venous EAV leakage influences leakage from the other segment.

Effect of zonal conditions and posture on pulmonary blood flow distribution to subpleural and interior lung.

Observations made on vessels seen directly beneath the pleura may not accurately reflect what occurs in vessels located deeper in the interior of the lung. We quantified flow to subpleural and deeper, interior regions under zone 1 or 2 conditions in excised (n = 5) and in vivo (n = 6) rabbit lungs, in the head-up or inverted position. After infusion of radiolabeled microspheres, lungs were dried at alveolar pressure of 25 cmH(2)O and sliced in 1-cm sections along the gravitational plane and in three planes in the dorsal-ventral axis. Regions located <1 mm from the pleural surface were dissected away from the remaining tissue. In both zonal conditions, 1) weight-normalized flow to the interior exceeded that found in subpleural regions; and 2) flow followed the gravitational gradient, with the correlation varying with the scale of measurement. We conclude that flow through subpleural vessels is less than that which occurs deeper in the interior, but the regional distributions of flow and the effects of zonal conditions are similar in the two regions.

Sites of leakage in three models of acute lung injury.

Fluid leaking from arterial and venous extra-alveolar vessels (EAV's) may account for up to 60% of the total transvascular fluid flux when edema occurs in the setting of normal vascular permeability. We determined if the permeability and relative contribution of EAV's was altered after inducing acute lung injury in rabbits by administering oleic acid (0.1 ml/kg) into the pulmonary artery, HCl (5 ml/kg of 0.1 N) into the trachea, or air emboli (0.03 ml.kg-1.min-1) into the right atrium for 90 min. Subsequently, the lungs were excised and continuously weighed while they were maintained in a warmed, humidified chamber with alveolar and pulmonary vascular pressures controlled and the lungs either ventilated or distended with 5% CO2 in air. The vascular system was filled with autologous blood and saline (1:1) to which papaverine (0.1 mg/ml) was added to inhibit vasospasm. Vascular pressures were referenced to the lung base. After a transient hydrostatic stress to maximize recruitment, vascular pressures were set at 5 cmH2O, and lungs were allowed to become isogravimetric (30-60 min). A fluid filtration coefficient (Kf) was determined by the use of a modification of the method of Drake and colleagues [Am. J. Physiol. 234 (Heart Circ. Physiol. 3): H266-H274, 1978]. EAV's were isolated by zoning techniques. In control preparations arterial and venous EAV's accounted for 26% (n = 9) and 38% (n = 11) of the total leakage, respectively. In all three models Kf increased two- to fourfold when the lungs were in zone 3 (alveolar vessels and arterial and venous EAV's contributing to the leakage).(ABSTRACT TRUNCATED AT 250 WORDS)

Glycolysis is not required for fluid homeostasis in isolated rabbit lungs.

We investigated whether glycolysis was necessary to maintain the integrity of vascular endothelial and alveolar epithelial barriers in continually weighed isolated rabbit lungs. Lungs were perfused with a cell-free buffered salt solution, and glycolysis was inhibited with a glucose analogue (alpha-methyl glucoside, alpha-MG) or one of two glycolysis inhibitors (iodoacetic acid, IAA, or NaF). Fluid filtration rates (FFR's, the change in lung weight/time) in response to a 7.5-min zone 3 hydrostatic stress (pulmonary arterial and venous pressures raised from 8 to 15 cmH2O, alveolar pressure kept constant at 4 cm on the deflation limb) were repeatedly measured for 120 min after which the lungs were lavaged. The total protein concentration was measured in the bronchoalveolar lavage fluid (BALP). Lactate production was measured to verify inhibition of glycolysis. Lower concentrations of IAA and alpha-MG eliminated lactate production but did not affect FFR or BALP. NaF also had no effect on the FFR or BALP. Only high concentrations of IAA increased FFR and BALP, seemingly by causing nonspecific membrane injury that was unrelated to its specific effects on glycolysis. The glycolytic pathway for energy production is not necessary to maintain the integrity of the pulmonary endothelial-epithelial barrier.

Prone position reverses gravitational distribution of perfusion in dog lungs with oleic acid-induced injury.

Although oxygenation improves in patients with the adult respiratory distress syndrome and in animals with oleic acid- (OA) induced acute lung injury when they are turned from the supine to the prone position, the mechanism(s) by which this improvement occurs is not known. Several groups have speculated that this improvement results from preferential edema accumulation in the dorsal lung regions and redistribution of perfusion away from these regions when the patients are turned to the prone position. We used radiolabeled microspheres to measure the regional distribution of perfusion (Qr) to the dorsal, mid, and ventral lungs of eight dogs in vivo in the supine and prone positions, before and after inducing acute lung injury with OA, and correlated the Qr observed after injury with the degree of regional extravascular lung water (EVLWr). Before OA, Qr increased along the gravitational gradient when the animals were supine but was more uniformly distributed when they were prone. After OA, Qr again followed a gravitational gradient when the animals were supine but was preferentially distributed to the nondependent regions when they were prone. EVLWr was similar in all regions, regardless of whether OA was injected when the animals were supine or prone. The gravitational Qr gradient is markedly reduced in the prone position, both before and after lung injury. The prone position-induced improvement in oxygenation is not the result of redistribution of Qr away from areas in which edema preferentially develops.

Extra-alveolar veins are contiguous with, and leak fluid into, periarterial cuffs in rabbit lungs.

We previously observed physiological evidence that arterial and venous extra-alveolar vessels shared a common interstitial space. The purpose of the present investigation was to determine the site of this continuity to improve our understanding of interstitial fluid movement in the lung. Orange G and Evans blue dyes were added to the arterial and venous reservoirs, respectively, of excised rabbit lungs as they were placed 20 cmH2O into zone 1 (pulmonary arterial and venous pressures = 5 cmH2O, alveolar pressure = 25 cmH2O). After 10 s or 4 h the lungs were fixed by immersion in liquid N2, freeze-dried, cut into 5-mm serial slices, and examined by light macroscopy. Serial sections of 0.25-0.5 mm were subsequently examined by scanning electron microscopy. In the animals subjected to the zone 1 stress for 4 h, arterial and venous extra-alveolar vessels were surrounded by cuffs of edema. The edema ratio (cuff area divided by vessel lumen area) was greater around arteries than veins and decreased with increasing vessel size. Periarterial cuffs usually contained orange dye and frequently contained both orange and blue dye. Lymphatics containing orange or blue dye were frequently seen in periarterial cuffs. Scanning electron microscopy demonstrated that extra-alveolar veins of approximately 100 microns diameter were anatomically contiguous with arterial extra-alveolar vessel cuffs. In rabbit lungs, both arterial and venous extra-alveolar vessels (and/or alveolar corner vessels) leak fluid into perivascular cuffs surrounding arterial extra-alveolar vessels, and lymphatics located in the periarterial cuff contain fluid that originates from both the arterial and venous extra-alveolar vessels.