The influence of prosthesis size and design on exercise dynamics after aortic valve replacement.

BACKGROUND AND AIM OF THE STUDY: Residual gradient following aortic valve replacement (AVR) may adversely affect clinical outcome. The size and design of the valve may influence these characteristics. The study aim was to determine the influence of prosthesis physical size and leaflet design on hemodynamic performance after mechanical AVR. METHODS: After AVR, two patient groups with a range of valve sizes were studied. Group 1 patients (n=19) each received a monoleaflet valve; group 2 patients (n=18) each received a bileaflet valve. Transthoracic echocardiography was performed at rest and after graded bicycle ergometry to assess prosthetic valve parameters, including mean and peak transvalvular gradient and effective orifice area (EOA). RESULTS: Transprosthetic gradients (mean and peak) measured at rest, maximum exercise and 3-min recovery were related to indexed geometric orifice area (IGOA) by an exponential decay function, with no significant advantage for either valve design. However, in valve sizes < or =25 mm the bileaflet valves demonstrated lower gradients, both at rest and under exercise conditions (mean gradient during exercise, bileaflet versus monoleaflet 19.9 +/- 7.2 mmHg versus 25.6 +/- 6.3 mmHg, p = 0.01). Similarly, EOAs were larger in the bileaflet group when equivalent GOAs < or =2.5 cm2 were compared (EOA: bileaflet versus monoleaflet 1.51 +/- 0.33 cm2 versus 1.14 +/- 0.26 cm2, p = 0.018). The total work performed correlated with prosthesis diameter (r2 = 0.81, p = 0.037) and was not influenced by valve design. CONCLUSION: The hemodynamic performance of mechanical aortic valves, including transprosthetic gradient and maximum exercise work performed, related principally to the prosthesis physical size. However, within the smaller valve sizes, the bileaflet design appeared to offer hemodynamic advantages.

Insect sting allergy with negative venom skin test responses.

BACKGROUND: In our 1976 controlled venom immuno rapy trial, 33% of 182 patients with a history of systemic reactions to insect stings were excluded because of negative venom skin test responses. There have been reports of patients with negative skin test responses who have had severe reactions to subsequent stings. OBJECTIVE: Our aim is to increase awareness about the patient with a negative skin test response and insect sting allergy and to determine the frequency and significance of negative skin test responses in patients with a history of systemic reactions to insect stings. METHODS: We prospectively examined the prevalence of negative venom skin test responses in patients with a history of systemic reactions to stings. In patients who gave informed consent, we analyzed the outcome of retesting and sting challenge. RESULTS: Of 307 patients with positive histories screened for our sting challenge study, 208 (68%) had positive venom skin test responses (up to 1 microg/mL concentration), and 99 (32%) had negative venom skin test responses. In 36 (36%) of the 99 patients with negative skin test responses, the venom RAST result was a low positive (1-3 ng/mL), or repeat venom skin test responses were positive; another 7 (7%) patients had high venom-specific IgE antibody levels (4-243 ng/mL). Notably, 56 (57%) of 99 patients with positive histories and negative skin test responses had negative RAST results. In patients with positive skin test responses, sting challenges were performed in 141 of 196 patients, with 30 systemic reactions. Sting challenges were performed on 37 of 43 patients with negative skin test responses and positive venom-specific IgE and in 14 of 56 patients with negative skin test responses and negative RAST results. There were 11 patients with negative skin test responses who had systemic reactions to the challenge sting: 2 had negative RAST results, and 9 had positive RAST results at 1 ng/mL. The frequency of systemic reaction was 21% in patients with positive skin test responses and 22% in patients with negative skin test responses (24% in those with positive RAST results and 14% in those with negative RAST results). CONCLUSIONS: Venom skin test responses can be negative in patients who will subsequently experience another systemic sting reaction. Venom skin test responses are negative in many patients with a history of systemic allergic reactions to insect stings and may be associated with positive serologic test responses for venom-specific IgE antibodies (sometimes strongly positive results). Venom skin test responses should be repeated when negative, along with a serologic IgE antivenom test. Better diagnostic skin test reagents are urgently needed.

The efficacy of slow versus faster inhalation of cromolyn sodium in protecting against allergen challenge in patients with asthma.

BACKGROUND: Approximately one third of patients with allergy-induced asthma who are treated with aerosolized cromolyn sodium (CS) fail to achieve a full therapeutic effect. This lack of effectiveness could involve nonhomogeneous distribution of drug in the lung as a result of high inspiratory flow rates. OBJECTIVE: We sought to determine the efficacy of slow versus faster inhalation of CS in protecting against allergen challenge in patients with asthma. METHODS: Eight patients with asthma underwent two allergen challenges 30 minutes after pretreatment with CS that was inhaled from a large holding chamber at approximately 30 L/min or approximately 70 L/min. Percent decreases in FEV1 at a common dose of allergen on the two challenge days were compared. Values of skew (an indicator of aerosol distribution homogeneity) obtained from gamma camera lung images after slow and faster inhalation of radiolabeled CS were also compared. RESULTS: Mean (+/- SD) allergen-induced decrease in FEV1 was 5.4% +/- 4.2% after slow inspiration of CS, which was significantly less than the allergen-induced decrease in FEV1 after faster inhalation of CS with 12.6% +/- 11% (p < 0.05). Mean skew values were also significantly decreased after slow inspiration of CS, and differences in decreases in allergen FEV1 and skew values for the two breathing maneuvers were significantly correlated. CONCLUSION: These data indicate that protection against allergen-induced asthma can be optimized by slowly inspiring CS from a large holding chamber compared with faster inhalation of the drug. These results appear to be related to enhanced distribution homogeneity of CS within the lungs.

Effects of peptide therapy on ex vivo T-cell responses.

BACKGROUND: Peptide therapy targets T cells directly with short peptides containing multiple T-cell receptor epitopes. Murine studies suggest T-cell anergy as the mechanism of action; however, changes in T-cell cytokine profiles may be more relevant in human beings. OBJECTIVE: We sought to study the effects of peptide therapy on ex vivo antigen-specific T-cell responses. METHODS: Antigen-specific T-cell lines were generated from subjects enrolled in a double-blind, placebo controlled, two-dose study of the ALLERVAX CAT therapeutic, containing Fel d 1 peptides (ImmuLogic Pharmaceutical Corp., Waltham, Mass.) (n = 7, 8, and 7, respectively, for groups receiving placebo, 75 microg, or 750 microg). Each subject had three lines propagated before and after receiving peptide therapy; antigens used were cat hair extract, Fel d 1 peptides, and tetanus toxoid (negative control). Proliferative responses and cytokine generation from each line were assessed after two restimulations with antigen and autologous antigen-presenting cells. RESULTS: The Fel d 1 peptide lines showed a dose-dependent decrease of IL-4 production (p = 0.02 and 0.025, respectively, for the 750 microg group vs both the 75 microg and placebo groups). IL-4 production from the cat hair allergen extract lines and interferon-gamma production from both the Fel d 1 peptide lines and cat hair allergen extract lines showed no statistically significant changes. The control tetanus toxoid lines showed no changes in cytokine production; there were no significant changes in proliferation with any of the antigens in any of the treatment groups. In the clinical arm of the trial, only the 750 microg dose of peptides produced a significant response. CONCLUSIONS: Peptide therapy induces a significant, dose-dependent decrease in peptide-stimulated IL-4 production, consistent with either a shift in T-cell phenotype or peptide-specific T-cell tolerance.

A double-blind study of the discontinuation of ragweed immunotherapy.

BACKGROUND: Immunotherapy effectively treats the symptoms of allergic rhinitis and improves its pathophysiology. We studied whether the effects of immunotherapy on the early response to nasal challenge with antigen and seasonal symptoms persist after discontinuation. METHODS: Twenty subjects with ragweed allergy who were receiving immunotherapy and who had nasal challenges performed before initiation of treatment were selected. The patients had been receiving maintenance therapy with aqueous ragweed extract at a dose of 12 microg of Amb a 1 equivalent for a minimum of 3 years, at which point they were randomized to receive either placebo injections or to continue with the maintenance dose. Nasal challenges were performed before and 1 year after randomization. Nasal challenges were monitored by counting the number of sneezes and measuring histamine, N-alpha-tosyl-L-arginine methyl ester-esterase activity, and kinins in recovered nasal lavages. In the same year symptom diaries were collected during the ragweed season. RESULTS: The initial immunotherapy significantly reduced responses to nasal challenge in both groups. The group continuing to receive active treatment showed no significant changes from the response before randomization. In contrast, the group randomized to placebo treatment showed a partial return of histamine, kinins, and N-alpha-tosyl-L-arginine methyl ester-esterase in nasal secretions and the numbers of sneezes. IgG antibodies to ragweed declined only in the group switched to placebo treatment. Seasonal rises of IgE antibodies to ragweed did not return during the first season after treatment was stopped. Symptoms reported during the ragweed season were not different between the groups. CONCLUSIONS: One year after discontinuation of ragweed immunotherapy, nasal challenges showed partial recrudescence of mediator responses even though reports during the season appeared to indicate continued suppression of symptoms.

Clinical and immunologic effects of component peptides in Allervax Cat.

Peptides have been designed to be T cell tolerogenic for the principal allergens of the cat. These have been administered in several dosage programs to cat-sensitive patients in multicenter blinded studies. In contrast to proteins in standard extracts, IgE sensitization to peptides is an uncommon event. Pretreatment prick tests with peptides will identify the occasional sensitized patient. Other side reactions consist of allergic symptoms occurring on the day of injections. These become less severe with subsequent injections and are easily treatable with antihistamines or bronchodilators, depending on the symptoms. Treatment with cat peptides ameliorated symptoms that occur upon exposure to cats 1-6 or more weeks later. A 2-week course of 4 injections is the most effective of the regimens so far tried. T-cell-active peptides offer a promising low-risk alternative for specific treatment of respiratory allergies.

Grass immunotherapy induces inhibition of allergen-specific human peripheral blood mononuclear cell proliferation.

The peripheral blood mononuclear cells (PBMC) from humans allergic to grass pollens (GR+ subjects) show strong in vitro proliferative responses to purified allergens from Lolium perenne pollen Lol p 1, and to a lesser extent to Lol p 2 and Lol p 3. By contrast, PBMC from grass allergic patients undergoing immunotherapy (GR + IT subjects) exhibit a very poor Lol p-specific proliferative response, similar to that observed in nongrass allergic subjects (GR-subjects). Unlike GR-subjects, both GR+ and GR + IT subjects have high levels of antigen-specific serum IgG and IgE antibodies to Lol p 1, Lol p 2 and Lol p 3. While GR+ subjects exhibit a significant correlation between antigen-specific serum antibody and PBMC responses, GR + IT subjects do not show a correlation between the two responses. The possible mechanisms by which immunotherapy may modulate allergen-specific T cell proliferative response are discussed.

Treatment of cat allergy with T-cell reactive peptides.

We induced in allergic humans the counterpart of murine experimental T-cell tolerance. T-cell lines from cat-allergic humans were used to map T-cell epitopes for the principal allergen of cat dander, Fel d 1. Two peptides of 27 amino acids each were synthesized to contain the dominant epitopes (ALLERVAX CAT). After a safety trial, we carried out a blinded study of the dose required for efficacy. We randomly divided 95 cat-sensitive patients into placebo, 7.5 micrograms, 75 micrograms, and 750 micrograms groups. Patients received a subcutaneous injection weekly for 4 wk. Before and after treatment, patients were exposed in a room inhabited by live cats and scored by nose and lung symptoms. Baseline nasal and lung scores (+/-SEM) were 6.2 +/- 0.56 and 5.4 +/- 0.73 in the 750 micrograms group; 7.8 +/- 0.53 and 4.7 +/- 0.68 in the placebo group. Six weeks after treatment, scores adjusted for baseline differences were reduced in the 750 micrograms group: -2.3 +/- 4.9 and -2.3 +/- 0.59 compared with -0.84 +/- 0.50 and -0.85 +/- 0.62 in the placebo group. The 75 micrograms group showed intermediate effects and the 7.5 micrograms group no effect. Linear trend analysis indicated a significant dose response effect: p = 0.05 for nose and 0.03 for lung symptoms. Allergic side effects occurred an hour or more after the first 750 micrograms dose in 16 of 24 patients but required little or no treatment with one exception. T-cell reactive treatment peptides safely improved allergic responses to cats.

Ragweed immunotherapy in adult asthma.

BACKGROUND: Although allergen immunotherapy is effective for allergic rhinitis, its role in treating asthma is unclear. METHODS: We examined the efficacy of immunotherapy for asthma exacerbated by seasonal ragweed exposure. During an observation phase, adults with asthma who were sensitive to ragweed kept daily diaries and recorded peak expiratory flow rates between July and October. Those who reported seasonal asthma symptoms and medication use as well as decreased peak expiratory flow were randomly assigned to receive placebo or ragweed-extract immunotherapy in doses that increased weekly for an additional two years. RESULTS: During the observation phase, the mean (+/- SE) peak expiratory flow rate measured in the morning during the three weeks representing the height of the pollination season was 454 +/- 20 liters per minute in the immunotherapy group and 444 +/- 16 liters per minute in the placebo group. Of the 77 patients who began the treatment phase, 64 completed one year of the study treatment and 53 completed two years. During the two treatment years, the mean peak expiratory flow rate was higher in the immunotherapy group (489 +/- 16 liters per minute, vs. 453 +/- 17 in the placebo group [P = 0.06] during the first year, and 480 +/- 12 liters per minute, vs. 461 +/- 13 in the placebo group [P = 0.03] during the second). Medication use was higher in the immunotherapy group than in the placebo group during observation and lower during the first treatment year (P = 0.01) but did not differ in the two groups during the second year (P = 0.7). Asthma-symptom scores were similar in the two groups (P = 0.08 in year 1 and P = 0.3 in year 2). The immunotherapy group had reduced hay-fever symptoms, skin-test sensitivity to ragweed, and sensitivity to bronchial challenges and increased IgG antibodies to ragweed as compared with the placebo group; there was no longer a seasonal increase in IgE antibodies to ragweed allergen in the immunotherapy group after two years of treatment. Reduced medication costs were counterbalanced by the costs of immunotherapy. CONCLUSIONS: Although immunotherapy for adults with asthma exacerbated by seasonal ragweed exposure had positive effects on objective measures of asthma and allergy, the clinical effects were limited and many were not sustained for two years.