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Abstract Background Severe cardiotoxicity is a documented, but very unusual side-effect of intravenous 5-fluorouracil therapy. The mechanism producing cardiotoxicity is poorly understood. Case presentation A case of 5-fluorouracil-induced cardiotoxicity, possibly due to coronary artery spasm, and mimicking acute anterolateral myocardial infarction is presented and discussed. Electrocardiographs highlighting the severity of the presentation are included in the report along with coronary angiograms demonstrating the absence of significant coronary atherosclerosis. Conclusion Severe 5-fluorouracil-induced cardiotoxicity is rare, but can be severe and may mimic acute myocardial infarction, leading to diagnostic and therapeutic dilemmas. Readministration of 5-fluorouracil is not advised following an episode of cardiotoxicity.

Specific immunotherapy was introduced for the treatment of grass pollen-induced hay fever in 1911. The treatment was soon extended to other pollens as well as perennial allergens, and to the treatment of bronchial asthma. Definitive studies of its efficacy for both rhinitis and asthma came only many decades later. Understanding gradually emerged of the underlying immunologic mechanisms that include the generation of regulatory T lymphocytes, immune deviation from allergen-specific Th2 to Th1 responses, and a shift in allergen-specific antibody production from immunoglobulin (Ig) E to IgG4. Along with understanding of the immune basis came an appreciation that immunotherapy modifies allergic disease expression, producing protection against disease progression and symptomatic improvement that persists for years after the treatment is discontinued. Recent new directions for immunotherapy include sublingual administration of inhalant allergens and use of the oral route to treat food allergy., (© 2014 S. Karger AG, Basel.)

Allergen immunotherapy continues to be used worldwide in the management of allergic rhinitis and asthma. We continue to refine our knowledge of the indications for immunotherapy, the allergens that can be used successfully, and the requirements for dosage and route of administration. Several additional allergens have been shown to be effective in controlled studies. The sublingual route of administration is safe and can be effective if the dose is large enough. Since reviews in 1998, further studies of immunologic changes after immunotherapy have confirmed that T(H)2 lymphocyte-mediated responses are suppressed, and T(H)1 responses are stimulated. Eosinophil and basophil inflammatory responses to allergen exposure are downregulated through one or both of these mechanisms. Research continues to seek improvements through allergen vaccine modifications suggested by recent immunologic discoveries. None of these is available in practice.

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.

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.

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.

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.

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.

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.

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.

Although common allergies have been considered as immediate IgE antibody mediated responses, attention is now turning to inflammatory responses that appear to be initiated by T-cell responses to peptides from allergens presented in combination with HLA class II molecules. Although classic immunotherapy with allergen extracts has been found to downregulate these T-cell responses, more efficient and safe methods are being sought.

We performed two seasonal studies to evaluate the effect of continuous treatment with intranasal steroids, beginning approximately 1 week before the appearance of ragweed pollen, on the level of ragweed-specific IgE antibodies in serum. In both studies the control groups showed the anticipated rise in ragweed-specific IgE antibodies after the ragweed season. In the first study, employing aqueous beclomethasone dipropionate (168 micrograms twice daily), no rise occurred in serum ragweed IgE after seasonal exposure and the level actually decreased in eight of 12 treated subjects. In the second study, with triamcinolone acetonide (220 micrograms twice daily), the expected rise in ragweed IgE antibody was also reduced, although less dramatically, probably as a result of the lower potency of the dose delivered. Our studies not only support the benefits of intranasal steroids in the treatment of seasonal allergic rhinitis but also suggest that specific IgE production may be down-regulated by their continuous use, which may alter the subsequent clinical course of the disease.

Immunotherapy with crude allergens prevents allergic symptoms in many patients, but its effects are temporary and variable. This type of intervention provokes a transient increase in IgE antibody synthesis that may produce untoward side effects. Recent research has suggested that such immunotherapy downregulates T-cell activity, indicating that regulation of proinflammatory T cells may be a critical mechanism of the therapeutic response. Animal studies have shown that T cells can be rendered anergic by the administration of nonimmunogenic, T-cell-active peptides. Peptides prepared by urea denaturation of purified allergens and by pepsin digestion of crude allergens have been evaluated in humans. Although evidence of specific immunosuppression was noted, allergic reactions occurred as well. Subsequently, researchers synthesized peptides representing short sequences from the protein chains of principal allergens, such as Amb a I of ragweed and Fel d I of cat. Assays of proliferation of T-cell lines from ragweed- and cat-sensitive patients have shown that relatively short sequences from these proteins are responsible for a major portion of the activity of the whole protein. One such cat peptide has shown no reactivity with human IgE. The characteristics of these peptides suggest they should be evaluated further in clinical trials of allergic patients. The anticipated outcome would be prolonged T-cell downregulation, which might result in suppression of late-phase allergic inflammation and IgE antibody synthesis. The question whether such changes will reduce clinical reactivity sufficiently to be clinically useful remains to be answered in future studies.

Food hypersensitivities contribute to disease exacerbation in a sub-group of children with atopic dermatitis (AD). It has been shown that only selected foods are capable of causing clinical reactions when ingested, whereas other foods, to which the patient is equally sensitive by skin-prick testing, may be tolerated. The purpose of this study was to examine the cutaneous late-phase response (LPR) to food antigens in food-allergic patients with AD and to determine if the skin reacted differently to 'relevant foods' (foods eliciting positive skin-prick tests and positive oral challenges) than to 'non-relevant foods' (foods eliciting positive skin tests but negative oral challenges). Using blister chambers adfixed to the skin, six children with AD were challenged epicutaneously with foods to which they had previously been shown to be sensitive. Histamine and PGD2 were measured hourly for 10-12 hr in parallel with quantitation of the cellular traffic. There appeared to be no difference in any of the measured parameters between relevant foods and non-relevant foods, and the patterns of the LPR cells and mediators were similar to those previously described with aero-allergens in patients with respiratory allergy. Histamine rose to 13.0 +/- 24 ng/ml (P < 0.005) during the first hours, declined to < 1 ng/ml by the fifth hour, and then rose a second time to 6.72 +/- 3.4 ng/ml (P < 0.05) during the 12th hour. PGD2 rose to an average of 312 pg/ml (P < 0.05) during the first 3 hr followed by a decline to baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine the relative efficacy, to compare the incidence of adverse experiences, and to assess the systemic glucocorticoid effect of nasal preparations of budesonide, 200 micrograms bid, and placebo, 50 adult patients with seasonal allergic rhinitis due to grass pollen were studied in a stratified, double-blind parallel group design. After a 2-week baseline period, budesonide nasal spray, 100 microgram per nostril twice a day, was compared with placebo nasal spray over a 4-week treatment period. Supplementary treatment with chlorpheniramine, 4-mg tablets, was permitted when necessary to control symptoms. Daily symptom and medication diaries were kept by the patients. Investigator assessments of symptoms and side effects were made at clinic visits at 2-week intervals. At baseline and again towards the end of the study, blood samples were drawn for the determination of plasma cortisol levels and 24-hour urine samples collected for the measurement of 17-hydroxycorticosteroid output. Of the 24 men and 26 women entering, 49 completed the study. Symptom scores for sneezing, stuffy nose, and nasal secretion all decreased dramatically from baseline when budesonide treatment was started. The decrease in symptoms was greater for budesonide than for placebo (P < .001). There was no difference between budesonide and placebo with regard to eye itch and rescue medication used. Morning nasal washes were taken during the grass season before treatment was started and 16 to 17 days after. They showed a significant decrease in TAME esterase levels in secretions in the budesonide treated patients (P = .03) but not in the placebo-treated patients.(ABSTRACT TRUNCATED AT 250 WORDS)

We investigated whether cutaneous antigen-induced inflammatory cell infiltration and mediator release were modified by H1 receptor antagonists. Three chemically unrelated antihistamines (cetirizine, promethazine and chlorpheniramine) were tested in three groups of allergic subjects in a double-blind, crossover design. Chamber fluids were collected for 12 hr and histamine release, prostaglandin D2 production and cellular infiltration were quantified. Cetirizine significantly decreased late leukocyte migration into antigen-challenged chambers: eosinophils by 68% (P less than .04), basophils by 64% (P less than .04) and neutrophils by 72% (P less than .04), whereas mononuclear cells were not significantly affected. No alteration in the numbers of peripheral blood leukocytes or eosinophils occurred while on cetirizine treatment, suggesting that the decrease in inflammatory cells during the late phase reaction in the skin is not secondary to alterations in the peripheral leukocyte pool. In contrast, neither promethazine nor chlorpheniramine induced any significant alteration in inflammatory cell infiltration. All three antihistamines caused significant inhibition of the immediate reaction to antigen without any significant alteration in late phase reaction cutaneous reactivity. None of the three antihistamines caused any significant alteration in histamine or prostaglandin D2 levels. Thus, cetirizine may be an antihistamine uniquely capable of downregulating the late phase reaction inflammatory cell milieu without altering either early or late mediator production. The mechanisms involved and the clinical relevance of these findings remain to be explored.

To evaluate changes in the nasal response to histamine, we challenged 19 subjects with allergic rhinitis caused by ragweed (RW) before, during, and after the RW season with increasing doses of histamine diphosphate. We compared their response, as measured by symptoms and the levels of TAME-esterase activity and albumin recovered in the nasal lavage fluid, with response of two groups with allergic rhinitis undergoing immunotherapy with moderate-dose (N = 16) and high-dose (N = 11) RW (2 and 24 micrograms of antigen E [Amb a I] as maintenance dose, respectively). Four challenges with histamine were performed in each group: before, at the peak of, near the end of, and 2 weeks after the RW season. The three groups of subjects had similar skin sensitivity to antigen and levels of TAME-esterase activity and albumin recovered from nasal lavages after histamine challenge performed before seasonal exposure. Symptom diaries obtained throughout the season revealed a significant reduction only in the high-dose immunotherapy-treated group. At the peak of the season, the untreated group had more symptoms in response to the challenge compared with the challenges before and after the season (p = 0.04 for both groups). The saline challenge occurring before challenging with histamine also demonstrated a significant increase at the peak of the season compared with increases before the season (p = 0.02). This observation was also true for the levels of albumin and TAME-esterase activity. If the response after saline challenge was subtracted from each response after histamine challenge, no difference was found in the results between any of the visits.(ABSTRACT TRUNCATED AT 250 WORDS)

It has been demonstrated that airway deposition of inhaled aerosols is more heterogeneous in patients with asthma than in normal subjects. Nevertheless, the influence of abnormal airway deposition on responses to bronchoactive aerosols is poorly understood. We altered bronchopulmonary deposition heterogeneity of methacholine aerosol in nine asymptomatic patients with asthma by controlling inspiratory flow at high (approximately 60 L/min) versus low (approximately 12 L/min) rates on 2 study days and determined the effect on the provocative dose of methacholine causing a 20% fall in FEV1 (PD20) (often used as a measure of airway responsiveness). Deposition uniformity was quantified from gamma-camera scans of the lungs in terms of the distribution of a technetium-labeled aerosol that was inhaled rapidly or slowly before the inhalation of methacholine. Increased deposition in an inner (large, central airways) versus an outer (peripheral airways and alveoli) zone of the right lung (inner/outer ratio, greater than 1) and higher values of skew (an index of deposition asymmetry) and kurtosis (an index of deposition range) indicated enhanced heterogeneity of deposition. Mean (+/- SD) inner/outer ratio was significantly higher during rapid inspiration compared to slow inspiration with 2.91 +/- 0.51 and 1.84 +/- 0.30, respectively (p less than 0.01). Mean skew and kurtosis were also significantly higher after rapid inspiration, with 1.12 +/- 0.35 and 3.86 +/- 1.25, respectively, compared to 0.74 +/- 0.36 and 2.64 +/- 0.77 after slow inhalation (p less than 0.01). Geometric mean PD20 methacholine was significantly reduced when the aerosol was inhaled rapidly, with 5.9 cumulative methacholine units compared to 15.7 units after slow inhalation (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

We studied the quantitative responses of short ragweed (RW)-pollen-specific serum antibodies in 22 patients with RW immunotherapy (IT) and in a different set of 31 patients, 16 of whom stopped RW IT after more than 5 years of treatment. Serum was assayed before and after season, 1 year before and 1 and 2 years after starting IT, and 1 year and 2 years after stopping IT. RW pan-IgG, RW IgG1, and RW IgG4 were measured by ELISA, and RW IgE by RAST. Absolute quantities of RW IgG1 and RW IgG4 in reference sera were estimated by least-squares multiple regression analysis of 223 sera with the equation RW pan-IgG = RW IgG1 + RW IgG4. IgG1 is dominant in the early immune response of IT and disappears relatively slowly when IT is stopped. In contrast, IgG4 appears in significant quantities only after prolonged IT and disappears rapidly when IT is stopped. The apparent average half-life of RW IgG4 (9 months) was significantly shorter than that of RW IgG1 (29 months) (p less than 0.001). Before IT, mean RW IgE rose 180% (p less than 0.01) during the RW pollination season (August to November). This seasonal rise in RW IgE was ablated after IT from 1 year up to 8 years, but returned the year after IT was stopped. After 2 years of IT, the RW IgG1 and IgG4 levels were significantly correlated with RW IgE (r = 0.94 and 0.81; p = 0.0001 and 0.005).

For approaches to the immunotherapy of allergic respiratory diseases now under study at Johns Hopkins are reviewed. Traditional high dose parenteral immunization with mixtures of allergens corresponding to patients' allergic sensitivities is being evaluated in the long-term management of allergic asthma in children. Oral desensitization employing doses of short ragweed extract 100 fold higher than for parenteral therapy has been proven safe and efficacious and is now being modified to render it practicable. Intradermal injections of autologous IgG immune complexes with D. pteronyssinus antigens has been reported to improve symptoms and reduce IgE synthesis; a trial to replicate these findings is underway. Immunization with immunodominant peptides from Fel d. I is also under development as a novel immunoregulatory intervention with potential clinical application., (© 1992 S. Karger AG, Basel.)

We investigated the effect of immunotherapy (IT) on eosinophil (EOS) migration into the nasal cavity after nasal provocation with ragweed antigen and during seasonal exposure. In the first study, three groups of subjects participated: one group with no treatment (N = 19), one group with 10 months of IT, reaching maintenance at 2 micrograms of Amb a I (antigen E) (N = 15), and one group with 22 months of IT, reaching maintenance at 24 micrograms of Amb a I (N = 10). The percent of EOSs in nasal lavages performed during December before and 24 hours after nasal challenge with ragweed extract was determined. No significant difference between groups existed before challenge. The no treatment group demonstrated a significant increase in the percent of EOSs from 26% to 69.5% (p less than 0.008), whereas the treated groups demonstrated no significant change. In the second study, 45 patients were divided into four groups based on maintenance dose in micrograms of Amb a I and duration of treatment: (1) no treatment (N = 15), (2) 1 year at 2 micrograms (N = 13), (3) 2 years at 2 micrograms (N = 11), and (4) 3 years at 24 micrograms (N = 9). Nasal mucosal brushings were done during the ragweed season. A significantly smaller percentage of EOSs in 3-year IT-treated individuals was obtained compared to the control group (18 versus 8.4; p less than 0.04). The smaller dose of IT, regardless of duration, did not reveal a reduction compared to that in the no-treatment group.(ABSTRACT TRUNCATED AT 250 WORDS)

We investigated the effects of immunotherapy (IT) on the early (ER), late (LPR), and rechallenge reactions (RCRs) to nasal challenge with antigen as well as on the cutaneous ER and LPR to intradermal skin challenge. Our expectation was that IT would have a preferential effect on the LPR, and our aim was to understand the mechanism. Twenty-one ragweed hay fever-sensitive subjects were treated with a moderate dose of antigen extract (maintenance dose of 1.94 micrograms of antigen E (Amb a I)) during a period of 8 months (total dose equivalent to 24 micrograms of antigen E), and 20 matched subjects received placebo injections in a double-blind manner. Both groups underwent identical nasal challenges and intradermal skin tests with ragweed-antigen extract both before (1985) and during (1986) IT. Symptom and medication diaries, recorded during seasonal exposure, and changes in specific serum IgE and IgG antibodies confirmed the efficacy of the administered IT dose. Between-group analysis revealed that IT significantly reduced the levels of histamine, TAME-esterase activity, and kinins, as well as symptoms of rhinorrhea and congestion generated during the ER to nasal challenge. Within-group paired analysis demonstrated ER, LPR, and RCR mediators and symptoms also to be reduced by IT. Surprisingly, the placebo-treated group demonstrated an increase in the ER. There was no decrease of the LPR without an antecedent decrease of the ER. IT did not clearly change the late cellular inflammatory response. In the case of skin challenge, IT significantly reduced the cutaneous ER. The reduction of the cutaneous LPR was more pronounced. We speculate that moderate-dose IT ameliorates seasonal symptoms of allergic rhinitis by reducing the ER, LPR, and RCR to antigen challenge but does not preferentially reduce the nasal LPR.

To better define the effect of systemic glucocorticoids on the cutaneous early and late phase response (LPR), nine atopic subjects were examined in a double-blind cross-over study using skin chambers fixed over denuded skin blisters. A challenge was carried out by placing allergen in the chamber for 60 min in subjects who received either a 3-day pretreatment with 60 mg/day of prednisone or placebo. Skin chamber cell counts and inflammatory mediators (histamine, PGD2, and leukotriene C4 (LTC4)) were measured at hourly intervals for 12 h. Prednisone pretreatment did not alter the immediate skin erythema or release of histamine but ablated the late secondary erythema and rise in histamine. The median histamine values during h 10, 11, and 12 in the placebo and prednisone pretreatment visits were 3.73 and 0.22 ng/ml, respectively (p less than or equal to 0.02). Prednisone did not alter PGD2 production; however, LTC4 production was suppressed during the LPR. The cumulative median LTC4 values during h 7, 8, and 9 were 5.6-fold (p less than or equal to 0.05) more after placebo than after prednisone pretreatment. Prednisone altered cellular traffic more dramatically than it did inflammatory mediators. The influx of eosinophils, which peaked during the 9th and 10th h in placebo-treated patients, was completely blocked by prednisone (p less than or equal to 0.02) for every h from 6 through 12. The influx of basophils, which started during the 9th h and peaked during the 12th h in placebo-treated patients, was suppressed at all time points (p less than or equal to 0.02) in prednisone-treated patients. There was no significant alteration in neutrophil transit into the skin chambers induced by prednisone. We suggest that the selective blockade of eosinophil and basophil influx by prednisone and the associated decrease in inflammatory mediators may contribute to the blockade of the clinical expression of the cutaneous LPR.

We challenge each of 55 consecutive ragweed (RW)-allergic patients with hay fever and with graded increasing doses of ragweed extract to investigate the frequency and relationship between the early (ER), late (LPR), and rechallenge reactions (RCRs) to nasal challenge. We evaluated the nasal response by measuring the levels of histamine, TAME-esterase activity, and kinins in the nasal lavage fluid and by grading symptoms. Fifty-one subjects (92.7%) had an ER consisting of a dose-dependent, concommitant increase in both mediators and symptoms. The total amount of TAME-esterase activity and kinins generated during ER correlated significantly with specific serum IgE (ssIgE), intradermal skin test (ST) sensitivity, and basophil histamine release (BHR) to antigen E (p less than 0.01 for each). Twenty-four (47%) subjects developed a late increase in mediators and 23 (45%) subjects in symptoms. None of the four subjects without an ER developed an LPR. The levels of the late-appearing mediators were not predicted by ST, ssIgE, or BHR. There was a significant but weak association between the intensity of ER and LPR, but there was no significant difference in the IgE antibodies, ST, BHR, and intensity or threshold of ER between dual and early only reactors. The number of eosinophils and neutrophils in the LPR lavages increased over the prechallenge baseline, and their numbers correlated (p less than 0.05) with ER kinins (r = 0.46, and 0.37, respectively), ER TAME-esterase activity (r = 0.28 and 0.24, respectively), and in the case of eosinophils, ER histamine (r = 0.29).(ABSTRACT TRUNCATED AT 250 WORDS)

Although immunotherapy has a long record of efficacy in certain allergies, its safety has recently been questioned. One problem is that physicians trained and certified in allergy are not the only ones who prescribe and administer allergen injections. Fundamental issues of diagnosis, patient and allergen selection, and management of adverse reactions are reviewed.

We compared specific airway conductance (SGaw) and the FEV1 after repetitive exercise or repetitive eucapnic voluntary hyperventilation (EVH) challenges. Replicate challenges were matched in terms of inspired air conditions and minute ventilations (VE) in order to determine the degree of refractoriness after each type of challenge in patients with exercise-induced asthma. Ten patients exercised or hyperventilated dry, room temperature air at matched VE on two study days. When the patients FEV1 had returned to 90% of baseline or better, or at 3.75 h if FEV, had not returned to 90% of baseline, patients repeated the identical exercise or the EVH challenge. Minimum FEV1 values expressed as a percent of predicted FEV1 after the first and second exercise challenges were 52 +/- 16 and 58 +/- 17, respectively, which were statistically different (p less than 0.001; paired t test). Minimum FEV1 values after the first and second EVH challenges were 52 +/- 13 and 59 +/- 9% of predicted, respectively, which were also statistically different (p less than 0.01; paired t test). Seven of 10 subjects demonstrated higher SGaw values after the second exercise challenge compared with the first challenge, whereas eight of 10 subjects showed higher SGaw values after the second EVH challenge compared with the first challenge. Paired t test analysis indicated that percent protection, measured by FEV1, was similar after either type of challenge. We conclude that replicate exercise or EVH challenges with similarly matched inspired air conditions and VE induce similar degrees of refractoriness.(ABSTRACT TRUNCATED AT 250 WORDS)

In 1982, 43 ragweed-sensitive patients receiving maintenance injections of full doses of ragweed allergoid were selected for a study of the immunologic and clinical efficacy of booster injections only four times a year. These patients had participated for 2 to 7 years as part of a trial of mixes of up to four allergoids to common pollens in the mid-Atlantic area tailored to each patient's skin test sensitivity. They were divided into a group (21 patients) to receive injections every 3 months and a group (22 patients) to receive injections about every 6 weeks (eight injections per year). Patients were rerandomized after 1 year so that half of each original group switched to the alternate treatment, and this program was continued until after the ragweed season of 1985. Thirty-four patients were still under study the last year. Doses, per injection, were 100 allergoid units (1 allergoid unit equals 100 PNU) of each allergen in the mixture. Symptom scores during the 8 weeks of each of the four ragweed seasons were not significantly higher in the 3-month treated group. IgG antibody levels to Amb a I (antigen E) were followed until early 1984 and were not significantly different in the two groups, even though the 6-week treated patients received a two times higher cumulative dose per year. Rates of local and systemic reactions (percent of injections eliciting reactions) were not different in the groups, which means that the 3-month treated group had about half as many reactions by virtue of taking half as many injections.(ABSTRACT TRUNCATED AT 250 WORDS)