Immunotherapy with keyhole lampet hemocyanin-conjugated decapeptide vaccine in cypress pollen allergy.

BACKGROUND: Cupressaceae pollen allergy is a world-wide pollinosis but immunotherapy has rarely been tested. Immunotherapy is usually allergen-specific but new forms may be targeted towards IgE. OBJECTIVES: A randomized, double-blind, placebo-controlled trial was carried out to assess the efficacy of a vaccine made of keyhole lampet hemocyanin (KLH)-conjugated decapeptide from the Fc(epsilon4) domain of the IgE in cypress pollinosis. METHODS: Sixty patients with cypress pollen allergy were studied. They were included on a suggestive clinical history, positive skin tests and nasal challenge to cypress pollen extract. Three intramuscular injections of the vaccine (250 microg) or placebo were administered monthly with a booster injection 5 to 8 weeks later. The primary end-point criterion was the threshold dose inducing a positive nasal challenge. The secondary end-point was the symptom-medication scores measured when cypress pollen grains were over 50 grains/m3. RESULTS: Nasal challenge before treatment was non-significantly different between the placebo and vaccine groups. After treatment there was no significant difference between the two groups. Pollen counts were over 50 grains/m3 for 8 weeks during the trial. There was no significant difference in total symptom scores between the placebo and vaccine groups. The vaccine was safe. CONCLUSIONS: The KLH-conjugated decapeptide vaccine was not effective in cypress pollen allergy.

Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. V. Duration of the efficacy of immunotherapy after its cessation.

Specific immunotherapy (SIT) using a standardized mite extract is effective and safe when administered under optimal conditions. However, the duration of its effectiveness after cessation of treatment remains unknown. Forty asthmatic subjects who had received SIT with a standardized Dermatophagoides pteronyssinus (Der p) extract under the same protocol were studied. All had received SIT for a period of 12-96 months and were not receiving pharmacologic treatment. The FEV1 was within normal range in all patients. After cessation of treatment, patients were followed for up to 3 years at 6-month intervals. The patient was considered to have relapsed when symptoms of asthma and/or rhinitis occurred and/or when pulmonary function tests were impaired. Skin tests with increasing concentrations of Der p were carried out before and at the end of SIT. Forty-five percent of the patients did not relapse. The duration of efficacy of SIT was related to the duration of SIT itself (P < 0.04). Most patients who did not relapse had a decrease in skin test reactivity at the end of SIT, whereas most patients who relapsed did not show any change (P < 0.003). The duration of efficacy of SIT after its cessation depends upon the duration of SIT and may be predicted by the effect of SIT on skin tests.

Quality of life in asthma. I. Internal consistency and validity of the SF-36 questionnaire.

Asthma is a chronic disease in which social life is altered. The importance of restrictions on social life may be greater in severe asthma or when symptoms are not adequately controlled. General scales of quality-of-life (QOL) may be used to detect the importance of social life impairment, but it is not yet known whether the scores of such QOL measures are reliable and valid in asthmatic patients. A study was carried out in 252 patients with asthma of variable severity (FEV1 ranging from 25 to 131% of predicted) to assess the validity of a general QOL scale, the first French version of the SF-36 health status questionnaire (SF-36). This is based on 36 items selected to represent nine health concepts (physical, social, and role functioning; mental health; health perceptions; energy or fatigue; pain; and general health). All nine SF-36 category scores were highly significantly correlated with the severity of asthma assessed by the clinical score of Aas (p < 0.0007 to p < 0.0001). Eight SF-36 category scores were highly significantly correlated with FEV1 (p < 0.003 to p < 0.0001). A high internal reliability of SF-36 was found using the alpha coefficient of Cronbach (0.91 for the whole questionnaire). The SF-36 questionnaire is valid and reliable in asthma and can therefore be used to examine QOL in asthmatic and nonasthmatic patients and to determine to what extent asthma impairs social life.

Current trends in the management of allergic diseases.

Treatment strategies for allergic diseases are based on allergen avoidance, pharmacotherapy and immunotherapy. Allergen avoidance should always be attempted, even if it is rarely complete and needs several days or weeks to be effective. Pharmacotherapy is aimed at reducing symptoms arising from allergen triggers and inflammation. In seasonal allergic diseases, a short treatment course is sufficient to reverse nonspecific hyperreactivity and symptoms. In chronic allergic diseases, however, inflammation is of major importance and symptoms are not always readily controlled. Moreover, the treatment should be prolonged as proposed by Guidelines for the Management of Asthma and Rhinitis (1, 2). Effective and well-tolerated drugs are now available and some may be combined for rhinitis or asthma therapy. In rhinitis, first-line therapy is still based on non-sedating antihistamines and topical corticosteroids. Cromoglycate and other drugs may also be used. For asthma, anti-inflammatory therapy is the first-line treatment. In mild sufferers, cromoglycate, nedocromil or low-dose inhaled steroids can be used. For more severe disease, high doses of inhaled corticosteroids are proposed. Bronchodilators are used as 'rescue' medications, though many patients with severe symptoms need regular bronchodilator therapy. Long-acting beta 2-agonists have been introduced recently, but their exact place in the management of asthma is not yet fully established. Immunotherapy was first introduced in 1911 and was based on decades of physicians' experience, rather than on rational thought. Standardized allergens have improved the efficacy of immunotherapy, but the safety of this treatment needs to be improved.(ABSTRACT TRUNCATED AT 250 WORDS)

Heterogeneity of atopy. I. Clinical and immunologic characteristics of patients allergic to cypress pollen.

The heterogeneity of pollen-allergic persons is well known but poorly characterized. Cypress is one of the major pollen-producing plants of the Mediterranean area. A study was undertaken to characterize the symptoms presented by patients allergic to cypress pollen and the heterogeneity of the IgE immune response between patients allergic only to cypress pollen and those who are polysensitized. Eighty-nine patients allergic to cypress pollen were studied, 26 being allergic only to cypress pollen. The IgE response was assessed by skin prick tests and the titration of serum total IgE and cypress-specific IgE by RAST. Clinical reactivity was assessed by symptom scores during the cypress pollen season and skin tests. Pollen counts were obtained. The clinical reactivity was similar in both patient groups. Rhinitis was present in all patients, conjunctivitis in 73.7-88.5%, and asthma in only 7.4-19.2%. The age of onset of symptoms caused by cypress pollen allergy was significantly greater in patients allergic to cypress pollen only. Total serum IgE was within the normal range in the cypress pollen group and significantly lower than in the polysensitized groups. Cypress pollen RAST was higher in the polysensitized group. We concluded that conjunctivitis is particularly common in cypress pollen allergy. Patients allergic only to cypress pollen may be unique in their way of expressing serum total IgE levels.

Systemic reactions occurring during immunotherapy with standardized pollen extracts.

Specific immunotherapy with standardized extracts administered by a rush protocol can induce systemic reactions (SRs). A prospective study was conducted in 454 pollen-allergic patients (aged 5 to 62 years) (1) to compare the incidence of SRs during a 3-day rush or step protocol, (2) to determine if patients presenting pollen asthma or those allergic to multiple pollen species would have an increased incidence of SRs, and (3) to attempt to decrease SRs. According to their sensitivity, patients received standardized extracts of orchard grass, and/or Parietaria, and/or olive, and/or plane-tree pollen with the same allergenically bioequivalent maintenance dose. Patients 10 years of age and older received 2000 BU; patients younger than 10 years, 1000 BU. The occurrence of SRs was carefully monitored. The incidence of SRs per patient ranged from 2.6% to 31.1%. With the rush protocol, there was a significant decrease in SRs after premedication (p less than 0.015). Severe SRs decreased further when the increase in doses was stopped because large local reactions occurred. Step protocol was only slightly better tolerated than rush protocol. Bronchial adverse reactions occurred more often in patients presenting asthma during previous pollen seasons. No reaction started 45 minutes or later after the last injection.

Precision of skin prick and puncture tests with nine methods.

New devices for puncture tests have been proposed recently, but their precision by comparison to the prick test method is poorly known. Seven puncture tests (Allerprick, Morrow Brown standardized needle, Phazer, Pricker, Stallerpointe, Stallerkit, and Wyeth bifucated needle) were compared with the modified prick test performed with hypodermic or intradermal needles in eight carefully selected normal volunteers. Skin tests with histamine hydrochloride (10 mg/ml) were only performed when there was no factor that might interfere with their interpretation. The site of skin tests on the forearm was demonstrated not to significantly influence the reaction size. The coefficient of variation of the tests ranged from 8.4% to 21.7%. Modified skin prick tests are satisfactory since they are highly reproducible (coefficient of variation: 13.4% and 16.5%) and there is no subject effect. Phazet was found to be more reproducible without subject effect. Pricker is satisfactory since it has no subject effect and a reproducibility similar to that of modified prick tests. Other tests are less reproducible (Stallerkit or Morrow Brown) or vary between subjects (Allerkit, Stallerkit, Stallerpointe, and Wyeth Needle).

Differences in clinical and immunologic reactivity of patients allergic to grass pollens and to multiple-pollen species. II. Efficacy of a double-blind, placebo-controlled, specific immunotherapy with standardized extracts.

The IgE response of patients only allergic to grass pollens differs from response of patients allergic to multiple-pollen species. The IgE immunoblots to orchard-grass pollens confirmed that polysensitized patients had more proteins revealed than patients only allergic to grass pollens. To determine if both groups of patients present a different response toward specific immunotherapy (IT), a double-blind, placebo-controlled study was performed in 70 patients. Patients receiving the active treatment had a rush IT with either a standardized orchard grass-pollen extract or with a standardized mixed-pollen extract prepared, depending on the sensitivity of the patients. The maintenance dose was defined as that dose effective in grass-pollen IT in previous experiments. The same equipotent maintenance dose was administered for all pollen species. Symptom-medication scores during the pollen season and nasal challenge with orchard grass-pollen grains demonstrated that grass pollen-allergic patients had a significantly improved efficacy by comparison to placebo treatment, whereas polysensitized patients had a nonsignificant improvement. Serum grass-pollen IgG was significantly increased after IT in both treated groups. This study demonstrate that the response toward specific IT differs in patients only allergic to grass pollens by comparison to polysensitized patients.

Clinical and immunologic reactivity of patients allergic to grass pollens and to multiple pollen species. I. Clinical and immunologic characteristics.

The heterogeneity of pollen-allergic individuals is well-known but poorly characterized. Twenty-six patients were studied to characterize their immunologic and clinical patterns. Thirteen patients were allergic only to grass pollens, and 13 other patients were allergic to grass-pollen and other pollen species, including Cupressaceae, plane tree, olive, and Parietaria. The IgE response was assessed by the titration of serum total IgE and orchard grass-specific IgE, as well as by IgE immunoblots to orchard-grass pollens. Clinical reactivity was assessed by nasal challenge with orchard-grass pollens before the pollen season and nasal and bronchial symptom-medication scores between April 1 and June 15. Pollen counts were obtained during this period of survey. Polysensitized patients had significantly increased levels of serum total and specific IgE and a greater heterogeneity of IgE immunoblots, suggesting an enhanced qualitative and quantitative IgE immune response. Polysensitized patients had nasal and bronchial symptoms occurring earlier than grass pollen-allergic individuals, confirming the priming effect caused by other plans flowering with an earlier season for both nasal and bronchial mucosa. Alternatively, the early symptoms may be attributable to the tree pollens or might reflect the higher grass-pollen IgE level in the polysensitized group. Bronchial symptoms appeared a few weeks after nasal symptoms. Nasal challenges were similar in both groups, and the severity of nasal symptoms during the season was not significantly different in both groups, suggesting that the intensity of symptoms is not related to the sensitization nor to the IgE immune response of the subjects.

Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. IV. Systemic reactions according to the immunotherapy schedule.

Specific immunotherapy with standardized extracts can induce systemic reactions (SRs), possibly increased by a rush immunotherapy (RIT) protocol. A prospective study in 1152 mite-allergic patients (3 to 63 years of age) examined the incidence of SRs during an RIT or a step protocol. All patients received the same standardized extract of Dermatophagoides pteronyssinus with the same maintenance dose. In the first group, 290 patients had an RIT protocol without any preventive measure. In a second group, the prevention of SRs during RIT was attempted by pretreating 160 patients with methylprednisolone (0.5 mg/kg/day), ketotifen (2 mg/day), and theophylline (10 mg/kg/day). In a third group (479 patients), the same pretreatment was associated with preventive measures and with FEV1 results and the occurrence of large local reactions. A fourth group consisted of 223 patients who received a step protocol with the same pretreatment and preventive measures. The incidence of SRs per patient was 36.2% with RIT alone, 16.2% when the pretreatment was added, and 7.2% when pretreatment and preventive measures were used. Patients receiving the step protocol had 5.4% SRs. Adrenaline had to be used from 10.0%, 4.6%, 0.2%, and 0.2%, respectively. No reaction started 45 minutes or later after the last injection. Children younger than 5 years of age had a significantly greater number of SR.

Double-blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. III. Efficacy and safety of unfractionated and high-molecular-weight preparations in rhinoconjunctivitis and asthma.

Specific immunotherapy with unmodified formalinized allergoids is effective in grass-pollen allergy, but systemic reactions have been observed. A high-molecular-weight formalinized allergoid (HMW-GOID) was fractionated by gel filtration, retaining molecules of greater than 85,000 daltons in the expectation of improving safety without sacrificing efficacy. HMW-GOID and unfractionated allergoid (GOID) had a similar allergenic activity assessed by RAST inhibition, but the HMW-GOID preparation was 65 times less reactive when it was tested by skin prick test than the GOID preparation. A double-blind, placebo-controlled study was carried out in grass pollen-allergic patients with placebo (14 patients), GOID (15 patients), and HMW-GOID (13 patients). An additional group of 18 patients was treated by a rush schedule with a standardized orchard grass-pollen extract. A similar mean cumulative dose was administered with both allergoids. The fractionated allergoid only elicited minor systemic reactions similar to reactions elicited by placebo, whereas 20% of patients treated by GOID and 5.5% of patients receiving the standardized extract had a severe systemic reaction. For rhinitis, conjunctivitis, and asthma, the HMW-GOID and the standardized extract had a similar efficacy, significantly greater than placebo. GOID was less effective than the other two active treatments but was significantly more effective than placebo treatment for asthma and conjunctivitis.

Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. Systemic reactions during the rush protocol in patients suffering from asthma.

Specific immunotherapy can induce severe systemic reactions (SRs), especially in patients with asthma. It also appears that potent standardized extracts may be more often involved in the generation of SRs than other extracts. Since these SRs may be potentially life threatening, it is desirable to predict their onset. A prospective study was carried out in 125 mite-allergic subjects with asthma ranging in age from 4 to 57 years to assess the incidence of SRs during a rush immunotherapy (RIT) protocol and maintenance injections and to attempt to predict the onset of the SRs. All patients received the same standardized extract of Dermatophagoides pteronyssinus with the same RIT and the same maintenance dose (3000 BU in subjects older than 10 years and 1500 BU in children younger than 10 years). Patients were carefully monitored during the RIT protocol, and possible SRs were followed for up to 2 hours after injections. Patients then received maintenance injections for a mean duration of 18.2 +/- 5.6 months. During maintenance injections, patients were under supervision of a physician for 30 minutes. Within 2 weeks before the RIT, all patients older than 6 years had a pulmonary function test, skin prick test end point with the standardized D. pteronyssinus extract, and RAST. The severity of asthma was examined with the score of Aas. Forty-seven patients had an SR during the RIT protocol: four mild generalized urticaria, 35 asthma exacerbations, and eight anaphylactic shocks. None of the patients had to be admitted to an intensive care unit. Most SRs started within 15 minutes, and none of the SRs started 45 minutes or later after the last injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Specific immunotherapy with a standardized Dermatophagoides pteronyssinus extract. II. Prediction of efficacy of immunotherapy.

House dust mites of the species Dermatophagoides pteronyssinus (Dpt) represent one of the major allergens inducing asthma. However, a strict allergy to Dpt is not always observed in Dpt-allergic patients, since nonallergic and other allergic triggering factors often coexist. It was suggested that specific immunotherapy with house dust-mite extracts is more effective in children than in adults. A controlled study was undertaken in 215 Dpt-allergic patients with asthma ranging in age from 3 to 72 years (mean +/- SD, 28.2 +/- 10.9 years) to investigate parameters that might predict the efficacy of specific immunotherapy before it is started; 171 patients received a rush immunotherapy protocol with a standardized Dpt extract and, subsequently, maintenance injections with 3000 BU of this extract, and 44 patients served as a control group. Before immunotherapy, all patients had a complete evaluation of the severity of asthma by symptom-medication scores and a pulmonary function test, as well as a study of other triggering factors by checking on seasonal and perennial allergens, sinusitis, and other possible causes, such as aspirin intolerance; 196 patients were investigated between 9 and 12 months after the onset of the survey by means of pulmonary function tests and symptom-medication scores. Medications were adapted according to peak flow rates. It was observed that patients with chronic sinusitis, and/or aspirin intolerance, and/or other perennial allergies did not benefit from specific immunotherapy; therefore, the treatment of a major etiologic factor did not demonstrate improvement in the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Nasal challenge with pollen grains, skin-prick tests and specific IgE in patients with grass pollen allergy.

Nasal challenges with pollen grains are as close as possible to natural pollen exposure, but they are not well documented in grass pollen allergy. Forty-four grass pollen allergic patients and ten non-allergic volunteers were tested by means of nasal challenge, quantitative skin-prick tests with a standardized orchard grass pollen extract and serum-specific IgE. Nasal challenges were performed with lactose and increasing concentrations of orchard grass pollen grains (15-3645 grains, three-fold increase). The test was considered to be positive when a symptom score over 5 was obtained, since this score had been previously correlated with the release of PGD2 in nasal secretions. All control subjects and 3/44 patients had a negative challenge. The number of orchard pollen grains required to elicit a positive challenge was 332 +/- 440 (range: 15-1215 grains) and the distribution was Gaussian. This number is higher than expected according to pollen calendars performed during the season, but owing to the priming effect of the nasal mucosa by allergens it is compatible to natural exposure. The correlation between nasal provocation tests and skin-prick test end-points was significant (P less than 0.005, Spearman rank test). Conversely there was no correlation between nasal challenge or skin-prick test end-point and serum-specific IgE.

Double-blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. I. Rush immunotherapy with allergoids and standardized orchard grass-pollen extract.

Forty-five grass pollen-allergic patients were randomly assigned to three groups according to their skin test and RAST sensitivities and the severity of seasonal rhinitis. Eleven patients were treated with placebo (group 1), 19 patients (group 2) were treated with a six-mixed grass-pollen allergoid prepared by mild formalinization with a two-step procedure, and 15 other patients were treated with a standardized orchard grass-pollen extract (group 3). Because of a different immunotherapy schedule, only patients placed in groups 1 and 2 received the extracts in a double-blind fashion. Rush immunotherapy was performed in 3 to 6 days, and the maintenance dose was subsequently administered weekly for 4 weeks and every 2 weeks until the end of the grass-pollen season. During the season, a coseasonal treatment was administered. Systemic reactions occurred during the rush protocol in 36.8% of patients treated with allergoid and 20% of patients who received the standardized extract. Only patients treated with allergoid had systemic reactions during maintenance dose. The reactions observed with the standardized extract were more severe. Total doses of allergoid ranged from 2350 to 13,500 protein nitrogen units. Symptoms and medication scores during the peak of the season were analyzed. Patients treated with the standardized allergen had a significant reduction of the number of days of symptoms during the month of June (9.5 +/- 6.7 days; p less than 0.005) and of medication scores (1.3 +/- 1.4; p less than 0.01) compared to patients receiving placebo (19.4 +/- 8.1 days; medication score, 2.8 +/- 2.1).(ABSTRACT TRUNCATED AT 250 WORDS)

Allergy in the Mediterranean area. II: Cross-allergenicity among Urticaceae pollens (Parietaria and Urtica).

Pollens of related species usually share common antigens and are cross-reacting but this is not always the case. The cross-allergenicity of two species of Urticaceae pollens (Parietaria and Urtica, nettle) was sought by means of RAST-inhibition and isoelectric focusing. A preliminary experiment in forty-two patients investigated by means of skin tests and RAST showed that most patients were either allergic to Parietaria or nettle and that both reactivities were uncommonly associated. The results of RAST-inhibition confirmed the total absence of cross-reactivity between these two related species. IEF patterns indicated that most proteins are in the acidic range of pH and did not reveal large discrepancies. Parietaria and Urtica pollens, although belonging to the same family and having close microscopic patterns, have very different allergenic activities. This study demonstrates that cross-allergenicity cannot be predicted.

Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. I. In vivo and in vitro parameters after a short course of treatment.

Dermatophagoides pteronyssinus (Dp) is the major allergen in allergic asthma in France. Standardized and lyophilized Dp extracts are available, and their effectiveness after a short course of rush immunotherapy was examined in a placebo-controlled, double-blind study. Twenty patients received the Dp standardized extract, and 10 other patients received a placebo extract. Before and 7 weeks after rush immunotherapy, in vivo and in vitro parameters were examined. Bronchial provocation tests performed in a standardized manner demonstrated that a provocative dose causing a 20% fall in FEV1, a 25% fall in maximum mild expiratory flow rate, a 25% fall in maximum flow when 50% of the forced vital capacity has been expired, and a 35% fall in specific airway conductance were significantly (p less than 0.005 to p less than 0.01, Wilcoxon W test) improved in the treated group and remained unchanged in the placebo group. Skin test titration demonstrated that patients placed in the treated group had a significant (p less than 0.001, Wilcoxon W test) decrease of both end point titer and size of the largest wheal. No significant difference was observed in the placebo group. Serum Dp-IgE did not vary significantly in either group. Serum Dp antigen P1-IgG was significantly (p less than 0.001, Wilcoxon W test) increased in the treated group and slightly increased in the placebo-treated group. This study demonstrated that a Dp standardized extract administered by a rush protocol elicits a rapid and significant immune response and leads to a significant protection of the patients.

Comparison between rush immunotherapy with a standardized allergen and an alum adjuved pyridine extracted material in grass pollen allergy.

Rush immunotherapy with a standardized and lyophilized cocksfoot pollen extract was performed in twenty-three allergic subjects and compared with classical immunotherapy done with an alum adjuved, pyridine extracted cocksfoot pollen extract (fifteen subjects) and a control group of ten patients. The three groups were perfectly matched. Clinical benefits were analysed by means of symptom scores. It was shown that rush immunotherapy gave significantly better results when asthma or rhinitis was considered than either classical immunotherapy (P less than 0.02) or in the control group (P less than 0.01 and 0.02). Skin tests were significantly reduced after rush immunotherapy and did not change in the two other groups. After the pollen season the skin test reactivity was increased in the rush immunotherapy group. Cocksfoot pollen specific IgE did not vary significantly in the three groups. Cocksfoot pollen specific IgG was significantly (P less than 0.05) increased in the rush immunotherapy group before the pollen season and did not vary significantly in the other groups.

Occupational allergy to sunflower pollen.

Although the sunflower belongs to the Compositeae family, allergy to sunflower pollen is not common. The occurrence of occupational allergy to this pollen species made it possible to characterize cross-reactive patterns of Compositeae pollens in a human experimental model. A 24-yr-old man developed rhinitis and conjunctivitis over 5 yr of exposure to sunflower pollens, and asthma developed during the fifth year. All respiratory and occular symptoms disappeared after he was removed from exposure, but he had a food allergic reaction while he was eating honey containing 30% sunflower pollens. The diagnosis of occupational allergy was based on history, skin prick tests and RAST to the pollen. Bronchial provocation tests performed after removal from exposure confirmed the sensitivity to sunflower pollens but there was no nonspecific hyperreactivity. It was found by RAST inhibition that sunflower pollen does not cross-react with other Compositeae pollens tested or with sunflower seed. The honey that elicited food intolerance was demonstrated to inhibit significantly sunflower pollen RAST.