The clinical and pathological spectrum of antineutrophil cytoplasmic autoantibody-related pulmonary disease. A comparison between perinuclear and cytoplasmic antineutrophil cytoplasmic autoantibodies.

Antineutrophil cytoplasmic autoantibodies (ANCAs), classified as either perinuclear (P-ANCAs) or cytoplasmic (C-ANCAs), have been recently recognized as important markers for the diagnosis and monitoring of systemic vasculitic disorders. The purpose of this study was to review retrospectively the clinical and pathological features in patients with P-ANCA-positive (P-ANCA+) patterns and pulmonary disease who underwent open lung biopsies and to contrast these findings with those found in patients with C-ANCA-positive (C-ANCA+) patterns who underwent open lung biopsies. Nine patients with ANCA+ pattern (five with P-ANCA+ and four with C-ANCA+ patterns) who had evidence of systemic vasculitis and pulmonary dysfunction underwent open lung biopsies. A comparison of the clinical presentation in patients with P-ANCA+ vs C-ANCA+ patterns showed few apparent differences in the clinical presentation or in the organ involvement. Histologic review of the findings from the open lung biopsies showed similar patterns of pulmonary injury, irrespective of the specific ANCA-staining pattern. Major pathologic changes included intra-alveolar hemorrhage (four patients with P-ANCA+ patterns vs three patients with C-ANCA+ patterns), necrotizing capillaritis (four patients with P-ANCA+ patterns vs three patients with C-ANCA+ patterns), vasculitis (three patients with P-ANCA+ patterns vs two patients with C-ANCA+ patterns), and necrotizing granulomatous inflammation (two patients with P-ANCA+ patterns vs one patient with C-ANCA+ patterns). Unusual pathologic findings included chronic interstitial fibrosis (two patients with P-ANCA+ patterns vs two patients with C-ANCA+ patterns), cavitary nodules with necrotic neutrophils and minimal granulomatous inflammation (one patient with P-ANCA+ patterns), and bronchiolocentric granulomatous inflammation (one patient with P-ANCA+ patterns vs one patient with C-ANCA+ patterns). In ANCA-related pulmonary disease, there are few significant clinical or pathological differences when patients with P-ANCA+ patterns are compared with patients with C-ANCA+ patterns.

Extravascular coagulation and fibrinolysis in murine lung inflammation induced by the mycobacterial cord factor trehalose-6,6'-dimycolate.

Diffuse pulmonary inflammation in interstitial lung diseases is associated with increased coagulation in the extravascular spaces of the lung. We hypothesized that conditions favoring coagulation over fibrinolysis in the lung are related to inflammation. Pulmonary coagulation and fibrinolysis were studied in two strains of mice susceptible or resistant to the development of lung inflammation in response to the mycobacterial cell wall glycolipid trehalose-6,6'-dimycolate (TDM). Susceptible animals treated with TDM intravenously develop well-organized collections of mononuclear cells in the lung parenchyma referred to as granulomas in this report. More granulomas were found in the susceptible ICR mice than in the resistant A/J mice after intravenous administration of TDM (7 +/- 1 granulomas/mm2 versus 1 +/- 0.3 granulomas/mm2, p = 0.005). Granuloma formation was associated with increased lung procoagulant activity (PCA) measured in bronchoalveolar lavage (BAL) cell lysates from susceptible mice. In contrast, TDM-resistant A/J mice challenged with TDM did not have a significant BAL cell PCA response, but expressed several-fold greater levels of lung BAL fluid plasminogen activator activity (PAA) than ICR mice. To examine the role of coagulation in the TDM pulmonary inflammatory response, susceptible C57Bl/10SnJ mice were anticoagulated by oral administration of warfarin prior to challenge of TDM; these mice developed fewer pulmonary granulomas than TDM-treated mice without warfarin treatment (2.6 +/- 0.5 granulomas/mm2 versus 6.5 +/- 0.8 granulomas/mm2, p < 0.001) but had similar BAL cell PCA and lung inflammatory changes as measured by lung weights and BAL cellularity.(ABSTRACT TRUNCATED AT 250 WORDS)

Induction of pulmonary granulomas, macrophage procoagulant activity, and tumor necrosis factor-alpha by trehalose glycolipids.

Trehalose 6,6' dimycolate (TDM), a mycobacterial glycolipid, induces granulomas and hemorrhagic toxic reactions when administered in oil but not as a suspension in saline. It was previously demonstrated by us that TDM forms highly structured layers at oil-water interfaces and then postulated that its toxicity derives from the adhesive properties of these layers. To test this hypothesis, an evaluation was made of the ability of TDM and two analogs, trehalose 6-monomycolate (TMM) and galactose-galactose 6, 6' dimycolate (GDM), to induce pulmonary granulomas and stimulate expression of procoagulant activity (PCA) and tumor necrosis factor-alpha (TNF-alpha). Intravenous injection in mice of oil-in-water emulsions of TDM produced more and larger pulmonary granulomas than injection of TMM or GDM. Similarly, TDM on the surface of beads induced higher levels of PCA and TNF-alpha in human mononuclear cells than the analogs. The correlation of these results with the structure of surface layers of the glycolipids strengthens the hypothesis that the particular surface structure formed by TDM is necessary for its biologic activity.

Elevated D dimer in the lungs and blood of patients with sarcoidosis.

The hypothesis of this study was that D dimer, a specific degradation product of cross-linked fibrin, would be increased in the bronchoalveolar lavage (BAL) fluids of patients with sarcoidosis and that it would be related to other BAL parameters of disease activity. Eight of 10 sarcoidosis patients but none of 18 healthy volunteers had detectable BAL D dimer by enzyme immunoassay. Autoradiography revealed the presence of fibrinogen and D dimer in the BAL fluids from sarcoidosis patients. Bronchoalveolar lavage D dimer levels in sarcoidosis patients correlated with total BAL cells per milliliter, lymphocytes per milliliter, and total protein level, but not macrophages per milliliter. The D dimer in the BAL fluids from sarcoidosis patients did not correlate with D dimer in the blood. Our findings indicate that BAL D dimer parallels directly the lymphocytic alveolitis that characterizes pulmonary sarcoidosis.

Interstitial lung disease: state of the clinical art.

Interstitial lung diseases pose a great challenge to the clinician because of the indolent and variably active nature of these disorders and the limited number of therapeutic options. Adjunctive therapy includes supplemental oxygen in hypoxic patients, bronchodilators in patients with an obstructive lung component, and aggressive use of antibiotics in febrile patients on potent immunosuppressive therapy and suspected or confirmed infections. In younger patients who present late in their illness or deteriorate on therapy, lung transplantation is the only option. Recent advances in our knowledge of the cellular and molecular mechanisms operating in ILD and techniques which include gene amplification and cloning promise to yield more effective treatments for these diseases which currently produce a high incidence of morbidity and mortality.

The influence of positive end-expiratory pressure on intrapericardial pressure and cardiac function after coronary artery bypass surgery.

The hemodynamic effects of positive end-expiratory pressure (PEEP) were studied in coronary artery bypass patients by recording intrapericardial and intracardiac pressures, measuring cardiac output by thermodilution, and determining left ventricular volumes by nuclear radiography. An elevation of PEEP to 5, 10, and 15 cm H2O led to a decrease in cardiac output (15% decrease at PEEP 15) as intrapericardial pressure increased and transmural left atrial pressure decreased. Modest volume loading (an increase in left atrial pressure of 3 mm Hg) greatly attenuated the deleterious effects of 15 cm H2O PEEP. There was an excellent correlation between pulmonary capillary wedge pressure and left atrial pressure at PEEP 0 and 5 (r = .85 and r = .83). This correlation was not nearly as reliable at PEEP 15 (r = .54). A predictable increase in intrapericardial pressure was observed as PEEP was applied in these patients. The magnitude of this increase can be estimated by multiplying the change in PEEP (in cm H2O) by 0.4 to estimate the change in intrapericardial pressure (in mm Hg). Using this estimation as a guide, modest volume loading can be used to maintain transmural filling pressures (and cardiac output) when PEEP is used after coronary artery bypass surgery.

Analysis of homogeneity of alveolitis in pulmonary sarcoidosis by bilateral bronchoalveolar lavage, gallium-67 lung uptake, and chest radiograph.

The use of unilateral lobar bronchoalveolar lavage (BAL) to assess disease activity in pulmonary sarcoidosis assumes that the alveolitis is homogeneous throughout the lung parenchyma. Three studies were used to evaluate this premise in 21 patients with sarcoidosis who had a broad range of abnormalities: bilateral BAL cell counts, quantitated regional gallium-67 lung uptake, and analysis of chest radiographs. Based on results of these studies, we conclude that the alveolitis in sarcoidosis is homogeneous in the majority of patients, although lavage of the lingula may give erroneous results due to the frequently increased proportion of neutrophils. The only moderate level of correlation between the BAL % lymphocytes and gallium-67 lung uptake, even when the same regions of the lung are studied, suggests that these tests may measure different aspects of disease activity.

Effectiveness of medical necessity guidelines in reducing cost of oxygen therapy.

Concern for the rising costs of respiratory therapy in patient care caused a third party payor to implement reimbursement guidelines for inhospital delivery of oxygen (O2) therapy. While these guidelines are physiologically appropriate, their effectiveness in cost reduction has not been documented. To determine the effect of similar guidelines on the cost of O2 therapy, we prospectively studied 77 noncritically ill patients for whom physicians ordered O2. If pretreatment arterial blood gas determinations had not been ordered, ear oximetry was performed. The cost of O2 therapy to each patient, as based on total patient charges for O2, appliances, delivery, and assessment of oxygenation throughout hospitalization, was computed in three ways: Cost A, actual charges for O2 therapy initiated by physician order; Cost B, projected charges for O2 therapy using physiologic guidelines alone (PaO2 less than 60 mm Hg or SaO2 less than 90 percent); and Cost C, projected charges for O2 therapy using combined physiologic and clinical guidelines (PaO2 less than 60 mm Hg, SaO2 less than 90 percent or clinical record reasonably indicating hypoxemia). Of the 77 patients, 23 (30 percent) met the physiologic guidelines and 48 (62 percent) met the combined physiologic and clinical guidelines. The cost (total patient charges) of O2 therapy can be reduced through implementation of medical necessity guidelines, but physiologic guidelines alone appear more cost effective than combined physiologic and clinical guidelines.

Comparison of clinical parameters, bronchoalveolar lavage, gallium-67 lung uptake, and serum angiotensin converting enzyme in assessing the activity of sarcoidosis.

A major problem in pulmonary sarcoidosis is the assessment of disease activity. We established a clinical score system composed of degree of dyspnea, chest radiographic stage, forced vital capacity, and clinical assessment of disease activity (normal = 0, maximum = 16). We evaluated this score in 50 patients with sarcoidosis along with other proposed measures of disease activity: bronchoalveolar lavage percent lymphocytes (% lymphs), Gallium-67 lung uptake measured as total lung to background ratio (TL/B ratio), and serum angiotensin converting enzyme (SACE) levels. The patients we studied had an average clinical score of 5.6 +/- 2.7 (+/- SD). Though bronchoalveolar lavage % lymphs (32 +/- 20%), TL/B ratio (192 +/- 73), and SACE (137 +/- 66) were all significantly elevated in these patients, Gallium-67 uptake was most frequently abnormal (80% of patients). However, the TL/B ratio was higher in smokers (231 +/- 91) than nonsmokers (178 +/- 64, p less than 0.05). There was no correlation between our clinical score, or any part of the clinical score, and other laboratory measures of alveolitis. Bronchoalveolar lavage % lymphs and TL/B ratio correlated weakly (n = 50, r = 0.36, p less than 0.02), while % lymphs and SACE correlated less well (n = 29, r = 0.36, p = 0.051). There was no correlation between TB/L ratio and SACE.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic and lung protein changes in sarcoidosis. Lymphocyte counts, gallium uptake values, and serum angiotensin-converting enzyme levels may reflect different aspects of disease activity.

BAL lymphocyte percentages, quantitated gallium-67 lung uptake, and SACE levels have all been proposed as measures of disease activity in sarcoidosis. We analyzed 32 paired sera and BAL fluids from sarcoidosis patients by high-resolution agarose electrophoresis to look for protein changes characteristic of systemic or local inflammation and compared the results with those from the above tests. Nine patients (group 1) had serum inflammatory protein changes and increased total protein, albumin, beta 1-globulin (transferrin), and gamma-globulin levels in fluid recovered by BAL. Thirteen patients (group 2) had normal protein levels in sera but abnormal protein levels in BAL specimens. Ten patients (group 3) had normal protein levels in sera and in BAL specimens. Patients in groups 1 and 2 had a disproportionate increase in beta 1-globulin (transferrin) and gamma-globulin levels in their BAL specimens. The BAL lymphocyte percentage changes paralleled the BAL protein level changes, suggesting relationships among the immunoregulatory role of these cells, increased local immunoglobulin synthesis, and the pathogenesis of altered alveolar permeability. Gallium-67 uptake was highest in patients with serum inflammatory protein changes. Thus, systemic inflammation may facilitate pulmonary gallium-67 uptake, possibly by changes in BAL fluid or serum transferrin saturation and/or kinetics. SACE levels showed no relationship to changes in the levels of serum or BAL proteins. These data suggest that the various proposed measures of disease activity reflect different aspects of inflammation in sarcoidosis.

Bronchoalveolar lavage cell differential in the diagnosis of sarcoid interstitial lung disease. Likelihood ratios based on computerized data base.

With the use of a microcomputer, the authors prospectively stored the bronchoalveolar lavage (BAL) cell differential counts from 208 patients undergoing initial evaluation for chronic interstitial lung disease. Sarcoidosis subsequently was diagnosed in 46% of these patients; the remainder had several other etiologies of their lung disease. The BAL lymphocyte count did not allow for clear separation between these two groups. To facilitate the interpretation of the BAL percent lymphocyte data, the authors applied a modification of Bayes' theorem to calculate likelihood ratios for the differential diagnosis of sarcoidosis versus other interstitial lung disease. These values ranged from 0.15 for patients with less than 6% lymphocytes to 3.5 when more than 40% lymphocytes were found. Similar results were obtained with a subsequent, independently analyzed group of 46 patients. To provide a more meaningful interpretation of the BAL fluid lymphocyte count, the authors designed a reporting scheme that includes both a written description and a graphic representation of the likelihood ratio. Prospective collection of data using microcomputers should extend this useful form of reporting to additional laboratory studies.

Prediction of therapeutic response in steroid-treated pulmonary sarcoidosis. Evaluation of clinical parameters, bronchoalveolar lavage, gallium-67 lung scanning, and serum angiotensin-converting enzyme levels.

To find a pretreatment predictor of steroid responsiveness in pulmonary sarcoidosis we studied 21 patients before and after steroid treatment by clinical evaluation, pulmonary function tests, bronchoalveolar lavage (BAL), gallium-67 lung scan, and serum angiotensin-converting enzyme (SACE) level. Although clinical score, forced vital capacity (FVC), BAL percent lymphocytes (% lymphs), quantitated gallium-67 lung uptake, and SACE levels all improved with therapy, only the pretreatment BAL % lymphs correlated with the improvement in FVC (r = 0.47, p less than 0.05). Pretreatment BAL % lymphs of greater than or equal to 35% predicted improvement in FVC of 10/11 patients, whereas among 10 patients with BAL % lymphs less than 35%, 5 patients improved and 5 deteriorated. Clinical score, pulmonary function parameters, quantitated gallium-67 lung uptake, and SACE level used alone, in combination with BAL % lymphs or in combination with each other, did not improve this predictive value. We conclude that steroid therapy improves a number of clinical and laboratory parameters in sarcoidosis, but only the pretreatment BAL % lymphs are useful in predicting therapeutic responsiveness.

Respiratory, cardiovascular, and metabolic effects of enteral hyperalimentation: influence of formula dose and composition.

Respiratory, cardiovascular, and metabolic changes were monitored during balance studies in undernourished patients receiving continuous enteral formula feeding. The nutrient solutions, either high carbohydrate (83% of kcal) or high fat (50% of kcal), were administered at doses ranging from 2.7 to 6.0 X 10(-2) kcal X kg fat free body mass-1 X min-1. For both formulas, the observed physiological changes between fasting and the lower rates of energy infusion (ie, maintenance-slow growth) were either zero or relatively small. As formula dose was advanced into the rapid repletional range, physiological changes were more pronounced; there were linear increases in oxygen consumption, carbon dioxide production, minute ventilation, heat production, heat release, nitrogen balance, and change in heart rate from the base-line (all p less than 0.05 for both formulas). The rate at which carbon dioxide production, minute ventilation, and heat production increased with advancing energy infusion rate was also greater for the high carbohydrate formula relative to the high fat formula (p less than 0.02, less than 0.07, and less than 0.06, respectively). The physiological changes caused by continuous intragastric feeding are therefore a function of formula infusion rate and composition. Knowledge of these changes can be applied to patients treated for semistarvation who suffer respiratory or cardiac insufficiency.

A simple and accurate indirect calorimetry system for assessment of resting energy expenditure.

An indirect calorimetry system was assembled from three readily available major components: a digital pneumotachograph, an oxygen analyzer, and a carbon dioxide analyzer. A one-way valve, face mask, and meteorological balloon completed the system. Accuracy was assessed by comparison to direct calorimetry in hospitalized patients undergoing enteral hyperalimentation. Each subject was on continuous infusion of formula during a 7-day metabolic balance. Direct and indirect calorimetry was performed over the last 4 days of the balance. The overall agreement between the two methods was within 1%. A simple and inexpensive calorimetry system can therefore be assembled to provide an accurate measure of resting energy expenditure.