A randomized clinical trial of alpha(1)-antitrypsin augmentation therapy. Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1-antitrypsin deficiency. Sulphasalazine therapy in ankylosing spondylitis: its effect on disease activity, immunoglobulin A and the complex immunoglobulin A-alpha-1-antitrypsin. Dyspnea management in alpha-1 antitrypsin deficiency: effect of oxygen administration. Sodium manipulation in the management of hypertension. The view against its general use. Probiotics: a novel approach in the management of food allergy. Minimal access surgery for cholelithiasis induces an attenuated acute phase response. Neither heparin nor acetylsalicylic acid influence the clinical course in human Plasmodium falciparum malaria: a prospective randomized study. Proteolytic enzyme activity in patients with severe head injury and the effect of a proteinase inhibitor. Controlled trial comparing two types of enteral nutrition in treatment of active Crohn's disease: elemental versus polymeric diet. Adverse effect of low-dose prophylactic human recombinant leukocyte interferon-alpha treatment in renal transplant recipients. Cytomegalovirus infection prophylaxis leading to an increased incidence of irreversible rejections.
We have investigated whether restoration of the balance between neutrophil elastase and its inhibitor, alpha(1)-antitrypsin, can prevent the progression of pulmonary emphysema in patients with alpha(1)-antitrypsin deficiency. Twenty-six Danish and 30 Dutch ex-smokers with alpha(1)-antitrypsin deficiency of PI*ZZ phenotype and moderate emphysema (FEV(1) between 30% and 80% of predicted) participated in a double-blind trial of alpha(1)-antitrypsin augmentation therapy. The patients were randomized to either alpha(1)-antitrypsin (250 mg/kg) or albumin (625 mg/kg) infusions at 4-wk intervals for at least 3 yr. Self-administered spirometry performed every morning and evening at home showed no significant difference in decline of FEV(1) between treatment and placebo. Each year, the degree of emphysema was quantified by the 15th percentile point of the lung density histogram derived from computed tomography (CT). The loss of lung tissue measured by CT (mean +/- SEM) was 2.6 +/- 0.41 g/L/yr for placebo as compared with 1.5 +/- 0.41 g/L/yr for alpha(1)-antitrypsin infusion (p = 0.07). Power analysis showed that this protective effect would be significant in a similar trial with 130 patients. This is in contrast to calculations based on annual decline of FEV(1) showing that 550 patients would be needed to show a 50% reduction of annual decline. We conclude that lung density measurements by CT may facilitate future randomized clinical trials of investigational drugs for a disease in which little progress in therapy has been made in the past 30 yr. Assessment of emphysema-modifying therapy is difficult, but newer outcome measures offer advantages over traditional methods. The EXAcerbations and Computed Tomography scan as Lung End-points (EXACTLE) trial explored the use of computed tomography (CT) densitometry and exacerbations for the assessment of the therapeutic effect of augmentation therapy in subjects with alpha(1)-antitrypsin (alpha(1)-AT) deficiency. In total, 77 subjects (protease inhibitor type Z) were randomised to weekly infusions of 60 mg x kg(-1) human alpha(1)-AT (Prolastin) or placebo for 2-2.5 yrs. The primary end-point was change in CT lung density, and an exploratory approach was adopted to identify optimal methodology, including two methods of adjustment for lung volume variability and two statistical approaches. Other end-points were exacerbations, health status and physiological indices. CT was more sensitive than other measures of emphysema progression, and the changes in CT and forced expiratory volume in 1 s were correlated. All methods of densitometric analysis concordantly showed a trend suggestive of treatment benefit (p-values for Prolastin versus placebo ranged 0.049-0.084). Exacerbation frequency was unaltered by treatment, but a reduction in exacerbation severity was observed. In patients with alpha(1)-AT deficiency, CT is a more sensitive outcome measure of emphysema-modifying therapy than physiology and health status, and demonstrates a trend of treatment benefit from alpha(1)-AT augmentation. Serum levels of immunoglobulin A (IgA) and the complex immunoglobulin A-alpha 1 antitrypsin (IgA-alpha 1AT) were measured at the commencement and after 3 months of a double-blind, placebo-controlled trial of sulphasalazine (SAS) in patients with active ankylosing spondylitis (AS). Twenty-eight patients were evaluated, 15 on sulphasalazine, 13 on placebo. Significant falls were seen in both IgA (p less than 0.01) and IgA-alpha 1AT (p less than 0.001) in the actively treated patients. In addition, significant improvement in clinical and laboratory measures of disease were observed. It is concluded that SAS is effective in AS and modulates the immune response. A deficiency of alpha-1 antitrypsin (AAT) can lead to pulmonary disease in middle-aged adults in whom dyspnea management can be a significant issue.
                The research addressed whether short-term oxygen (O2) administration during activities might decrease dyspnea and improve exercise performance in nonhypoxemic patients with emphysema caused by a deficiency of alpha-1 antitrypsin.
                This was a double-blind, randomized crossover study of 31 subjects with a deficiency of AAT (mean + SD, age = 47 +/- 7), moderate emphysema and a resting PaO2 > 70 mm Hg. Oxygen saturation (SpO2), 6-minute walk distance, and end of walk dyspnea were measured during three practice walks and during walks with nasal cannula administration of O2 (intervention) and compressed air (control).
                Repeated measures analysis of variance (ANOVA) showed significant differences across the walks for SpO (F= 18.9, p = 0.0001), 6-minute walk distance (F= 6.07, p = 0.004), and dyspnea (F= 4.44, p = 0.016). Using post hoc contrasts, SpO2 was the only variable that differed between 20, and compressed air (p < 0.0001). There was, however, an interaction effect of gender with O2 for dyspnea (F= 9.85, p = 0.004). Mean values showed that men did not benefit from O2 (p = 0.87). However, women experienced less dyspnea when receiving O2 as compared with compressed air (p = 0.0025), and although not statistically significant, the lower dyspnea with O2 corresponded with an increased walk distance of 79 feet.
                O2 administration may be useful for reducing dyspnea during exercise in selected populations. Extreme changes in sodium intake do have an effect on blood pressure of both normotensive and hypertensive individuals. Cross-population correlates of average sodium intake and mean population blood pressure are discordant with the results of studies within single populations and cannot be used as sufficient evidence to justify a reduction of dietary sodium intake in the general population to prevent hypertension. Both explanatory and management trials of sodium restriction have yielded contradictory results, and convincing evidence on the nature and size of subgroups of hypertensives with enhanced sodium sensitivity is lacking. The proportion of patients who will follow a moderately restricted sodium diet is low, unless expensive and time-consuming programs of instruction and monitoring are introduced. In light of this evidence, it is premature to recommend diets that are low in sodium as a public health measure and as initial and sole treatment of hypertension. The gastrointestinal microflora is an important constituent of the gut mucosal defense barrier. We have previously shown that a human intestinal floral strain, Lactobacillus GG (ATCC 53103), promotes local antigen-specific immune responses (particularly in the IgA class), prevents permeability defects, and confers controlled antigen absorption.
                The aim of this study was to evaluate the clinical and immunologic effects of cow's milk elimination without (n = 14) and with (n = 13) the addition of Lactobacillus GG (5 x 10(8) colony-forming units/gm formula) in an extensively hydrolyzed whey formula in infants with atopic eczema and cow's milk allergy. The second part of the study involved 10 breast-fed infants who had atopic eczema and cow's milk allergy. In this group Lactobacillus GG was given to nursing mothers.
                The severity of atopic eczema was assessed by clinical scoring. The concentrations of fecal alpha 1- antitrypsin, tumor necrosis factor-alpha, and eosinophil cationic protein were determined as markers of intestinal inflammation before and after dietary intervention.
                The clinical score of atopic dermatitis improved significantly during the 1-month study period in infants treated with the extensively hydrolyzed whey formula fortified with Lactobacillus GG. The concentration of alpha 1-antitrypsin decreased significantly in this group (p = 0.03) but not in the group receiving the whey formula without Lactobacillus GG (p = 0.68). In parallel, the median (lower quartile to upper quartile) concentration of fecal tumor necrosis factor-alpha decreased significantly in this group, from 709 pg/gm (91 to 1131 pg/gm) to 34 pg/gm (19 to 103 pg/gm) (p = 0.003), but not in those receiving the extensively hydrolyzed whey formula only (p = 0.38). The concentration of fecal eosinophil cationic protein remained unaltered during therapy.
                These results suggest that probiotic bacteria may promote endogenous barrier mechanisms in patients with atopic dermatitis and food allergy, and by alleviating intestinal inflammation, may act as a useful tool in the treatment of food allergy. Some benefits of laparoscopic (LC) and minilaparotomy (MC) cholecystectomy may reflect attenuation of the acute phase response. The authors examined components of this response.
                Patients were randomized to LC (n = 11) or MC (n = 11). C-reactive protein (CRP), alpha-1-antitrypsin (AAT), retinol-binding protein (RBP), transferrin, and albumin were measured preoperatively and on postoperative days 1, 2, 4, and 7. Interleukin-1 receptor antagonist (IL-1ra), IL-6, and tumor necrosis factor (TNF-alpha) were measured more frequently perioperatively. Peak expiratory flow rate, forced expiratory volume in 1 second, and forced vital capacity were measured daily.
                The IL-6 increase was more persistent and marked in the MC patients from hour 8 to day 7 postoperatively (P < 0.05). Alterations in CRP, AAT, and albumin were similar. Postoperative deficits of respiratory function correlated with the magnitude of acute phase protein alteration.
                Minimal access surgery induces an acute phase response that is less prominent after a laparoscopic technique. Procoagulant alterations and thrombocytopenia in falciparum malaria correlate with parasitemia, serum levels of tumor necrosis factor alpha (TNF alpha), and clinical severity. Thus, heparin or acetylsalicylic acid (ASA), which are used frequently to prevent thrombosis and (in the case of ASA) to control fever, could be potentially beneficial. We randomized 97 patients with falciparum malaria into three groups: 33 patients received low-dose heparin subcutaneously, 31 received ASA intravenously, and 33 did not receive either drug. All patients received appropriate antiparasitic treatment. Eighteen of 97 patients (seven receiving heparin, five receiving ASA, and 6 in the control group) had complications upon admission. During therapy, elevated TNF alpha and lactate dehydrogenase levels and decreased platelet counts returned to normal values. Except for a minimal partial thromboplastin time prolongation with heparin, heparin or ASA did not affect any laboratory parameter, duration of parasitemia, fever clearance, or the length of hospitalization. Thus, it appears that ASA and heparin do not influence the course of falciparum malaria. Hence, in view of possible side effects, these substances should not be recommended for routine use in the treatment of human malaria. A study was performed to detect the inhibitory effect of intravenously administered aprotinin (Trasylol) on brain and CSF protease activity in 25 patients with severe head injury. The data presented include measurements of CSF protease activity, alpha-1-antitrypsin, alpha-2-macroglobulin, haptoglobulin, polyacrylamidgel-electrophoresis pattern, total protein and hemoglobin content. The results indicate that increased protease activity is present and that this induces autolytic processes which can be inhibited by aprotinin treatment. The survival rate was higher after aprotinin treatment. Total CSF protein content was significantly higher in nonsurvivors than in survivors. To determine whether an elemental diet or a polymeric defined formula diet would be more effective for treating active Crohn's disease, we conducted a prospective randomised clinical trial in 30 patients with active Crohn's disease unresponsive to steroids and/or complicated by malnutrition. They received a four to six week enteral nutrition course with either an elemental diet or a polymeric diet. Clinical remission occurred in 10 of the 15 patients on elemental diet compared with 11 of the 15 patients assigned to polymeric diet. Both groups showed similar improvements in nutritional status, biological inflammation, alpha 1 antitrypsin clearance, and colonoscopic lesions (diminished in 17 out of 24 patients). Most patients relapsed during the year after discharge. We conclude that enteral nutrition, whatever the diet, is an efficient primary therapy for active Crohn's disease but does not influence the long term outcome. Since infections with Herpetoviridae after kidney transplantation still remain a major clinical problem, we conducted a double-blind, placebo-controlled trial using low-dose recombinant interferon-alpha-2C (rIFNa2C) prophylaxis in 50 renal graft recipients immunosuppressed with cyclosporine and methylprednisolone. Ten patients were excluded from further analysis because of graft loss due to surgical complications, side effects of rIFNa2C, and because of lack of compliance. There was a significant difference in graft loss due to irreversible rejections between the verum and the placebo group (6 vs. 0; P less than 0.05), whereas no difference was observed with regard to the occurrence of viral infections. We conclude, that low-dose rIFNa2C prophylaxis is harmful in renal allograft recipients treated with cyclosporine in view of the high incidence of irreversible transplant rejections without beneficial effects on the occurrence of viral infections.
Augmentation therapy with alpha-1 antitrypsin cannot be recommended, in view of the lack of evidence of clinical benefit and the cost of treatment.