Pierre-Michel Bédard

Allergic rhinitis to ragweed pollen: II. Modulation of histamine-releasing factor production by specific immunotherapy

A number of cytokines, including histamine-releasing factors (HRFs), have a role to play in IgE-mediated asthma. However, the influence of HRF in allergic rhinitis without asthma remains to be revealed. This article presents a double-blind, placebo-controlled study on the role of HRF in ragweed-allergic rhinitis and its modulation by natural pollen exposure and specific immunotherapy (IT). Twenty-seven patients allergic to ragweed were randomly assigned to receive either preseasonal alum-precipitated aqueous extracts of ragweed or placebo. Before the onset of therapy and during the ragweed-pollen season, subjects were evaluated for each of the following: clinical scores, ragweed IgE and IgG antibody levels, and spontaneous and allergen-driven HRF production. Thirteen nonatopic volunteers were also studied in the same protocol. First, before the initiation of therapy, more HRF was produced by both unstimulated and ragweed-stimulated mononuclear cells (MNCs) of atopic subjects as compared to MNCs of nonatopic subjects. Second, MNCs of the placebo-treated group produced significantly more spontaneous and ragweed-specific HRF during the pollen season compared to the preseasonal values. Finally, specific IT not only improved the clinical manifestation of allergy but also prevented the seasonal rise of spontaneous and ragweed-driven HRF production, along with a well-known change in other immunologic parameters associated with successful IT.

Increased compound 48/80 induced local histamine release from nonlesional skin of patients with chronic urticaria

Histamine released from skin mast cells in normal skin sites of patients with idiopathic chronic urticaria (CU) and normal volunteers was assessed with the skin chamber technique. Small amounts of histamine were spontaneously and continuously released during the 4-hour observation in both groups but were twofold greater in patients with CU. In addition, histamine levels were significantly more elevated in sites challenged with compound 48/80 than in unstimulated sites. Patients with CU differed from normal volunteers in that histamine release induced by 48/80 compound was significantly greater at 1 and 2 hours after challenge. The number of mast cells and the histamine content of the skin did not differ in the two groups. These observations could suggest a functional defect at the mast cell level rather than a difference in their numbers.

Efficacy and safety of loratadine (10 mg once daily), terfenadine (60 mg twice daily), and placebo in the treatment of seasonal allergic rhinitis

A total of 317 patients received loratadine, 10 mg once daily, terfenadine 60 mg twice daily, or placebo in a 14-day, double-blind, randomized study in seasonal allergic rhinitis. Four nasal and four nonnasal symptoms were evaluated. At the end point evaluation, mean total scores of combined nasal and nonnasal symptoms decreased from baseline (improved) 46%, 44%, and 35%, respectively, for loratadine, terfenadine, and placebo. The difference between loratadine and placebo treatment was significant (p = 0.03). Loratadine was particularly effective compared with placebo in relieving nasal discharge, sneezing, and itching/burning eyes. Therapeutic response to treatment was good or excellent in 66 (64%) of 103 loratadine-treated patients, 58 (56%) of 104 terfenadine-treated patients, and 48 (47%) of 102 placebo-treated patients. Adverse experiences reported during the study were usually mild or moderate and were not significantly different among the three treatment groups. Sedation (somnolence) was reported by 10 loratadine-treated patients, seven terfenadine-treated patients, and eight placebo-treated patients. Loratadine, 10 mg once daily, was comparable to terfenadine, 60 mg twice daily, and significantly superior to placebo in the symptomatic relief of seasonal allergic rhinitis.

Allergic rhinitis to ragweed pollen: I. Reassessment of the effects of immunotherapy on cellular and humoral responses

This work presents a double-blind, placebo-controlled study of 27 patients with allergic rhinitis to ragweed who received preseasonal desensitization immunotherapy [IT] with alum-precipitated aqueous ragweed extracts. We reassessed the following parameters in relation to clinical responses: clinical scores, nasal reactivity to a provocative dose of ragweed causing a 75% fall in airflow rate (PD75), ragweed IgE and IgG, and ragweed-induced basophil histamine release (BHR). First, the nasal PD75 correlated with the severity of nasal symptoms (p less than 0.05). Second, we confirmed a significant symptomatic improvement in the IT-treated group either by clinical scores (p less than 0.05) or the prevention of the seasonal fall of the PD75 (p less than 0.005). Also, IT reduced the seasonal rise of IgE (p less than 0.02) and induced an increase in IgG (p less than 0.01) and a decrease in BHR (p less than 0.03). There was a significant correlation between IgE and BHR (r = 0.80; p less than 0.01). After selecting out the effects of IgE, the BHR was still higher in the placebo-treated group than in the IT-treated group (p less than 0.02), suggesting the involvement of other modulating factors. Symptomatic improvement after IT correlated only with the summation of both IgE and BHR (PD75; r = 0.64; p less than 0.005). This observation suggests that the severity of clinical symptoms is determined by several interacting factors and not by the antibody response alone.

Chronic idiopathic urticaria: Profiles of skin mast cell histamine release during active disease and remission

Chronic idiopathic urticaria (CIU) is characterized by the increased releasability of histamine by mast cells in normal-appearing skin. In active CIU, this abnormality is consistently present. To determine if this finding subsides when the disease goes into remission phase, we analyzed the histamine secretion in patients with CIU in remission (CIUR) compared with that of patients with CIU and in normal control (NC) subjects, with the skin-chamber technique. The profiles of histamine release in sites challenged with compound 48/80 were significantly different in the groups with CIU and CIUR. Furthermore, patients with CIUR did not differ from NC subjects in terms of histamine releasability under compound 48/80 stimulation (p greater than 0.1). These data suggest that the state of excessive skin mast cell sensitivity is a reversible and transient phenomenon in CIU disease.

Chronic idiopathic urticaria: Possible contribution of histamine-releasing factor to pathogenesis

BACKGROUND Histamine-releasing factor was recently shown to be clinically relevant in allergic rhinitis and asthma. HRF could also be involved in the pathogenicity of chronic idiopathic urticaria (CU). The purpose of this study was to investigate the role of HRF in the pathophysiology of CU. METHODS Blisters were induced on lesional and nonlesional skin of 12 patients with CU and on normal skin of five control subjects. HRF activity and histamine content were measured in all samples recovered from each skin site. RESULTS Significantly more HRF was found in blister fluids from lesional skin of patients with CU as compared with nonlesional skin and skin of control subjects. In addition, histamine content in blister fluids from affected skin of patients with CU was significantly higher in comparison with both nonlesional skin of patients with CU and skin of control subjects. HRF activity was also higher in blister fluids from nonlesional skin of patients with CU than that of control subjects, in spite of equivalent histamine content. CONCLUSION These data suggest that the inflammatory reaction found in CU disease is associated with the cutaneous release of HRF.

Comparison of the efficacy and safety of loratadine, terfenadine, and placebo in the treatment of seasonal allergic rhinitis

The efficacy and safety of loratadine, 40 mg once daily, were compared with terfenadine, 60 mg twice daily, and placebo in controlling symptoms of ragweed hay fever. The study was a randomized, multicentric, parallel-group, double-blind design involving 280 patients divided into three groups receiving either loratadine, terfenadine, or placebo for a period of 14 days in the autumn of 1984. Both loratadine and terfenadine demonstrated a statistically greater reduction in symptom score compared to placebo. They were not statistically different from each other, and there was no statistical difference in the incidence of side effects between the two drugs.

Effects of H1-antihistamine drug regimen on histamine release by nonlesional skin mast cells of patients with chronic urticaria

Profiles of compound 48/80-induced histamine release (HR) from mast cells of uninvolved skin from patients with chronic urticaria (CU) and from a normal control (NC) group were compared, and the effects of anti-H1 medications were assessed versus placebo. Then, patients with CU (15) and NC subjects (10) were randomly assigned to take either hydroxyzine (100 mg/day), terfenadine (120 mg/day), or placebo for 28 days. The effects of such treatment on the clinical response and on the profile of compound 48/80-induced HR during a 4-hour period were analyzed. Treatment with hydroxyzine in patients with CU improved the clinical symptoms and modified the profile of HR; more histamine was recovered at 1 hour (p less than 0.05) and 2 hours (p less than 0.05), as compared with baseline. Terfenadine and placebo had no effect on the clinical response or on the profiles of HR. In the NC group, the amounts of histamine recovered at 1 hour after challenge with compound 48/80 were lower than amounts of the pretherapy values (p less than 0.01). It could be concluded that (1) the profile of HR in patients with CU is reproducible during a period of 28 days, (2) only hydroxyzine modifies both the clinical response and the profile of HR, and (3) anti-H1 compounds decrease the HR in the NC group.

Analysis of compound 48 80 -induced skin histamine release and leukotriene production in chronic urticaria

Profiles of histamine release by nonlesional skin mast cells from patients with chronic urticaria (CU) and normal control (NC) subjects were compared on stimulation with a wide range of concentrations of compound 48/80 (0.15 to 4.8 mg/ml). One previous observation demonstrating spontaneous and 48/80-induced release of histamine greater in patients with CU than in NC subjects was confirmed with a concentration of 48/80 believed to produce mast cell activation in most subjects (2.4 mg/ml). In fact, higher concentrations of histamine were released by patients with CU than by NC subjects on stimulation with 48/80 at concentration greater than 0.6 mg/ml. With 0.6 mg/ml of 48/80, the profiles of histamine release were comparable in the two groups, and for concentration less than 0.6 mg/ml, the profiles of release were completely different, being higher in NC subjects than in the group with CU. The peak histamine response was higher in the group of NC subjects (6500 pg/ml) than in the group with CU (5100 pg/ml), and the concentration of 48/80 needed to trigger maximum release was lower in the NC subjects than in the subjects with CU (0.15 versus 0.6 mg/ml). The production of leukotriene B4 and leukotriene C4 was also compared in these two groups after stimulation with 2.4 mg/ml of compound 48/80. No significant amount of leukotriene B4 was found in the collection chambers, but small amounts of leukotriene C4 were measured into skin chamber fluids during a period of 4 hours. No significant difference could then be observed between the two groups.

Recurrent acute epiglottitis in adults: defective antibody response

BACKGROUND Recurrent acute epiglottitis is uncommon in adults. In the medical literature, very little is known about the immune status of this population. OBJECTIVE To evaluate the immune system of a group of four adult patients with recurrent acute epiglottitis, in what represents the largest series ever reported. METHODS The clinical course of these episodes was carefully evaluated and a basic immune deficiency work-up was carried out for each patient. RESULTS All four patients displayed clinical and laboratory evidence of impaired humoral immunity. One patient was splenectomized. Another patient had a below normal immunoglobulin G level. At the time of their first evaluation, none of our patients had specific antibodies against Haemophilus influenzae and one had a subnormal Streptococcus pneumoniae immunoglobulin G level for a majority of serotypes. After specific vaccination, two patients had persistent abnormalities in their response to one or more polysaccharides or conjugate-polysaccharide antigens. In the other two, the transient abnormalities were corrected by immunization. CONCLUSIONS When recurrent acute epiglottitis occurs in adults, it is important to investigate the immune system because a quantitative or a specific antibody deficiency could be found. It also follows that these patients will be successfully treated either by immunization or antibody replacement.