The angiotensin converting enzyme in pulmonary sarcoidosis and the relative diagnostic value of serum lysozyme

The serum lysozyme and angiotensin converting enzyme (ACE) levels in 39 untreated patients with sarcoidosis were compared to values obtained from 106 healthy subjects. Only minor variations due to age and sex could be demonstrated in the values of ACE and lysozyme in the healthy control groups. ACE and lysozyme activities were significantly elevated in sarcoidosis, and a correlation was established between the level of these enzymes in this disease (r=0.54,P<0.01). In addition, the serum ACE and lysozyme levels were studied in three groups of disorders which are occasionally confused with sarcoidosis, namely tuberculosis (10 patients), lymphoma (10 patients) and bronchogenic carcinoma (14 patients). In distinguishing sarcoidosis from these illnesses, ACE was demonstrated to be a more specific test than lysozyme as none of our other disease groups demonstrated elevated levels of ACE, but as many as 40% had elevated lysozyme levels. We suggest that in the presence of an appropriate clinical picture, an elevated serum ACE may be sufficient evidence to eliminate the need for biopsy in sarcoidosis.     

Air pollution: Political initiative,scientific reality,and the process of decision making

The serum lysozyme and angiotensin converting enzyme (ACE) levels in 39 untreated patients with sarcoidosis were compared to values obtained from 106 healthy subjects. Only minor variations due to age and sex could be demonstrated in the values of ACE and lysozyme in the healthy control groups. ACE and lysozyme activities were significantly elevated in sarcoidosis, and a correlation was established between the level of these enzymes in this disease (r=0.54,P<0.01). In addition, the serum ACE and lysozyme levels were studied in three groups of disorders which are occasionally confused with sarcoidosis, namely tuberculosis (10 patients), lymphoma (10 patients) and bronchogenic carcinoma (14 patients). In distinguishing sarcoidosis from these illnesses, ACE was demonstrated to be a more specific test than lysozyme as none of our other disease groups demonstrated elevated levels of ACE, but as many as 40% had elevated lysozyme levels. We suggest that in the presence of an appropriate clinical picture, an elevated serum ACE may be sufficient evidence to eliminate the need for biopsy in sarcoidosis.     

Elevated Levels of Type II Soluble Tumor Necrosis Factor Receptors in the Bronchoalveolar Lavage Fluids of Patients with Sarcoidosis

Since tumor necrosis factor (TNF) is known to be involved in granuloma formation in sarcoidosis, and soluble TNF receptors (sTNF-Rs) inhibit TNF action in vivo, we evaluated the levels of sTNF-Rs in the bronchoalveolar lavage fluids (BALF) of 31 subjects using an enzyme-linked immunosorbent assay. Our group consisted of 13 patients with sarcoidosis (7 sarcoidosis patients who received no treatment and 6 who received corticosteroid therapy) and 18 control subjects (11 healthy nonsmokers and 7 asymptomatic smokers). Type II (75-kDa), but not type I (55 kDa) sTNF-R in BALF was elevated significantly in patients with sarcoidosis compared with the healthy nonsmokers (type I: 126.7 ± 17.6 pg/ml BALF vs 79.4 ± 16.5 pg/ml BALF, p > 0.05; type II: 98.3 ± 27.8 pg/ml BALF vs 26.7 ± 4.9 pg/ml BALF, p < 0.05). Although levels of type I sTNF-R in BALF from sarcoidosis patients were not correlated with any cellular profiles of BALF, concentrations of type II correlated significantly with the numbers of lymphocytes in BALF. We concluded that sTNF-R is a normal constituent of the epithelial lining fluids and that levels of type II sTNF-R are elevated significantly in the BALF from individuals with sarcoidosis. This suggests that sTNF-Rs may influence the local bioactivity of TNF and may also contribute to the pathogenesis of sarcoidosis. Accepted for publication: 7 November 1996     

Serum Vascular Endothelial Growth Factor as a Possible Prognostic Indicator in Sarcoidosis

Sarcoidosis is a systemic granulomatous disorder of unknown etiology, which involves the lung, eye, liver, and other organs. Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis involved in an important role in the development of granuloma. However, only a limited number of studies have reported on the relationship between serum VEGF values and the clinical status of sarcoidosis. Concentrations of serum VEGF were determined in 33 patients with sarcoidosis. We investigated the correlation between serum VEGF values and extent of disease, prognosis, and radiographic stage compared with serum angiotensin converting enzyme (ACE) values as another candidate. Concentrations of serum VEGF in patients who received corticosteroid treatment were significantly higher than those of patients with spontaneous remission (p < 0.05). In addition, serum VEGF values in patients with extrathoracic involvements were significantly higher than those of patients with sarcoid lesions limited to the thoracic space (p < 0.05), accompanied by a tendency to increase the number of organs involved. The values of serum ACE revealed no relationship to the values of serum VEGF, administration of corticosteroid, or extrathoracic involvements. We concluded that serum VEGF values in patients with sarcoidosis is a predictive factor in determining extrathoracic organ involvements and as a parameter for deciding the necessity of treatment with corticosteroid. Serum VEGF might be a useful marker as a prognostic indicator in sarcoidosis.     

Clinical significance of serum KL-6 in pulmonary sarcoidosis]

We investigated whether the level of serum KL-6 could be an activity marker for pulmonary sarcoidosis. In 33 patients with pulmonary sarcoidosis, the relationships between serum KL-6 levels and diagnostic imaging, serum angiotensin-converting enzyme (ACE) levels, serum lysozyme levels, steroid therapy, and prognosis were evaluated. There were no significant differences in the level of serum KL-6 when the patients were divided on the basis of radiographic findings, but the level of serum KL-6 was markedly elevated in some patients with stage-II pulmonary sarcoidosis. There was a significant correlation between serum KL-6 levels and the following two parameters: serum ACE and lysozyme levels. Among patients with a high initial level of serum KL-6, pulmonary sarcoidosis tended to become exacerbated within one year. Steroid therapy significantly decreased the level of serum KL-6, suggesting that the level of serum KL-6 could be an activity indicator for pulmonary sarcoidosis. Immunohistochemical staining by anti-KL-6 antibody revealed that KL-6 was localized in proliferating type-II alveolar epithelial cells.     

Fibroblasts as Target and Effector Cells in Japanese Patients with Sarcoidosis

Fibroblasts play a crucial role in progressive lung fibrosis, acting not only as target cells but also as effector cells. To clarify these functions in sarcoidosis, lung fibroblasts from Japanese sarcoid patients were studied for their proliferative capacity and cytokine productivity. Fibroblasts were cultured from transbronchial lung biopsy specimens from seven patients with sarcoidosis. As a comparison, fibroblasts from open lung biopsy specimens of four patients with idiopathic pulmonary fibrosis (IPF) were studied. For controls, fibroblasts were cultured from specimens of normal resected lung tissue of five patients with localized lung cancer. The proliferative activity of cultured fibroblasts from patients with sarcoidosis was highest among the three groups (p < 0.05). However, the proliferative capacity in all groups was suppressed when fibroblasts were cultured with interleukin-1β (IL-1β). No significant differences were noted in the degree of inhibition among the three groups. Addition of interferon-γ (IFN-γ) also resulted in inhibition of fibroblast growth in all groups, but the degree of inhibition was significantly greater in both the sarcoid and IPF groups than in controls (p < 0.05). The amount of interleukin-6 (IL-6) in the culture supernatants from sarcoid fibroblasts cocultured with IL-1β was significantly higher than in controls. Sarcoid fibroblasts are not only proliferatively active but also possess effector cell function to produce cytokines. IL-6 may enhance the immunologic reaction to sarcoidosis and cause the disease to become chronic. IFN-γ suppresses proliferation of sarcoid fibroblasts and may prevent fibrotic changes of the lungs in the Japanese sarcoid patients. Accepted for publication: 4 June 1997     

Evaluation of Cyfra 21-1: a potential tumor marker for non-small cell lung carcinomas

Cyfra 21-1 is a tumor marker based on the determination of water-soluble cytokeratin 19 which is secreted by normal or malignantly transformed epithelial cells. It is suggested to be a valuable marker in patients with non-small cell lung carcinoma (NSCLC). A prospective clinical study was conducted to investigate the value of Cyfra 21-1 for diagnosis, determination of subtypes, staging, and evaluation of therapy response in patients with lung carcinoma (Ca). Sixty-nine patients (mean age: 60.9 ± 9.2 years, M/F:12.8) treated between 1994 and 1998 inclusive, and 13 healthy smokers (mean age:50.9 ± 4.8 years, M/F:1.6) constituted the study group and control group, respectively. Venous blood samples (10 ml) were obtained from all subjects. Posttreatment blood samples were also obtained from 14 NSCLC patients. Cyfra 21-1 levels (cutoff value 3.3 ng/ml) were determined by ELSA-Cyfra 21-1 kit (CIS bio international, France) through immunoradiometric assay (IRMA). Cyfra 21-1 levels did not differ between smoking and non-smoking subjects within each group (p > 0.05). Cyfra 21-1 was significantly elevated in lung Ca cases irrespective of the cell type (p < 0.05). It was significantly elevated in squamous cell and adenocarcinoma varieties with the most prominent elevation in squamous cell type (p < 0.05). In lung Ca, the specificity and sensitivity of Cyfra 21-1 was 92.3% and 52.2%, respectively. Sensitivity was 65.5% for NSCLC, 70.5% for squamous cell, and 45.5% for adenocarcinoma varieties, with highest sensitivity rates in Stage IIIA + IIIB (87.5%) and Stage IV (75%) of squamous cell lung Ca. Cyfra 21-1 level was significantly decreased after treatment in NSCLC patients (n 14) (p < 0.01). Cyfra 21-1 is a tumor marker that helps to establish the diagnosis and differentiation of cell type and evaluation of response to therapy in patients with NSCLC. Accepted for publication: 3 April 2001     

Decreased Selenium Concentration and Glutathione Peroxidase Activity in Blood and Increase of These Parameters in Malignant Tissue of Lung Cancer Patients

We studied the selenium (Se) concentration in whole blood and plasma, glutathione peroxidase (GSH-Px) activity in red blood cells and plasma, as well as both of these parameters in cancerous and tumor-free lung tissue of lung cancer patients. Blood samples were taken from 84 cancer patients and 61 healthy controls. Normal and neoplastic lung tissues were obtained from 57 patients at the time of surgery. Se concentrations in whole blood and palsma were lower by 23% (p < 0.001) in patients compared with controls. GSH-Px activity in red cells was lower by 20.2% (p < 0.004) and in plasma by 11.7% (p < 0.05) in patients than in the control group. On the other hand, the tumor Se level was higher by 66.6% (p < 0.0001) and GSH Px activity by 49.5% (p < 0.0001) than in adjacent tumor-free tissue. No differences in Se concentrations and GSH-Px activities were found between squamous cell carcinoma and adenocarcinoma nor among the clinical stages of the disease. In the whole blood and plasma of cancer patients significantly lower Se concentrations were found in smokers than in nonsmokers. Significantly lower Se concentrations were also found among cancer patients who were smokers compared with controls. These findings show that in the blood of cancer the antioxidant ability, as measured by Se and GSH-Px, is reduced significantly. The cause of increased Se and GSH-Px in the malignant part of the lung is not understood and requires further studies. Accepted for publication: 17 April 1997     

Levels of serum interleukin-10 reflect disease activity in patients with cardiac sarcoidosis

Cardiac involvement is the major determinant of morbidity and mortality in patients with sarcoidosis, but clinical evaluation of the disease activity is occasionally difficult in cardiac sarcoidosis. The present study examined whether serum levels of interleukin-10 (IL-10) could reflect the disease activity of patients with cardiac sarcoidosis. Serum IL-10 levels were measured using an enzyme-linked immunosorbent assay, and compared with clinical manifestation, levels of angiotensin-converting enzyme (ACE), levels of lysozyme and accumulation of gallium-67 citrate. Sera were collected from 8 patients with cardiac sarcoidosis (CS group), 22 patients with miscellaneous heart diseases except for sarcoidosis (MHD group), and 8 healthy control subjects (HC group). Serum IL-10 levels of the CS group were significantly higher than those of the 2 control groups. Before steroid therapy, the levels of IL-10 in the CS group showed a significantly positive correlation with levels of ACE (r=0.868, p<0.05) and lysozyme (r=0.890, p<0.05). In 5 patients who were analyzed before and after steroid therapy, the levels of IL-10 tended to correlate with a decrease of an abnormal accumulation in gallium-67 citrate. Serum IL-10 levels may play a role in evaluation of the disease activity in patients with cardiac sarcoidosis.     

Oxidative Inactivation of Surfactants

Reactive oxygen species (ROS) may play an important role in the chronic pulmonary morbidity of preterm infants. We therefore studied the magnitude and mechanisms of oxidative inactivation of a natural lung surfactant (NLS) and of two surfactants used for treatment of respiratory distress syndrome, beractant and KL₄ surfactant (KL₄). Incubation with Fenton reagents, 2-4 mM peroxynitrite (ONOO⁻) or 0.5 mM hypochlorous acid (OCl⁻), resulted in an increased minimum surface tension (MST) of all surfactants; the order of effect on MST was beractant > KL₄ > NLS. After incubation with Fenton reagents, NLS contained a higher concentration of conjugated dienes (p < 0.01) but lower concentration of malondialdehyde (p < 0.001) than beractant. Protein carbonyl concentrations after treatment with Fenton reagents were higher in NLS and KL₄ than in beractant (p < 0.05). Surface area cycling for 24 h with 2 mM ONOO⁻ or 0.5 mM OCl⁻ caused both beractant and KL₄ to increase the proportion of light subtypes from 8–10% to 26–29%; with Fenton reagents, there was disappearance of the light subtype and formation of ultraheavy subtype 74–91% with poor MST. Natural and therapeutic surfactants differ markedly in their sensitivity to ROS, which may be important for surfactants in therapeutic use because oxidative inactivation may limit their effect. Oxidation of natural surfactant may result in reduced function and contribute to chronic lung disease. Accepted for publication: 8 January 1999     

Serial investigation of Angiotensin-Converting Enzyme in sarcoidosis patients treated with Angiotensin-Converting Enzyme Inhibitor

BackgroundAngiotensin-converting enzyme (ACE) is an acid glycoprotein that converts angiotensin I into angiotensin II. It is produced mainly by activated alveolar macrophages and it resulted elevated in sarcoidosis patients. ACE is the only biomarker mentioned in WASOG international guidelines for the diagnosis and follow-up of sarcoidosis patients but its sensitivity and specificity are low. This study aimed to analyze serial measurements of ACE levels in sarcoidosis patients stratified according to concomitant ACE-inhibitor therapies (ACEIs).Subjects and methods136 serum samples from sarcoidosis patients were retrospectively enrolled in the study. Serial ACE concentrations were measured once year for each patient. Population were divided according to radiogical stages and ACEIs.ResultsACE concentrations resulted higher in non-ACEIs than ACEIs group (p<E-04). This result was confirmed also stratifying population according to radiological stages particularly in stage 3 (p=2E-03) or stage 2 of the disease (p<1E-04). Considering ACEIs, serum ACE levels proved to be higher in sarcoidosis patients treated with zofenopril than in those treated with perindopril (p=2E-02), enalapril (p=2E-03) or ramipril (p=2E-04). Patients treated with ACEIs showed a progressive reduction in ACE levels to five years of follow-up (p=1.3E-02) and the zofenopril group recorded the highest ACE levels (p<1E-04).ConclusionsThis retrospective study investigated changes in ACE levels in patients with sarcoidosis treated or not treated with ACEIs. Considering the overall low sensitivity and specificity of this biomarker, we suggest systematically investigating medical drugs prescribed for patients with sarcoidosis, in order to optimize the interpretation of ACE in clinical management.     

Initial Pleural Pressure Measurement in Spontaneous Pneumothorax

To assess whether pleural pressure (PP) measurement is helpful in evaluating the evolution of spontaneous pneumothorax (SP). To measure the inspiratory and expiratory PP at tidal volume in the SP in 85 cases. Ninety-one percent were cured with medical treatment, whereas the remaining 9% required surgery. In the cases medically resolved, the inspiratory pleural pressure (IPP) was −9 ± 5 mbar, and the expiratory pleural pressure (EPP) was −3 ± 6 mbar, whereas in the surgical cases, IPP was −7 ± 2 mbar (p= not significant), and EPP was 1 ± 3 mbar (p < 0.01). In the SP cases, which resolved in less than 7 days of drainage, IPP was −10 ± 5 mbar, and EPP was −3 ± 5 mbar, whereas IPP was −8 ± 3 mbar (p < 0.01), and EPP was 0 ± 4 mbar (p < 0.001) in those cases in which SP resolution required more than 7 days. The sensitivity to predict the need for surgery with an EPP ≥ 2 mbar was 100%, with a specificity of 49%. The cutoff of the curve was ≥ 1 mbar, with a sensitivity of 65% and specificity of 70%. The values of PP at the end of an expiration to tidal volume were negative in the SP cases, which were resolved by medical treatment, whereas they were atmospheric in those cases that required surgery. The static inspiratory and expiratory PP in the SP cases requiring thoracic drainage during <7 days showed more negative PP than those that resolved in a period longer than 7 days. Accepted for publication: 11 August 2000     

β2-Agonist-Elevated Stress Response in Human Bronchial Epithelial Cells in Vivo and in Vitro

Recent studies report high baseline levels of stress (heat shock) proteins in bronchial epithelial cells from asthmatic individuals. The promoter of the gene encoding the 72-kDa heat shock protein has an element responsive to cAMP, which may be affected by β-agonists. This study examined stress protein levels in subjects enrolled in a segmental lung allergen challenge study to determine whether β-agonist medication could contribute to a stress response. Subjects were divided on the basis of no premedication (n= 17), metered dose inhalations of albuterol (n= 24), or placebo inhalation (n= 3) prior to bronchoscopy. Levels of the inducible stress protein Hsp72 and constitutive Hsp73 were quantitated in bronchial epithelial cells from brush biopsy of allergic nonasthmatic, allergic asthmatic, and normal individuals. Mean levels were increased significantly (p < 0.003 and p < 0.004, respectively) in those subjects who received albuterol premedication. No significant differences were found between clinical groups of individuals or for placebo inhalation vs nonpremedication. Albuterol in vitro increased the levels of Hsp72 and Hsp73 in epithelial cells from either nonpremedicated or placebo-treated donors; the Hsp72 levels correlated linearly with increased albuterol concentration (r= 0.81, p < 0.01). Therefore, β-agonists elevate or prolong an elevated stress response in epithelial cells, possibly through cAMP-mediated effects. Accepted for publication: 20 December 1996     

Influence of angiotensin converting enzyme (ACE) genotype on interpretation of diagnostic tests for serum ACE activity

Background: The discovery that an insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene influences the circulating concentration of ACE may have implications for the proper use of serum ACE activity measurements in screening for sarcoidosis. Aim: To determine whether the sensitivity of the serum ACE test improves if ACE genotype is taken into account. Methods: A retrospective determination of ACE genotype and clinical diagnosis was done in 54 patients with serum ACE activity above the upper limit of the reference range for the insertion (II) genotype. ACE was measured by radioenzymatic and spectrophotometric techniques, and genotype by PCR. Results: When serum ACE values determined diagnostically were related to the appropriate genotype-specific reference range, sensitivity and specificity for diagnosis of sarcoidosis were 65–70% and 58% respectively, compared to 47–57% and 77% with a reference range unsegregated for genotype. Conclusion: ACE genotyping may be helpful in determining the diagnostic significance of mildly elevated serum ACE activity in patients with the II and ID genotypes.     

Lavage versus serum measurements of lysozyme, angiotensin converting enzyme and other inflammatory markers in pulmonary sarcoidosis

The aim of this study was to explore whether amounts of angiotensin converting enzyme (ACE) and lysozyme produced within the lungs correlate more closely than serum levels of these enzymes, or other inflammatory markers, with chest radiographic profusion scores, lung function and therapy response in patients with pulmonary sarcoidosis. We have studied 25 patients, and levels in bronchoalveolar lavage (BAL) were used to determine "local" enzyme production by reference to serum and lavage albumin. Before treatment, serum lysozyme levels were elevated in more patients (80%) than serum ACE levels (40%). They also gave the best overall correlation with clinical measurements prior to treatment and falls in serum lysozyme closely parallelled improvement in lung function (transfer factor for carbon monoxide (DLCO)) on therapy. The only other markers showing significant correlations with disease severity were lavage neutrophil counts per ml and "local" ACE measurements prior to treatment. The value of pre-treatment levels of the different inflammatory markers in predicting response to corticosteroid therapy was explored and the only significant finding was that BAL lymphocyte percentages and numbers.ml-1 were initially higher in patients with lower post-treatment chest X-ray scores (p less than 0.01 and p less than 0.05, respectively). We conclude that serum lysozyme levels appear to be a more useful marker of overall disease activity in sarcoidosis than measurements of other inflammatory markers. However, BAL lymphocyte counts were the best predictive marker of radiographic response to corticosteroids.     

Guinea Pig Pulmonary Mechanics: Altered Sensitivity to Carbachol by Cadmium and/or Selenium

Male Hartley guinea pigs (480–610 g) were treated intratracheally as follows: saline, cadmium (Cd, 0.3 mg), selenium (Se, 0.3 or 0.06 mg), or Se (0.06 mg) and Cd (0.3 mg) simultaneously. Selenium and Cd were administered as sodium selenite and cadmium chloride, respectively. Twenty-four h later, dynamic lung compliance (C_dyn) and pulmonary resistance (R_p) were measured before (baseline C_dyn and R_p) and after carbachol administration (0.0001, 0.001, 0.01, and 0.1 μmol/kg, intravenously). Results indicated a significant decrease in baseline C_dyn caused by 0.3 mg of Cd, 0.3 mg or 0.06 mg of Se, and 0.3 mg of Cd with 0.06 mg of Se (p < 0.05). A significant increase in baseline R_p due to 0.3 mg of Se was observed (p < 0.05). Carbachol decreased C_dyn significantly below baseline, evident after lower doses of carbachol, in guinea pigs pretreated with 0.3 mg of Se, whereas a significant improvement in C_dyn was seen after 0.0001 μmol/kg carbachol in the group pretreated with Se and Cd simultaneously (p < 0.05) compared with the respective baseline values of the saline-treated group. Similarly, a significant increase in R_p was observed after carbachol in groups pretreated with 0.3 mg of Cd or Se (p < 0.05). Results also indicated a significant increase in large airway constriction caused by Cd and/or Se (p < 0.05). A leftward shift in the carbachol dose-response curve indicated increased sensitivity to carbachol in Cd- and/or Se-pretreated guinea pigs. Accepted for publication: 14 March 1997     

In vitro synthesis of angiotensin-converting enzyme by alveolar macrophages is increased in disseminated sarcoidosis

To determine the responsibility of alveolar macrophage (AM) for the increased concentration of angiotensin-converting enzyme (ACE) in bronchoalveolar fluid of patients with sarcoidosis, we cultured AM recovered by bronchoalveolar lavage of 30 subjects: 9 were normal control subjects (group C), 10 had intrathoracic localized sarcoidosis (group LS), and 11 had disseminated intrathoracic and extrathoracic sarcoidosis (group DS). Cells were cultured for 7 days and synthesis of ACE was evaluated according to the difference between final (ACEqe) and initial (ACEqi) ACE content. In groups C, LS, and DS, ACEqi were, respectively, 3.0 ± 1.7, 3.3 ± 1.9, and 4.8 ± 2.4 U/10⁶ AM, and ACEqe were 6.2 ± 1.7, 6.7 ± 2.5, and 11.3 ± 2.8 U/10⁶ AM. ACEqe was higher than ACEqi in all 3 groups (p < 0.01). When cycloheximide was added to the AM culture, ACEqe did not differ from ACEqi, in opposition to what was observed without cycloheximide (p < 0.002). ACEqi in group LS and DS did not differ from ACEqi in Group C, but ACEqe in Group DS was higher than in Groups C and LS (p < 0.01). We conclude that AM both from normal subjects and from subjects with sarcoidosis contain ACE, cultured AM synthesize ACE, and that a greater amount of ACE is produced when AM are obtained from patients with disseminated sarcoidosis.     

The Effect of Compliance on Clinical Outcomes for Patients with Dysphagia on Videofluoroscopy

This study investigates clinical outcomes and the degree of compliance in patients who received advice on dysphagia management and the effect of the level of compliance on the incidence of chest infections and aspiration pneumonia, cause of death, and hospital readmission. We performed a retrospective cohort study of 140 patients who had videofluoroscopic studies at Princess Margaret Hospital, Christchurch, New Zealand, from 1 January 1996 to 30 June 1997. The degree to which recommendations on dysphagia management were followed was correlated with the incidence of chest infections, aspiration pneumonia, and readmissions to the hospital. Cause of death, including the contribution of aspiration pneumonia, was assessed by review of medical records and death certificates. Information was available for 89% of the cohort. Twenty-one percent of the survivors never complied with the advice given. Noncompliant subjects were younger (p<0.05) and more likely to be living at home rather than receiving institutional care (p=0.05). Noncompliers had more hospital admissions because of chest infections or aspiration pneumonia (22% vs. 1.5%; p<0.001). Home-dwelling noncompliant subjects received more courses of antibiotics (p<0.02), but there was no difference in the number of chest infections. Fifty-four people died during the study period. Aspiration pneumonia was recorded as a definite or probable cause of death in 26 (52%) of the 50 subjects for whom reliable information was available and in 6 of 7 subjects who made a deliberate and documented decision not to comply. We conclude that noncompliance with recommendations about dysphagia management is associated with adverse outcomes. There was a high mortality rate and aspiration pneumonia was a common cause of death. Submitted October 4, 1999; accepted September 15, 2000 with revision     

Airway Eosinophilic Inflammation and Bronchial Hyperresponsiveness after Allergen Inhalation Challenge in Asthma

Allergen exposure in atopic asthmatic patients is associated with recruitment and activation of eosinophils in the airways. Once activated, eosinophils release toxic products, including the eosinophil cationic protein (ECP), able to damage bronchial structures and to increase bronchial hyperresponsiveness. With this background, the present study was designed to evaluate whether ECP levels in bronchoalveolar lavage (BAL) fluid could reflect, better than BAL eosinophil counts, the cellular activation that follows allergen exposure in atopic asthmatics. Twenty-two atopic patients attended the laboratory on two separate days. On the 1st day, they underwent methacholine (MCh) inhalation challenge to detect the degree of nonspecific bronchial hyperresponsiveness. On the 2nd day, they underwent fiberoptic bronchoscopy and BAL, at baseline or 4–6 h after allergen inhalation challenge. In this latter patient group, MCh challenge was repeated 3–5 h after allergen challenge, 1 h before fiberoptic bronchoscopy. The analysis of the mean baseline FEV₁ values and the degree of bronchial reactivity to MCh (MCh Pd₂₀) on the 1st study day did not demonstrate differences between the two patient groups (p > 0.1, each comparison). In addition, in the allergen-challenged group, MCh Pd₂₀ was decreased significantly after allergen challenge (151.4 μg/ml and 67.6 μg/ml, respectively, before and after challenge; p < 0.05). Evaluation of the different BAL cell types demonstrated that the proportions of eosinophils and epithelial cells were increased significantly in the allergen-challenged group compared with the group evaluated at baseline (p < 0.01 and p < 0.05, respectively). Moreover, ECP levels, corrected by the correspondent albumin levels (ECP/Alb), were higher in the allergen-challenged group compared with the group evaluated at baseline (p < 0.05). In addition, although a positive correlation was demonstrated between BAL eosinophil percentages and ECP/Alb values (r= 0.72, p < 0.05) in the group evaluated at baseline, no links were found between these parameters in the allergen-challenged group (p > 0.1). However, in this latter group, a weak positive correlation was demonstrated between eosinophil percentages and ΔMch, i.e., the increased nonspecific bronchial reactivity, which is observed after allergen challenge (r= 0.55; p < 0.05). Thus, in stable asthmatic patients an ongoing activation of eosinophils parallels their migration, but this eosinophilic inflammation is not strictly related to bronchial reactivity to Mch. By contrast, after allergen inhalation challenge, eosinophil recruitment and activation seem to follow different temporal kinetics, and eosinophilic inflammation may be partially associated with the degree of airway hyperresponsiveness. Accepted for publication: 15 September 1997     

Incomplete Upper Esophageal Sphincter Relaxation: Association with Achalasia but Not Other Esophageal Motility Disorders

Incomplete upper esophageal sphincter (UES) relaxation is not well understood. We compared clinical and manometric characteristics of patients with normal and abnormal UES relaxation. Consecutive patients (n = 208) underwent manometric evaluation of the lower esophageal sphincter (LES), esophageal body, and UES/pharynx. The patients were divided into those with abnormal UES relaxation (residual pressure >6.7 mmHg) (n = 21) and normal relaxation (n = 187). Clinical and manometric profiles were compared. Sex, age, and presenting complaint did not correlate with UES relaxation. Normal esophageal peristaltic sequences were more frequently present in the normal UES group (73.6%) compared with the abnormal (55.8%) (p < 0.01). The UES relaxation was shorter in the group with abnormal relaxation (410.0 ms vs. 510.2 ms, p < 0.001). All other manometric parameters were not different between the two groups. When individual manometric diagnoses were analyzed, only achalasia was noted to be more common in the abnormal UES group (23.8% vs. 9.1%, p < 0.05), and a trend was noted toward diffuse esophageal spasm being more common (14.3% vs. 9.6%, not significant). We conclude that incomplete UES relaxation is a rare manometric finding, associated with achalasia and not specifically associated with any other motility disturbance. This finding may represent a secondary response to the poor esophageal emptying seen in achalasia.