Treatment of ragweed hay fever with urea-denatured antigen E

Urea-denatured antigen E (UDE) has lost the major determinants of antigen E (AgE), eliciting neither IgE nor IgG antibodies to native AgE in mice. UDE, however, stimulates T cells so that repeated injections result in specific but partial suppression of ongoing IgE responses to native AgE. An attempt was made to apply this property to the treatment of 10 ragweed-allergic human volunteers by repeated subcutaneous injections of UDE over about 18 mo. Local and systemic allergic reactions limited the dose to 4 to 75 microgram UDE per injection. Little or no antibody response to AgE was induced. Five patients had increased basophil sensitivity to UDE after 4 mo of injections. Five of eight patients who completed the study had evidence of suppression of IgE responses by exhibiting a 20% or less increase of IgE antibodies to ragweed on natural seasonal exposure. Three patients still exhibited this evidence at the next season of exposure 10 mo after the last injection. The two patients who received the lowest doses had greater than usual seasonal rises of IgE antibodies. There was no clinical evidence of improvement of hay fever symptoms. The results indicate that the immunologic properties of UDE in humans are similar to those in mice. The clinical applicability of these properties remains doubtful.     

Treatment of ragweed hay fever with flurbiprofen, a cyclooxygenase-inhibiting drug

Sixty-two volunteer hay fever patients participated in a 2-week trial which examined the protective effect of the cyclooxygenase-inhibiting drug flurbiprofen. The drug suppressed symptom severity significantly, though it was not as protective as the antihistamine also employed in the trial. Flurbiprofen's effects suggests that prostaglandin release may contribute to the symptoms of allergic rhinitis.     

Treatment of hay fever with sodium cromoglycate, hyposensitization, or a combination

In 77 consecutive patients with grass pollen rhinitis as the only allergic disease, treatment with sodium cromoglycate (SCG) nasal spray, hyposensitization with aluminium hydroxide adsorbed extract of grass pollen as perennial treatment, and a combination of the two was compared. Specific serum-IgE, IgG and IgG4 were determined in patients who participated in three consecutive seasons. Significant immune response was found in the hyposensitization group, but not in the group treated with SCG. No correlation between the immunoglobulin responses and the individual symptom and/or medicine scores was found. Symptom and medicine scores were analysed in the 3 weeks with the highest pollen counts each year during 4 consecutive years. Higher scores were found in the group treated with sodium cromoglycate compared with the other two groups, but the difference was only significant for eye and total symptoms in the first season. None of the groups, however, suffered from more than mild to moderate symptoms even in the weeks with peak pollen counts. A significantly larger decrease in the wheals of the skin prick test was shown during hyposensitization than during treatment with SCG. No difference was found in the frequency of patients who became symptom-free or developed pollen asthma.     

The immune response of patients with ragweed hay fever treated with polymerized ragweed antigens.

This report describes the immune response of patients with ragweed hay fever treated with polymerized ragweed antigens (PRW). Their IgG antibody responses to crude ragweed extract, antigen E, antigen K, and antigen Ra3 were determined by a solid-phase radioimmunoassay. The results indicate that PRW contains an array of clinically important antigens that are available for immunologic processing and result in an immune response in patients treated with this new form of immunotherapy for ragweed hay fever.     

Allergen-controlled study of intranasal immunotherapy for ragweed hay fever

Previous studies of intranasal immunotherapy have not included control groups treated with an irrelevant allergen. In the present double-blind study, we tested the effectiveness of intranasal immunotherapy in 20 patients sensitive to both short ragweed (SRW) and orchard grass (OG). Patients sprayed increasing concentrations of either SRW (n = 11) or OG (n = 9) extract intranasally six times per day for 8 wk before the SRW pollination season. The effects of this treatment were determined by analysis of symptom score diaries and clinical examinations during the SRW pollination season. SRW-treated patients received cumulative AgE doses from 3 to 59 micrograms (mean 21); this mean dose was approximately sevenfold less than that used in a previous study from our laboratory. All patients reported immediate hay fever symptoms after use of the nasal spray. Five patients (four SRW- and one OG-treated) reported episodes of mild epistaxis during treatment; no other unexpected side effects were noted. During the treatment period, more SRW-treated patients showed signs of nasal obstruction and edematous nasal mucosa than OG-treated control patients (p less than 0.03). During the SRW pollination season, the SRW-treated patients reported lower mean weekly symptom scores than the OG-treated control patients, but the difference was not statistically significant. Supplemental antihistamine use was significantly higher (p less than 0.016) in the OG-treated control patients during the SRW pollination period. Subjective assessment of treatment efficacy by patients was similar in both treatment groups. We conclude that intranasal immunotherapy was of only marginal benefit in this study.     

Treatment of ragweed hay fever with an intranasal spray containing flunisolide,a new synthetic corticosteroid

Flunisolide, a new synthetic fluorinated corticosteroid, was administered as a nasal spray via a squeeze bottle to patients with ragweed hay fever for 4 wk during the hay fever season. Fifty-one patients, paired on the basis of similar skin sensitivity to intradermal ragweed (? 10^?1 PNU/ml), were randomly assigned in a double-blind manner either an aerosol-containing flunisolide dissolved in vehicle (a mixture of polyethylene glycol and propylene glycol) or vehicle alone. Flunisolide was sprayed as a 0.025% solution two times in each nostril twice a day. Forty-eight patients completed the study. Three patients dropped out for reasons unrelated to flunisolide usage. On the basis of physician interviews and daily symptom diary scores, patients receiving flunisolide showed significant improvement of hay fever symptoms when compared to their counterparts receiving vehicle. No systemic steroid side effects were observed. Morning plasma cortisol levels measured prior to and after 3 wk of flunisolide therapy showed no significant difference between the treatment groups. Adverse local efiects were minor and were noted less frequently with flunisolide than with vehicle. Flunisolide's topical efficacy and lack of adrenal suppression provide distinct advantages over other steroid preparations available in the United States for treatment of seasonal allergic rhinitis.     

Immunotherapy with short ragweed fraction A: d-glutamic acid: d-lysine polymer in ragweed hay fever

We report the first human trial of immunotherapy employing the nonimmunogenic carrier, d-glutamic acid: d-lysine linked to short ragweed (SRW) fraction A (fraction A:d-GL). Twelve SRW-sensitive patients with no immunotherapy during the previous 19 yr received a 2-mo ($\text{7}\text{79}$ to $\text{9}\text{79}$) course of fraction A: d-GL (average dose 49.5 mg, range 21 to 78 mg). We compared their symptom scores and serologic changes with two control groups of SRW-sensitive patients. Patients receiving fraction A: d-GL demonstrated at least a tenfold decrease in skin-test sensitivity to SRW and had statistically lower mean seasonal symptom scores (p < 0.02) than untreated controls. Mean seasonal symptom scores did not differ statistically from those of control patients on year 4 of immunotherapy. In contrast to the expected suppression of IgE, we found that fraction A:d-GL stimulated both IgE and IgG responses to SRW and SRW-antigen E. These increases in IgE and IgG antibodies were significantly greater than in the control groups and appeared to be due largely to injection of fraction A: d-GL. Though fraction A: d-GL was generally well tolerated, we noted mild generalized urticaria in three patients, and large local reactions in five others. The differences between our results and the earlier results in mice may reside in the particular characteristics of this preparation of fraction A: d-GL.     

The clinical and immunologic efficacy of immunotherapy with modified ragweed extract (allergoid) for ragweed hay fever

A double-blind study comparing formaldahyde modified ragweed allergen (allergoid) and placebo in the treatment of allergic rhinitis was carried out. Twenty ragweed-sensitive patients were studied, ten receiving 10,710 PNU of allergoid pre-seasonally and ten receiving placebo injections. Daily symptom score sheets were kept by each patient during August and September of 1983. A significant difference in average daily symptom scores (P = 0.01) between the two groups was noted. Significant differences were also observed in symptom scores for individual weeks during the ragweed season. Post-treatment allergen-specific IgG blocking antibody was significantly higher (P = 0.001) in the treatment group compared to pre-treatment levels and when compared to the control group (P = 0.01). No significant local or systemic reactions occurred. The results suggest that the dosage protocol used in this study is appropriate as an initial treatment schedule in clinical practice.     

Immunologic responses to conjugates of antigen E in patients with ragweed hay fever

Allergens conjugated with several simple repeating polymers have reduced allergenicity in man, but large doses retain the ability to suppress ongoing allergen-specific IgE synthesis in strains of high-responder mice. To determine whether suppression of IgE antibodies could be induced in man, preliminary trials of immunologic responses to conjugates in man were carried out in ragweed hay fever patients treated with antigen E (AgE) coupled to methoxypolyethylene glycols ( MPEGs ) of 5000 and 2000 daltons, lauryloxypolyethylene glycol of 1200 daltons, and a random copolymer of D-lysine and D-glutamic acid of 69,000 daltons. In varying degrees all these conjugates had reduced allergenicity by basophil histamine release when these conjugates were compared with native AgE and could suppress IgE response in mice. Patients received one of these conjugates or native AgE in a series of subcutaneous injections and were observed for allergic reactions. The conjugates induced a lower rate of systemic reaction than native AgE but failed to induce early suppression of IgE antibodies. Instead, early rises in IgE antibody occurred in the several groups and were followed by a slow decline during a year or more that was similar to that observed with standard immunotherapy. Because the conjugates eventually caused local and systemic allergic reactions as the dose was raised, it was not possible to test the IgE-suppressive effects at doses similar to those used in mice. In contrast, rapid sustained rises in IgG antibodies occurred in all groups. The MPEG conjugates appeared to be more effective than native AgE in this regard. The reduced rate of systemic reaction and rapid rise in IgG antibody that was noted with MPEG conjugates make them worth further exploration as agents for immunotherapy.     

Controlled evaluation of allergoid in the immunotherapy of ragweed hay fever

Immunotherapy with ragweed allergoid administered in a clustered regimen, placebos in a clustered regimen, and unaltered ragweed extract (allergen) in a weekly regimen were compared in three groups of hay fever patients carefully matched for ragweed sensitivity. The allergoid and placebo comparison was performed double-blind and the unaltered ragweed extract comparison was single-blind. In terms of antigen E (AgE) equivalents, doses were about 50 times higher in the allergoid-treated group than in the allergen-treated group. Whereas there was no immunologic response to placebos, the allergoid regimen produced a more rapid serum IgG antibody response, with significantly higher posttreatment levels than those in the allergen regimen. Initial IgE antibody rises and subsequent slow declines were similar. Symptom-medication scores were similar in the two specifically treated groups and significantly less than scores reported by the placebo group (p less than 0.01). Due to an overestimate of the initial allergoid doses, systemic reactions occurred mostly in the early visits with allergoid treatment, whereas systemic reactions appeared late in the allergen treatment. The overall incidence was similar. In a second year, after 8 mo of no injections, a preseasonal booster regimen with both materials produced virtually no untoward reactions. During the period of no injections, IgG antibody declines were modest and, after boosters, IgG antibody levels rose promptly. Clinical results in both groups were again excellent, with an advantage for allergoid.     

Treatment of hay fever.

The range of treatments for hay fever available to the general practitioner has changed considerably in recent years. New antihistamines have addressed the problem of sedation and moved towards one daily dose; nasally applied corticosteroids avoid the need for systemic steroid therapy and its potential adverse effect; and regulatory decisions have set a trend away from immunotherapy in general practice. However, knowledge about the mechanism of action of immunotherapy is increasing and new developments with improved safety profiles include allergen polymers, allergoids, oral immunotherapy and nasal immunotherapy. Choice of treatment depends, as always, on the individual circumstances of the patient and his or her disease.     

A comparison of immunotherapy schedules for injection treatment of ragweed pollen hay fever

In 44 patients highly sensitive to ragweed, we compared weekly injections of single doses of ragweed extract (RW-Wk, 15 patients) with clustered doses of ragweed extract at 3-wk intervals (RW-Cl, 18 patients) and with placebo (11 patients) for effects on ragweed hay fever symptom-medication scores and immunologic variates. Patients were matched and randomly assigned to treatment groups. Ragweed doses were advanced to the highest tolerated dose. Doses and number of visits were lower in the RW-Cl group than in the RW-Wk group. Despite lower doses, systemic reactions were not reduced and antiragweed IgE levels increased significantly more in the RW-Cl group than those in the RW-Wk group. Both the RW-Cl and RW-Wk groups had significant increases in antiragweed IgG levels, decreases in seasonal rise in antiragweed IgE levels, and lower symptom-medication scores (p < 0.01) in comparison with the placebo group. We conclude that the RW-Cl regimen offered no important advantage over RW-Wk. Seventeen patients had previously received Rinkel-method immunotherapy with 0.5 ml of end-point dilution of ragweed extract for 1 to 2 yr without significant clinical improvement or immunologic changes. After adequate treatment with either RW-Wk or RW-Cl, these patients had significantly lower symptom-medication scores than those of the placebo group and immunologic changes similar to those of the entire active-treatment group. Therefore, treatment failures on Rinkel immunotherapy respond well to adequate dose immunotherapy by either schedule.     

Comparison of alum-precipitated aqueous extracts and modified ragweed tyrosine adsorbate vaccine in the treatment of ragweed hay fever

Thirty-five ragweed-sensitive patients received immunotherapy with either alum-precipitated aqueous extracts (AP) or modified ragweed tyrosine adsorbate vaccine (Pollinex-R). Symptoms decreased with AP therapy only. Immunologically, there was a blunted specific IgE response and little specific IgG increase associated with both groups. Alum-precipitated aqueous extracts appeared to be more efficacious than Pollinex-R.     

Preseasonal IgE ragweed antibody level as a predictor of response to therapy of ragweed hay fever with intranasal cromolyn sodium solution.

Intranasal administration of a 4% solution of cromolyn sodium for the treatment of ragweed hay fever was tested in an 8-week double-blind matched-pair study involving 66 patients. Patients on active drug received 5.2 mg into each nostril 6 times daily; control patients received a placebo spray. The treated group showed a significant reduction in mouth breathing (p less than 0.001), stuffy nose (p less than 0.002), runny nose (p less than 0.003), and postnasal drip (p less than 0.035). Patients receiving the active drug also reported fewer sneezing episodes (p less than 0.003) and nose blowing episodes (p less than 0.015). One patient using cromolyn solution developed nasal ulceration, tongue swelling, coughing, and wheezing. Other side effects were minimal and occurred with equal frequency in both groups. In the treated group relief of symptoms was most marked in patients with high preseasonal levels of IgE ragweed antibody. Intranasal 4% cromolyn solution appears to be an effective drug for the treatment of ragweed hay fever; measurement of the preseasonal level of IgE ragweed antibody is a useful screening test to identify patients most likely to achieve a maximal beneficial response to treatment.     

Profile of ragweed hay fever symptom control with terfenadine started before or after symptoms are established

Forty-two ragweed hay fever patients participated in a study which examined the profile of symptom relief provided by terfenadine, and the relative adequacy of symptom control with the drug given from the beginning of the season compared with treatment started after symptoms were well established. Compared with placebo, terfenadine effectively relieved sneeze, itch and eye symptoms. It had no effect on running, blowing and drainage. Subjectively perceived congestion benefited marginally. When the drug was begun after symptoms were well established, sneezing responded quickly and maximally. Eye discomfort lessened but not to the level experienced by those dosed from the beginning of the season. The pattern in other symptom categories was less clear. Overall, terfenadine improved all rhinitis symptoms except those related to hypersecretion. Some symptoms appeared to respond better when drug dosing commenced at the beginning of the season.     

Specific inhibition of allogeneic reactions with disodium cromoglycate

Milligram amounts of disodium cromoglycate (DSCG) inhibit allogeneic responses in mixed lymphocyte culture (MLC) reactions, but do not affect cell viability or suppress lymphocyte responses to either phytohemagglutinin (PHA) or pokeweed (PKW) mitogens. Preincubation of lymphocytes with DSCG is without effect, indicating that membrane binding is an unlikely explanation for inhibition. The HLA-DR tissue typing of cells in the presence of optimal MLC-inhibitory doses of DSCG is normal suggesting that MLC-reactive lymphocytes are not denied recognition of these antigens. Timed studies demonstrate that DSCG must be present continuously during the induction period, for removal of DSCG after 16 hr culture restores MLC reactivity and addition of the drug after 48 hr is without effect. Both natural killing (NK) and cell mediated lympholysis (CML) assays proceed normally in the presence of optimal MLC-inhibitory concentrations of DSCG; however, CML reactions are eliminated by the addition of drug during cytotoxic T cell priming. Background CML reactivity also disappears when lymphocytes are continuously cocultured in DSCG, implying that such killing cannot be attributed to NK activity. DSCG is said to inhibit allergic reactions by impeding calcium flux across mast cell membranes, thereby preventing degranulation, but other mechanisms are required to explain the selective effects on in vitro lymphocyte reactivity.