Crohn's disease mimicking sarcoidosis in bronchoalveolar lavage.

Granulomatous disorders like sarcoidosis or Crohn's disease are commonly associated with extrapulmonary or extraintestinal manifestations which occasionally may represent the only symptoms. We describe a 28-year-old female patient suffering from atypical erythema nodosum and arthritis. Although the chest x-ray was unremarkable bronchoalveolar lavage revealed lymphocytic alveolitis with an elevated CD4/CD8 ratio of 8 and 11.4 at repeated examinations suggesting a diagnosis of sarcoidosis. Further diagnostic workup included endoscopy of the bowel. The macroscopic aspect and histology of the terminal small bowel and colon ascendens indicated Crohn's disease. The patient recovered on steroids and sulfasalazine. Six months later she developed a perianal abscess for which she needed surgery supporting the diagnosis of Crohn's disease. This is the first case of a significantly (>6) elevated CD4/CD8 ratio in Crohn's disease previously regarded as highly specific for sarcoidosis.     

Predictive value of bronchoalveolar lavage in pulmonary sarcoidosis

We investigated whether analysis of cellular composition (including lymphocyte subsets) in bronchoalveolar lavage (BAL) fluid at the start of follow-up in patients with untreated sarcoidosis has any predictive value for further evolution of the disease. The outcome was evaluated by the chest roentgenograms, the lung volumes, and the single breath diffusing capacity for CO (DCO) after 22 to 36 months. In contrast to the general belief, patients who improved radiologically had a significantly higher T4 cell count (as percentage of BAL lymphocytes) (p less than 0.02) and a higher T4-T8 ratio in the initial BAL sample (9.3 vs 3.2; p less than 0.05) than those whose chest roentgenogram showed deterioration or remained unchanged. Total cell count and the percentage of lymphocytes in BAL fluid were not different between both groups. The change in DCO at the end of the follow-up period correlated positively with the baseline BAL T4 cells (Rs = 0.44; p less than 0.05) and with the BAL T4-T8 ratio (Rs = 0.51; p less than 0.03) and negatively with the baseline BAL T8 cells (Rs = -0.48; p less than 0.04). In only three patients progression of the disease necessitated steroid therapy, and they all had a low to normal T4-T8 ratio in the initial BAL sample. Bronchoalveolar lavage was repeated at least once in ten patients. Improvement of the chest roentgenograms in these patients was accompanied by a decrease of the BAL T4 cell count (as percentage of lymphocytes) and of the T4-T8 ratio. We conclude that a high lymphocyte count, a high T4 cell count (as percentage of lymphocytes), and a high T4-T8 ratio in BAL fluid reflect an intense alveolitis at the time of the procedure, but they are not indicators of poor prognosis on which therapeutic decisions can be based.     

CD8 dominant sarcoidosis in bronchoalveolar lavage]

In patients with sarcoidosis, we examined the differences in bronchoalveolar lavage fluid (BALF) findings between a low CD4/8 ratio group (< or = 1: n = 7) and a high CD4/8 ratio group (> or = 4: n = 47). On initial examination, no significant difference in gender, age, serum ACE level, eye lesions, or skin lesions was observed between the two groups, but the rate of negative PPD skin tests was significantly lowered in the low CD4/8 ratio group. No significant difference in initial BALF findings was observed between the two groups. In the low CD4/8 ratio group, the CD4/8 ratio increased significantly after three years from the initial BALF, but not in the high CD4/8 ratio group. The CD4/8 ratio is not associated with the clinical manifestation on first examination, but our data suggest that there may be some differences in clinical manifestations at the first examination and in the changes with time in the BALF findings between two groups. However, a greater accumulation of data is necessary before this can be confirmed.     

Uniformity of bronchoalveolar lavage in patients with pulmonary sarcoidosis

Sarcoidosis is a granulomatous disease of unknown cause characterized by a lymphocytic alveolitis. Previous studies have shown that the inflammatory cell population of the distal lung units of patients with this disorder can be accurately assessed using bronchoalveolar lavage (BAL). The present study evaluated the uniformity of BAL between different sites of the lung in patients with sarcoidosis. In general, there was a good correlation between sites for percentages of lymphocytes (LYM) (r = 0.750, p less than 0.0001), LYM number (r = 0.356, p = 0.0007), percentages of neutrophils (NEUT) (r = 0.917, p less than 0.0001), NEUT number (r = 0.999, p less than 0.0001), and macrophage (MAC) number (r = 0.858, p less than 0.001). Despite the good overall correlation, we found that 43% of the patients with high percent LYM (greater than 30%) had this finding on one side only. These patients did not differ from the group as a whole based on radiographic stage of their disease but did differ in the number of radiographs demonstrating focal infiltrates (2 of 28 patients with both sides less than 30% LYM, 2 of 14 with both sides greater than 30% LYM, and 4 of 9 with only one side greater than 30% LYM p less than 0.05 by chi-square); and in each situation the highest percent LYM was seen on the side with focal changes on the chest radiograph.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of gallium-67 scanning, bronchoalveolar lavage, and serum angiotensin-converting enzyme levels in pulmonary sarcoidosis. Predicting response to therapy

Patients with active pulmonary sarcoidosis underwent bronchoalveolar lavage, gallium scan, and serum angiotensin-converting enzyme (ACE) level determination prior to treatment with corticosteroids. Pulmonary function was tested before and after therapy. Increase in vital capacity after treatment ranged from 40 to 1,030 ml; 12 of the 16 patients studied had an increase of more than 200 ml. There was a close correlation between the percentage uptake of gallium scan and the increase of the vital capacity after therapy (r = 0.95, p less than 0.01). There was no relationship between the percentage of lymphocytes obtained on lavage and the changes in vital capacity with therapy (r = 0.05). There was a positive correlation between the changes in vital capacity and the ratio of T4(+):T8(+)lymphocytes (r = 0.62, p less than 0.05) and number of T4 (+) lymphocytes (r = 0.92, p less than 0.01) in the bronchoalveolar fluid. There was a low correlation between the pretreatment ACE level and the change in vital capacity (r = 0.368, p greater than 0.05).     

Interrelationship between bronchoalveolar lavage cellular constituents and pulmonary functions in sarcoidosis

Bronchoalveolar lavage (BAL) using a fiberoptic bronchoscope was done in 36 patients with sarcoidosis on 45 occasions and in 19 control subjects over a period of seven years. Total cell, polymorphonuclear cell and eosinophil cell counts of bronchoalveolar lavage fluid (BALF) in patients with sarcoidosis were not significantly different from control subjects. However, lymphocyte count (% total cells) in BALF was significantly higher (P less than 0.001) in patients with sarcoidosis as compared to control subjects. Alveolar macrophage was the predominant cell type in BALF in control subjects. A significant positive correlation (r = 0.46; P less than 0.01) between vital capacity (VC) and pulmonary diffusing capacity (DLCO) and a negative correlation (r = -0.52; P less than 0.001) between BAL fluid lymphocytes (%) and DLCO (per cent predicted) was found in patients with sarcoidosis. An increase in lymphocytes in BALF is considered to be one of the parameters indicating activity of sarcoidosis. In view of the relationship between this parameter and the reduction in DLCO, the latter may also be an indicator of disease activity.     

Angiotensin converting enzyme in bronchoalveolar lavage in ARDS

Angiotensin converting enzyme (ACE) is present in the endothelial cells of the normal lung where it converts angiotensin I to angiotensin II and inactivates bradykinin. It has been suggested that during endothelial injury ACE is sloughed into the blood, and that if the alveolar capillary membrane is injured, also into the alveolar lining fluid. Seven patients with adult respiratory distress syndrome (ARDS), were compared to 11 normal control subjects, nine patients with sarcoidosis, and six with idiopathic pulmonary fibrosis. Total, differential cell counts and ACE determinations were performed on bronchoalveolar lavage fluid in the ARDS group. ACE was detectable in the BAL of all but one ARDS patient. It was concluded that BAL ACE is elevated in some ARDS patients, especially those with infectious causes of lung injury. Increased ACE may reflect endothelial damage or local increase in ACE production in response to sepsis.     

Angiotensin-converting enzyme in sarcoidosis: a British study.

Serum angiotensin-converting enzyme (ACE) activity was measured in 18 healthy controls, 26 patients with active sarcoidosis, 13 patients with inactive sarcoidosis and seven patients with extensive tuberculosis. The serum ACE activity showed no significant difference between male and female in the control or sarcoidosis groups. There was no correlation between ACE activity and age except in the female active-sarcoid group. ACE activity in the active-sarcoid group was significantly higher than in the control, inactive-sarcoid and tuberculosis groups. The ACE activities at Stages I, II and III of the disease were not significantly different.     

Elevated concentrations of soluble interleukin-2 receptors in serum samples and bronchoalveolar lavage fluids in active sarcoidosis

Sarcoidosis is a granulomatous disorder of unknown cause characterized by activation of T-lymphocytes. We here report the use of an enzyme-linked immunosorbent assay for the soluble interleukin-2 receptor (IL-2R) as a measure of T-cell activation in serum samples and bronchoalveolar lavage fluids in 15 patients with active sarcoidosis. The geometric mean (x divided by SEM) value for soluble IL-2R in serum samples from patients with sarcoidosis was 1,110 (x divided by 1.17) versus 224 (x divided by 1.08) U/ml for normal control subjects (p less than 0.001). Detectable levels of soluble IL-2R were present in bronchoalveolar lavage fluids from 10 of 15 patients with sarcoidosis versus only 2 of 36 normal control subjects (p less than 0.001). Levels of soluble IL-2R in serum samples from untreated patients with sarcoidosis correlated with 67gallium lung scanning scores (p less than 0.05) but not with serum angiotensin-converting enzyme concentrations or constituents of bronchoalveolar lavage. In 5 patients, the level of soluble IL-2R in serum samples fell from 1,499 (x divided by 1.20) to 476 (x divided by 1.58) U/ml (p less than 0.05) after 6 wk of successful treatment with corticosteroids, whereas the changes in soluble IL-2R in bronchoalveolar lavage fluids were more variable. These observations suggest that measurements of soluble IL-2R, particularly in serum samples, may reflect disease activity and be clinically useful in the management of patients with sarcoidosis.     

Bronchoalveolar lavage, serum angiotensin-converting enzyme, and gallium-67 scanning in extrathoracic sarcoidosis

Results of bronchoalveolar lavage (BAL), 67Ga scanning, and serum angiotensin-converting enzyme (SACE) assay are compared in the assessment of pulmonary involvement in ten cases of extrathoracic sarcoidosis. Standard clinical, radiologic, and pulmonary function tests detected no pulmonary changes in these patients, but BAL demonstrated an increased alveolar lymphocytosis in eight of ten cases. SACE levels were increased in two cases, and the thoracic gallium uptake was normal in all cases. BAL appears to be the best technique for diagnosing latent pulmonary involvement in extrathoracic sarcoidosis.     

Platelet-activating factor in bronchoalveolar lavage from patients with sarcoidosis.

Platelet-activating factor (PAF), a lipid mediator of inflammation and anaphylaxis, may play a role in several physiopathologic alterations of the lung. A lipid compound with physicochemical and biologic characteristics similar to synthetic PAF was extracted and purified from bronchoalveolar lavage (BAL) fluid of 15 of 34 patients with sarcoidosis. PAF was quantitated by a bioassay on washed rabbit platelets. The specificity of platelet aggregation was assessed by using two different PAF receptor antagonists. The incidence of detectable amounts of PAF in BAL fluid of sarcoid patients was statistically significant (chi 2 = 4.064, p = 0.044) when compared with the 14 normal control subjects. The results demonstrated an increased production of PAF in the lower respiratory tract of patients with sarcoidosis. The presence of PAF in BAL fluid, however, did not correlate with radiologic stage, intensity of alveolitis, gallium scanning positivity, angiotensin-converting enzyme serum level, or lung function tests. Therefore, a direct relationship between presence of PAF in BAL fluid and activity of lung disease in patients with sarcoidosis was not directly established.     

Cotinine levels in serum and bronchoalveolar lavage fluid

Cotinine is a major metabolite of nicotine. This study was planned to investigate the relationship between bronchoalveolar lavage (BAL) fluid cotinine levels and serum cotinine levels in smokers and nonsmokers with various pulmonary diseases and to investigate whether these levels are affected by passive smoking. Serum and BAL fluid cotinine levels were measured in 27 patients. BAL cotinine levels were measured using a sensitive ELISA kit produced to measure cotinine in saliva. Plates were read by microuant (BioTek, USA) micro plate reader. All patient serum cotinine levels were detectable except for one nonsmoker patient. However, BAL fluid cotinine levels were measurable in only 6 patients (two of them were nonsmokers). A significant positive correlation was seen between serum and BAL fluid cotinine levels (r = 0.726; p = 0.000). Serum cotinine levels were significantly higher in present smokers than non-smokers (21.0 +/- 16.01; 5.35 +/- 7.65; p = 0.004). However, there were no significant differences in BAL fluid cotinine levels between smokers and nonsmokers. Passive smoking can increase nicotine metabolites in serum and other body fluids, including BAL fluid. Since BAL fluid and serum cotinine levels were well correlated, there is no need to use invasive procedures, such as bronchoscopy and expensive, time consuming BAL fluid analyses. Serum cotinine levels can give a rough idea of smoking status. BAL fluid cotinine meaurements should be done for only scientific reasons.     

Shed soluble ICAM-1 molecules in bronchoalveolar lavage cell supernatants and serum of patients with pulmonary sarcoidosis

The soluble form of intercellular adhesion molecule-1 (sICAM-1) might be a serum parameter of inflammatory activity gauging cellular interactions with possible relevance in sarcoidosis. To address this question we measured sICAM-1 by enzyme-linked immunosorbent assay in serum and shedding of this molecule by bronchoalveolar lavage (BAL) cells in sarcoidosis patients (44 and 40, respectively) and in controls (10 and 19, respectively). Serum concentrations of sICAM-1 (588.3 ± 72.2 ng/ml) and its spontaneous release by BAL cells (9.9 ± 1.5 ng/ml) in patients with active sarcoidosis were significantly higher than in those with inactive disease or controls, although no correlation was observed. Significant correlations of sICAM-1 shedding by nonstimulated BAL cells with the serum level of neopterin and of shedding by lipopolysaccharide-stimulated BAL cells with percentage of alveolar macrophages were observed in active sarcoidosis. Kinetic cell culture experiments with peripheral blood mononuclears disclosed a rapid up-regulation of sICAM-1 shedding and tumor necrosis factor-α release; however, at 5 h after stimulation a dissociation of their releases was observed. sICAM-1 release was maintained over 2 days, whereas tumor necrosis factor-α release peaked at 5 and ceased after 43 h. These results provide evidence that circulating and BAL cell culture-derived sICAM-1 reflect the stage of sarcoid inflammation. Although sICAM-1 in BAL cell supernatants originates from alveolar macrophages; the absence of a correlation with serum sICAM-1 concentration indicates that other cells are additional sources of the circulating pool of this molecule. Accepted for publication: 17 June 1996     

Antibody activity to Propionibacterium acnes in bronchoalveolar lavage fluid in sarcoidosis

While increased levels of circulating antibody to various microorganisms have been reported in sarcoidosis patients, the pathogenesis of the disease is still unknown. In this report, the levels of antibody activities against Propionibacterium acnes (P. acnes) were measured in bronchoalveolar lavage fluid (BALF) in patients with sarcoidosis, using an enzyme-linked immunosorbent assay method. Each immunoglobulin class of antibody activity to P. acnes was corrected by albumin concentrations in BALF. The levels of whole immunoglobulin antibody activities to P. acnes in BALF were as follows: 412.3 +/- 443.9 O.D./albumin 1 mg (M +/- SD) in 31 untreated sarcoidosis patients, 556.6 +/- 341.8 in 10 sarcoidosis patients treated with prednisolone, and 231.5 +/- 156.8 in 16 control individuals. The levels of antibody activities were significantly elevated in untreated patients (p less than 0.05) and in treated patients (p less than 0.02) compared to those of controls. However, considering the treated vs. untreated patients, there was no significant difference in levels. The serum levels of whole immunoglobulin antibody activities were 0.484 +2- 0.191 O.D. in 38 untreated patients, 0.410 +/- 0.166 in 13 treated patients and 0.571 +/- 0.254 in 52 controls. The levels of antibody activity were significantly lower in treated patients than in the controls (p less than 0.05). However, there was no significant difference between the untreated patients and controls. To assess the site of antibody production, the secretion ratio was calculated by dividing the levels in BALF to those in serum. For this purpose, each serum level of antibody activity was also corrected by serum albumin concentration as with BALF.(ABSTRACT TRUNCATED AT 250 WORDS)     

Significance of lymphocytosis in bronchoalveolar lavage in suspected ocular sarcoidosis.

Ocular sarcoidosis is frequent in Japan, but in many cases the condition remains undiagnosed in patients with suspected ocular sarcoidosis. Bronchoalveolar lavage (BAL) was performed in order to study the clinical implications of lymphocytosis of BAL fluid in such patients with characteristic ocular manifestations. The subjects included in this study were 39 patients with suspected ocular sarcoidosis. The patients were divided into four types based on high-resolution computed tomography (HRCT) findings; no lung involvement (HRCT-0), bilateral hilar lymphadenopathy (BHL) without lung involvement (HRCT-I), lung involvement and BHL (HRCT-II), and lung involvement and no BHL (HRCT-III). Transbronchial lung biopsy (TBLB) and BAL were conducted after examining serum angiotensin-converting enzyme and serum lysozyme values, skin test for purified protein derivative chest radiograph, HRCT, and gallium scintigram. Twenty patients were histologically diagnosed as having sarcoidosis, and 19 patients remained undiagnosed. Granuloma was identified by TBLB in 19 of 20 patients in type HRCT-II but in only one of 19 patients in types HRCT-0 and HRCT-I (p<0.0001). Lymphocytosis in BAL (>15%) was identified in all patients who showed lung field involvement (type HRCT-II) and in 16 of 19 patients without lung field involvement (types HRCT-0 and HRCT-I). There were 10 patients whose only relevant findings were lymphocytosis in BAL. Among these 10 patients, an increased CD4+/CD8+ ratio (>3.5) in BAL was seen in 60%. The authors conclude that high-resolution computed tomography results yield the same degree of diagnostic accuracy as transbronchial lung biopsy in ocular sarcoidosis suspects. However, bronchoalveolar lavage revealed significant lymphocytosis in patients with negative high-resolution computed tomography results. It should be kept in mind that a diagnostic group of patients with sarcoidosis who manifest ocular involvement and lymphocytosis in bronchoalveolar lavage exists.     

Pulmonary function in normal subjects and patients with sarcoidosis after bronchoalveolar lavage

To determine if fiberoptic bronchoscopy (FOB) with bronchoalveolar lavage impairs pulmonary function in normal subjects or those with sarcoidosis, we measured flow-volume loops, thoracic gas volume, and single breath carbon monoxide diffusing capacity before, one half hour and 24 hours after lavage. We studied 12 normal subjects; six underwent a large volume lavage (approximately 500 ml saline instilled), and six underwent a small volume lavage (approximately 175 ml). Five subjects with sarcoidosis also had a small volume lavage. Six control subjects underwent FOB without lavage. The FOB alone produced no significant changes in pulmonary function one half hour after the procedure. Small volume lavage in normal subjects produced no change except for a 16.3 +/- 5.1 percent (mean- +/- SEM) decline in peak expiratory flow rate (p less than .05) one half hour postlavage which returned to normal by 24 hours. This contrasts with sarcoidosis subjects in whom forced expiratory volume in one second, peak expiratory flow rate, and vital capacity declined by 20 +/- 4.8 percent, 26.7 +/- 7.3 percent, and 15.2 +/- 4.1 percent, respectively, (all p less than 0.05) one half hour postlavage. No change occurred in total lung capacity or diffusing capacity. Only with large volume lavage did decrements in lung function occur in normal patients that were comparable to those seen in the sarcoidosis subjects. Our findings suggest that bronchoalveolar lavage in normal patients can be associated with a significant and volume-related decline in pulmonary function and that in subjects with sarcoidosis, the deterioration is more pronounced.     

Angiotensin-converting enzyme gene polymorphism in relation to HLA-DR in sarcoidosis

OBJECTIVES: To investigate if an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene associates with HLA-DR alleles previously found to be of prognostic interest in Scandinavian sarcoidosis patients. This may contribute to characteristics associated with these HLA-DR alleles, such as a good (DR17) or poor (DR14 or 15) prognosis. DESIGN, SETTINGS AND SUBJECTS: Polymerase chain reaction (PCR) was used for analysing an I/D polymorphism in the gene coding for ACE in 138 subjects; 65 controls and 73 sarcoidosis patients, and for HLA-DR genotyping 67 patients. Serum ACE level (S-ACE) was measured in all controls and 72 patients. Sixty-one patients were classified as chronic or nonchronic after 2 years follow-up. All patients were recruited and followed at our outpatient clinic. RESULTS: No significant differences in ACE alleles or genotypes were seen between controls and patients or between patients positive and negative for DR17 or DR14/15. The ACE genotype did not differ between nonchronic and chronic patients. The ACE genotype tended to influence the S-ACE in patients, whilst in controls S-ACE significantly differed between the ACE genotypes. CONCLUSION: This study does not support an association between ACE genotype and sarcoidosis or disease outcome. However, because significantly (P < 0.001) more DR17 positive (17 of 19) than DR14/15 positive (seven of 26) patients were classified as nonchronic, these results instead strengthen the prognostic importance of HLA-DR alleles in Scandinavian sarcoidosis patients.     

Elevated level of soluble HLA class I antigens in serum and bronchoalveolar lavage fluid in patients with sarcoidosis

OBJECTIVE: Soluble HLA class I antigens (sHLAs) in human serum have been reported to be associated with allografts and autoimmune disease and could modify immunological reactions induced by membrane type HLAs. To investigate the clinical significance of sHLAs in sarcoidosis, we assessed concentrations of sHLAs in both serum and bronchoalveolar lavage fluid (BALF) and also examined their production by peripheral blood mononuclear cells (PBMCs) and BALF cells. METHODS: Concentrations of sHLAs were determined by enzyme-linked immunosorbent assay, using a monoclonal antibody against HLA class I (W6/32) and an enzyme-labeled polyclonal antibody to human beta2-microglobulin. PBMCs and BALF cells were cultured in the presence or absence of either LPS or PHA. PATIENTS: Serum levels of sHLAs were assessed in 96 patients with sarcoidosis and in 32 healthy control subjects. sHLAs concentrations in BALF were also investigated in 17 active sarcoidosis patients and in 13 control subjects. RESULTS: sHLAs levels in both serum and BALF were higher in sarcoidosis cases than in control subjects (p<0.05, in both). In the patients, values were significantly higher in active than in inactive stages (p<0.001) and significantly correlated with angiotensin-converting enzyme (ACE) levels. Both PBMCs and BALF cells produced enhanced amounts of sHLAs in patients with active sarcoidosis compared with those in control subjects. CONCLUSION: These results demonstrated that the level of sHLAs in serum is a useful index of disease activity of sarcoidosis, partly reflecting production by PBMCs and BALF cells.