Effects of omalizumab treatment on serum cytokine concentrations of atopic patients with chronic spontaneous urticaria: a preliminary report.

SUMMARY: Omalizumab has recently obtained indication for chronic spontaneous urticaria both in the US and Europe. However, the mechanism of action of this drug has yet to be fully elucidated. Previous studies have shown elevations in cytokine serum levels in patients with chronic spontaneous urticaria, and it is not known whether omalizumab treatment may affect cytokine serum levels in this condition. Besides, a proportion of chronic spontaneous urticaria patients have concomitant atopy, which may be associated, at least in theory, with prevalence of serum Th2-type cytokines. In this study, serial serum samples from five patients (4 atopic and 1 nonatopic) with chronic spontaneous urticaria were assayed for cytokine concentrations by means of flow-cytometry-based multiplex bead assays, before and during omalizumab treatment. Omalizumab appeared to significantly affect the concentrations of multiple cytokines in a case of severe, long-lasting chronic spontaneous urticaria. Interestingly, IL-22 serum levels were found to progressively increase in three of five patients. Further studies are thus needed in larger patient populations, to conclusively establish whether the mechanism of action of omalizumab in chronic spontaneous urticaria also includes modulation of cytokine synthesis.

Pre-discharge stress echocardiography and exercise ECG for risk stratification after uncomplicated acute myocardial infarction: results of the COSTAMI-II (cost of strategies after myocardial infarction) trial.

OBJECTIVE: To compare in a prospective, randomised, multicentre trial the relative merits of pre-discharge exercise ECG and early pharmacological stress echocardiography concerning risk stratification and costs of treating patients with uncomplicated acute myocardial infarction. DESIGN: 262 patients from six participating centres with a recent uncomplicated myocardial infarction were randomly assigned to early (day 3-5) pharmacological stress echocardiography (n = 132) or conventional pre-discharge (day 7-9) maximum symptom limited exercise ECG (n = 130). RESULTS: No complication occurred during either stress echocardiography or exercise ECG. At one year follow up there were 26 events (1 death, 5 non-fatal reinfarctions, 20 patients with unstable angina requiring hospitalisation) in patients randomly assigned to early stress echocardiography and 18 events (2 reinfarctions, 16 unstable angina requiring hospitalisation) in the group randomly assigned to exercise ECG (not significant). The negative predictive value was 92% for stress echocardiography and 88% for exercise ECG (not significant). Total costs of the two strategies were similar (not significant). CONCLUSION: Early pharmacological stress echocardiography and conventional pre-discharge symptom limited exercise ECG have similar clinical outcome and costs after uncomplicated infarction. Early pharmacological stress echocardiography should be considered a valid alternative even for patients with interpretable baseline ECG who can exercise.

Impairment of coronary circulation by acute hyperhomocysteinaemia and reversal by antioxidant vitamins.

OBJECTIVE: To evaluate the effect of acute hyperhomocysteinaemia with and without antioxidant vitamins pretreatment on coronary circulation and circulating chemokine levels. DESIGN: Observer-blinded, randomized crossover study. SETTING: This study was conducted at a university hospital and at a general hospital in Italy. SUBJECTS: Sixteen healthy hospital staff volunteers (nine men, seven women), aged 26-40 years. INTERVENTIONS: Subjects were given each three loads in random order at 1-week intervals: oral methionine, 100 mg kg(-1) in fruit juice; the same methionine load immediately following ingestion of antioxidant vitamin E, 800 IU, and ascorbic acid, 1000 mg; and methionine-free fruit juice (placebo). MAIN OUTCOME MEASURES: Coronary flow velocity reserve (CFVR), assessed by noninvasive transthoracic Doppler echocardiography, blood pressure, heart rate, lipid and glucose, monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) parameters evaluated at baseline and 4 h following ingestion of the loads. RESULTS: The oral methionine load increased plasma homocysteine from 12.8 +/- 1.8 to 33.3 +/- 3.4 micromol L(-1) at 4 h (P < 0.001). A similar increase was observed with same load plus vitamins (P < 0.001) but not with placebo (P = 0.14). Circulating MCP-1 and IL-8 levels rose after the methionine load (P < 0.001), but not after placebo or methionine plus vitamins. The methionine load significantly reduced CFVR (decrease, 26 +/- 8.2%; P < 0.001). The methionine load with ingestion of vitamins partially prevented the impairment of CFVR (decrease, 11 +/- 4%; P < 0.001). CONCLUSION: Our data suggest that acute hyperhomocysteinaemia reduces CFVR and increases plasma MCP-1 and IL-8 levels in healthy subjects. Pretreatment with antioxidant vitamin E and ascorbic acid prevents the effects of hyperhomocysteinaemia, suggesting an oxidative mechanism.

Cigarette smoking and appendectomy are risk factors for extraintestinal manifestations in ulcerative colitis.

OBJECTIVE: Two common factors, cigarette smoking and appendectomy, have been found to play a role in ulcerative colitis (UC). Data on their role in the development of extraintestinal manifestations (EIM) are scarce. METHODS: The relationship between cigarette smoking, appendectomy, and EIM was examined in a prospective study involving 535 (M/F = 319/216) consecutive UC patients followed up for 18 yr. We considered the major EIM: seronegative spondyloarthropathy, pyoderma gangrenosum/erythema nodosum, acute anterior uveitis, and primary sclerosing cholangitis. We excluded patients with a history of EIM or those colectomized before study entry, ex-smokers, and those who started to smoke during the course of UC. RESULTS: In UC patients, seronegative spondyloarthropathy and dermatologic complications were found increased in smokers (p < 0.0001; p = 0.001) or in subjects with appendectomy (p = 0.0003; p = 0.02), while acute anterior uveitis and primary sclerosing cholangitis did not differ. The Kaplan-Meier analysis showed 18-yr rates for EIM of 71% in smokers and 45% in nonsmokers (log-rank test, p = 0.0001), and of 85% in patients with appendectomy and 48% in those without (p = 0.0001). Cox proportional-hazard model showed that cigarette smoking and appendectomy are independent factors promoting EIM. In smokers with appendectomy the adjusted hazard ratio (3.197, 95% CI 1.529-6.684) was higher than in patients with appendectomy alone (2.617, 95% CI 1.542-4.442) or smoking alone (1.947, 95% CI 1.317-2.879). CONCLUSIONS: In UC patients, appendectomy and cigarette smoking are prognostic factors for the development of EIM. The unfavorable effect of cigarette smoking on EIM is additive to that of appendectomy.

Ulcerative colitis, seronegative spondyloarthropathies and allergic diseases: the search for a link.

BACKGROUND: Allergic diseases and seronegative spondyloarthropathies are frequently observed in ulcerative colitis (UC). In this report we have investigated possible relationships between IgE-mediated allergic disease (AD), allergic contact dermatitis (ACD) and seronegative spondyloarthropathy (SpA) in UC patients at different grades and extensions of mucosa inflammation. METHODS: Forty-five UC consecutive outpatients were graded according to clinical, endoscopic and histologic activity scores. SpA was diagnosed according to the European Spondyloarthropathy Study Group criteria. AD was detected by skin prick tests and confirmed by specific provocation tests, while ACD was diagnosed using the European standard series of patch tests. Thirty-seven patients' spouses or partners served as controls. RESULTS: Fourteen patients and 1 control subject showed SpA (P = 0.001). Diagnosis of rhinitis, conjunctivitis or asthma was made in 19 patients and in 5 controls (P = 0.004), while ACD was found in 10 and in 4 (P = 0.17), respectively. In UC, AD coexisted with SpA in 2 cases (P = 0.01), AD with ACD in 1 case (P = 0.03) and ACD with SpA in 5 (P = 0.24). CONCLUSIONS: Notwithstanding the high frequency of AD and SpA found in UC, the concurrence of AD with SpA or ACD is an unusual finding, while SpA and ACD may coexist. These data suggest that, in UC, atopy and seronegative arthritis, as well as atopy and delayed-type allergy, are strongly polarized conditions tending to mutual exclusion. In UC, the presence of AD without SpA or ACD, and of SpA or ACD without AD may indicate subgroups of patients in which T-helper-2 cell or T-helper-1 cell responses predominate.

Relationship between total and allergen-specific IgE serum levels and presence of symptoms in farm workers sensitized to Tetranychus urticae.

BACKGROUND: Clinical complaints in atopic subjects with asthma and rhinitis occur more frequently in the presence of high total and allergen-specific IgE serum levels. Here we report on the relationship between total and allergen-specific IgE serum levels and presence of symptoms in an unselected farmer population sensitized to Tetranychus urticae (TU). METHODS: Farmers were recruited as previously described. Total IgE and allergen-specific IgE were measured by immunoassay in TU-positive skin prick test (SPT) farmers (n = 58) and two control groups including Dermatophagoides pteronyssinus (Dp)-positive SPT subjects (n = 40) and non-atopic, TU-negative SPT healthy farmers (n = 25). RESULTS: Both TU+ and Dp+ subjects had significantly higher total IgE values (P < 0.001) than healthy non-atopic subjects. TU-specific IgE levels were significantly more elevated in symptomatic than non-symptomatic TU+ subjects (P = 0.028). Dp-specific IgE levels were higher in symptomatic than non-symptomatic Dp+ subjects (P = 0.003). Finally, total IgE levels were significantly higher in the symptomatic than non-symptomatic subgroups in both TU+ and Dp+ subjects (P < 0.0001 and P = 0.007, respectively). Logistic regression analysis showed that only total IgE concentrations were significant predictors of current symptoms in TU+ subjects. CONCLUSIONS: High total IgE and allergen-specific IgE levels are associated with symptoms in TU+ subjects. Definition of their predictive value requires further studies.

Epidemiology of allergic occupational diseases induced by Tetranychus urticae in greenhouse and open-field farmers living in a temperate climate area.

BACKGROUND: The role of Tetranychus urticae (TU) as an occupational allergen has thus far been investigated only in selected farmer samples. METHODS: The prevalence of TU-induced sensitization and occupational diseases in a randomized sample of farmers living in a temperate climate area was investigated. Occupational/nonoccupational symptoms, skin prick test (SPT) results with common allergens and TU, specific occupational test results, and greenhouse or open-field sources of TU exposure were assessed. The study design was cross-sectional. RESULTS: The prevalence of positive SPT to TU was 6%. TU-induced allergic/nonallergic complaints accounted for 65% of farmers with challenge-confirmed occupational disease. In all farmers, sensitization to common allergens was a risk factor for both current occupational and nonoccupational complaints, while TU sensitization was a prominent risk factor for occupational complaints. Furthermore, in SPT-positive farmers, only the presence of seasonal occupational complaints was significantly associated with TU sensitization. Common allergen sensitization was a risk factor for development of TU sensitization, which was more frequent in greenhouse than in open-field workers. CONCLUSIONS: TU was a common nontraumatic, allergic occupational hazard for farmers. Since occupational seasonal symptoms could be directly related to the presence of TU sensitization, allergy to this mite should be routinely investigated in farmers.

Long-term absence of sensitization to mepivacaine as assessed by a diagnostic protocol including patch testing.

BACKGROUND: Prospective assessment of non-reactivity to local anaesthetics is a frequent reason for allergy consultation. OBJECTIVES: To investigate the clinical profiles of subjects referred for allergy evaluation; to prospectively reduce the frequency of evaluation by assessing the persistence, during clinical use, of non-reactivity to contaminant/additive-free mepivacaine; and to determine the usefulness of a diagnostic protocol involving patch testing. METHODS: In a prospective study, 198 consecutive patients underwent collection of clinical data, skin prick tests and patch tests using allergens/antigens relevant for the investigation, and an intradermal/subcutaneous challenge procedure using contaminant/additive-free mepivacaine, as appropriate. Patients were followed up for 3 years for assessment of non-reactivity persistence using the same diagnostic protocol. RESULTS: Only one-third of the patients had a history of previous adverse local anaesthetic reactions. Absence of sensitization to contaminant/additive-free mepivacaine persisted in all subjects completing the follow-up. Controlled challenge with mepivacaine was negative in 196 patients with both negative specific skin prick tests and patch tests but it was eventful in two subjects with positive specific patch tests. A few subjects displayed positive skin prick tests and/or patch tests for latex and/or additives. CONCLUSIONS: A few patients had a relevant history for potential local anaesthetic-induced adverse reactions. Upon assessment of absence of sensitization and reactivity, contaminant/additive-free mepivacaine could safely be given for as long as 3 years. The patch testing was shown to be useful and safe for prediction of challenge outcomes. True allergic reactions to contaminant/additive-free mepivacaine were not observed in our patient series.

Response to flecainide infusion predicts long-term success of hybrid pharmacologic and ablation therapy in patients with atrial fibrillation.

OBJECTIVES: We tested the hypothesis that the response to flecainide infusion can identify patients with atrial fibrillation (AF) in whom the hybrid pharmacologic and ablation therapy reduces the recurrences of AF. BACKGROUND: Infusion of class IC anti-arrhythmic drugs may promote transformation of AF into atrial flutter. Catheter ablation of atrial flutter has been demonstrated to be highly effective in preventing recurrences of atrial flutter. METHODS: Seventy-one consecutive patients with paroxysmal or chronic AF, in whom flecainide infusion (2 mg/kg body weight, intravenously) determined the transformation of AF into common atrial flutter (positive response), were randomized to receive one of the following treatments: oral pharmacologic treatment with flecainide (group A, n = 23); the hybrid treatment (catheter ablation of the inferior vena cava-tricuspid annulus isthmus, plus oral flecainide) (group B, n = 24); or catheter ablation of the isthmus only (group C, n = 24). Thirty-seven patients with a negative response to flecainide, who chose to be submitted to the hybrid treatment, were selected as the control group (group D). RESULTS: During a mean follow-up period of 24 +/- 7.2 months, the recurrences of AF and atrial flutter in group B (42%) were significantly lower than those in group A (78%, p < 0.001), group C (92%, p < 0.001) and group D (92%, p < 0.001). CONCLUSIONS: The creation of a complete bi-directional conduction block at the inferior vena cava-tricuspid annulus isthmus, plus flecainide administration, reduces the recurrences of both AF and atrial flutter in patients with class IC atrial flutter. Moreover, the early response to flecainide is safe and reliable in identifying patients who may benefit from this therapy.

Long-term prognostic value of dipyridamole and dobutamine stress echocardiography in patients with known or suspected coronary artery disease.

BACKGROUND: Pharmacological stress echocardiography (PSE) is increasingly used for cardiac risk stratification. Our study was undertaken to assess the long-term prognostic significance of PSE in patients with known or suspected coronary artery disease. METHODS: We studied 622 consecutive patients who underwent PSE with either dobutamine or dipyridamole. Outcome was finally assessed in 448 patients for a mean period of 32.9 months. Death and hard events (death and myocardial infarction) were considered as endpoints. RESULTS: PSE was positive for ischemia in 192 patients (42.9%). During the follow-up, 53 hard events occurred, including 28 deaths and 25 acute non-fatal myocardial infarctions. With multivariate analysis, peak ejection fraction < 40% appeared to be the strongest predictor of cardiac-related deaths and of hard endpoints (chi2 28.4 and 32.0, respectively). Peak wall motion score index revealed a strong predictive value of the same events (chi2 8.6 and 16.3, respectively). An ischemic pattern at PSE predicted a 2.4 higher cardiac mortality rate over a 5-year follow-up (9.4 vs 3.9%, p < 0.01; log rank 5.68), while patients with a peak ejection fraction < 40% had a cardiac-related mortality 4 times higher (16.3 vs 4.1%, p < 0.00001; log rank 21.16). Hard events occurred in 6.7% of patients with a negative test vs 18.8% of patients with a positive test (p < 0.001; log rank 15.8), while hard event rate was 8.4% in patients with a peak ejection fraction > 40% vs 27.5% in patients with a peak ejection fraction < 40% (p < 0.00001; log rank 38.64). CONCLUSIONS: The ischemic response to PSE showed a sustained prognostic value for cardiac events, especially in patients considered at either intermediate or high risk on the basis of recognized clinical risk factors. However, only the evaluation of both descriptors of global left ventricular performance and of the extension of induced ischemia may better help to select patients at higher risk of cardiac death.

Dipyridamole-atropine stress echocardiography versus exercise SPECT scintigraphy for detection of coronary artery disease in hypertensives with positive exercise test.

OBJECTIVES: Many different stress echocardiographic and radionuclide perfusion imaging tests have been proposed for detecting epicardial coronary artery disease (CAD) in hypertensive patients. Their relative diagnostic and prognostic value has not been exactly established. BACKGROUND: A positive exercise electrocardiography test has a low diagnostic specificity in hypertensive patients and warrants for a complementary imaging test to confirm the diagnosis of coronary artery disease. METHODS: Hypertensive patients (n = 53), (29 males, aged 58 +/- 10 years) with normal left ventricular function detected by echocardiography and previous positive exercise test ( > or = 0.15 mV of ST segment depression on 12 lead electrocardiogram) underwent dipyridamole-atropine stress echocardiography (DASE) and thallium-201 stress/ rest myocardial single-photon emission computed tomography (SPECT). All patients had coronary angiography within 15 days and independently of imaging test results. RESULTS: Coronary angiogram showed significant ( > or = 50% qualitatively assessed diameter reduction) epicardial coronary artery disease in 23 (43%) patients. Sensitivity for detection of coronary artery disease was significantly higher for scintigraphy (DASE = 78% versus SPECT = 100%, P < 0.05) while specificity was higher for echo (DASE = 100% versus SPECT = 47%, P < 0.00001). Diagnostic accuracy was also higher for echo (DASE = 91% versus SPECT = 70%, P < 0.01). CONCLUSION: In patients with exercise-nduced ST segment depression, dipyridamole stress echo and SPECT perfusion scintigraphy are both good diagnostic options, with DASE characterized by higher specificity, lower sensitivity, and at least comparable diagnostic accuracy than SPECT.

Gastroesophageal reflux disease and asthma: an intriguing dilemma.

BACKGROUND: Gastroesophageal reflux disease (GORD) is characterized by typical reflux symptoms and multiple atypical extraesophageal symptoms. Gastric asthma is a prominent extraesophageal manifestation of GORD. There is persistent debate about the pathophysiologic mechanisms triggering asthma by GOR. METHODS: We conducted a review of the literature. RESULTS: The pathogenic mechanism could be either a vagally transmitted reflex or an intratracheal aspiration of refluxed material. In both hypotheses, the role of inflammatory mediators has been proposed. CONCLUSIONS: Neurogenic inflammation is a good theoretic basis for a pathogenic interpretation of the disorder. In atopic patients, food allergy has been recently proposed as a possible cause of GOR and associated respiratory symptoms, and it should be considered in the diagnostic work-up of all patients with GORD.

Allergy and mucosal eosinophil infiltrate in ulcerative colitis.

BACKGROUND: Data on allergy in ulcerative colitis (UC) have led to conflicting conclusions without proving any causal association. In this report we have investigated the presence of allergy and its possible relation with chronic colonic inflammation in patients with UC. METHODS: Fifty UC patients underwent clinical, endoscopic, and histologic evaluations. The allergologic study included family/personal history; prick/patch exposition to airborne, food, and contact allergens; total serum IgE; and quantification of eosinophils in peripheral blood and intestinal mucosa. Diagnosis of rhinitis, conjunctivitis, and asthma was confirmed by specific provocation tests. Fifty healthy subjects were studied as control group. RESULTS: A higher prevalence of allergic symptoms was found in patients (56%) and their first-degree relatives (52%) than in controls (18% and 26%) (P < 0.0001; P = 0.008). In patients skin tests showed increased rates of immediate (54%) and delayed-type (20%) hypersensitivity compared with controls (30% and 6%) (P= 0.01; P= 0.03). Diagnosis of allergic IgE-mediated disease was made in 19 cases and 6 controls (P= 0.01), and allergic contact dermatitis in 10 and 3, respectively (P= 0.03). IgE levels were higher in UC patients than in controls (P=0.02). No dose-response relationship was found between degree of colonic tissue eosinophilia and clinical. endoscopic, and histologic disease severity. The degree of colonic tissue eosinophilia was higher in the presence of skin reactivity to food allergens. CONCLUSIONS: UC patients frequently show several markers of allergy. In particular, our data suggest an association between ulcerative colitis, tissue eosinophilia, and type-I allergy.

[The echo-stress test with dipyridamole-atropine on the 3rd-5th day of an uncomplicated acute myocardial infarct for risk stratification and early discharge]. / Eco-stress con dipiridamolo-atropina in terza-quinta giornata nell'infarto miocardico acuto non complicato per la stratificazione del rischio e la dimissione precoce.

BACKGROUND: The aim of this study was to evaluate if dipyridamole-atropine stress echocardiography (DASE) performed between the third-fifth day in uncomplicated acute myocardial infarction allows for an effective risk stratification with an early discharge in some cases. METHODS: Between February 1997 and September 1998, 190 patients (138 males and 52 females, mean age 59 +/- 10.3 years), with acute myocardial infarction, were enrolled in the study. DASE was performed between the third-fifth day with a dipyridamole infusion of 0.84 mg/kg over 10 min followed by 1 mg of atropine from the twelfth to the fifteenth minute. DASE was considered positive in the presence of a new or worsening dyssynergy. Patients with heart failure, angina, major arrhythmias, and poor acoustic window were excluded. In the follow-up spontaneous events were defined as cardiac death, non-fatal myocardial reinfarction, unstable angina or heart failure (with hospitalization). RESULTS: DASE was performed in 92 patients (48.4%), all without complications: 29 patients (31.5%) had a negative DASE result, and 63 patients (68.5%) had a positive DASE. The average hospital stay of patients with a negative test was significantly lower in comparison with that of patients with a positive test (7.55 +/- 1.32 vs 9.29 +/- 1.61 days, p < 0.0001). Events occurred in 19 patients (20.6%), 2/29 patients with a negative DASE (6.9%), 17/63 patients with a positive DASE (27%), 6/43 patients with homozonal positivity after atropine or high-dose dipyridamole (14%), 11/20 patients with heterozonal positivity or homozonal positivity after low-dose dipyridamole (55%). On univariate analysis the variables significantly associated with spontaneous events were: age (chi 2 = 6.41, p = 0.019), left ventricular ejection fraction at rest (chi 2 = 8.89, p = 0.004), number of asynergic segments after stress (chi 2 = 6.87, p = 0.010), increase in the number of asynergic segments after stress (chi 2 = 4.01, p = 0.039), wall motion score index after stress (chi 2 = 9.60, p = 0.003), increase in wall motion score index after stress (chi 2 = 3.60, p = 0.049), DASE positivity (chi 2 = 4.89, p = 0.029), homozonal positivity after low-dose dipyridamole (chi 2 = 8.57, p = 0.013), heterozonal positivity (chi 2 = 13.10, p = 0.001). On Cox's multivariate analysis independent predictors of events were: age (relative risk 3.92, p = 0.0146), DASE positivity (relative risk 1.79, p = 0.0054). CONCLUSIONS: DASE between the third-fifth day in uncomplicated acute myocardial infarction is feasible, tolerable, safe, and effective for early risk stratification. A negative DASE detects a "very low-risk" patient group, and allows for an earlier hospital discharge, without an increased risk of events. The heterozonal positivity or the homozonal positivity after low-dose dipyridamole indicates the need for a coronarography, due to the high risk of events at follow-up.

Microscopic inflammatory changes in colon of patients with both active psoriasis and psoriatic arthritis without bowel symptoms.

OBJECTIVE: To evaluate colonic mucosa of patients with both active psoriasis and psoriatic arthritis (PsA) without bowel symptoms. METHODS: Fifteen persons (9 men, 6 women) who had both active psoriasis and PsA without bowel symptoms underwent colonoscopy with multiple biopsies of bowel mucosa. Ten nonhospitalized healthy subjects in followup colonoscopy after resection of benign polyps (8 men, 2 women) took part as a control group. RESULTS: Six psoriatic patients (40%) showed macroscopically normal colonic mucosa. In the remaining 9 reddening was frequently recorded (6 cases). while edema and granular changes appeared less commonly (3 cases each, respectively). Friability was markedly rare (only one case) and bleeding and ulcerations were absent. All 15 patients showed microscopic changes. Increase in lamina propria cellularity (consisting of plasma cells and lymphocytes) and lymphoid aggregates were found in all cases. Active inflammation, evident as neutrophilic polymorph infiltration occurred in 9 patients. Glandular atrophy was found in 3 cases; mucosal surface changes and crypt abnormalities occurred in one case each. No control had macroscopic or microscopic inflammatory changes of bowel mucosa. CONCLUSION: Bowel mucosa of patients with PsA without bowel symptoms show microscopic lesions even when mucosa appeared macroscopically normal. This result may support a pathogenetic link between skin, joints, and gut in psoriatic patients with arthritis even in the absence of bowel symptoms.