Relevance of serum ECP measurements for monitoring acute asthma in children.

To evaluate the role of serum eosinophil cationic protein (ECP) concentration as a monitoring parameter in acute bronchial asthma, 11 children (mean age 10.2 years) were studied during an acute exacerbation of their disease. Under an appropriate anti-inflammatory therapy, FEV1 increased significantly at day 1 (p < 0.05), day 14 (p < 0.05), day 28 (p < 0.03), and day 56 (p < 0.03) compared to baseline values at referral to hospital. Serum ECP concentration decreased in the group of patients significantly at day 28 (p < 0.02) and day 56 (p < 0.04). However, considering the individual serum ECP time courses, most of the patients did not show a uniform pattern of continuously decreasing values. From our data, we conclude that measuring serum ECP concentration during acute asthma episodes in children may play a role in some patients, whereas in others--probably those without acute eosinophil inflammation--monitoring by serum ECP concentration is of limited value.

Prevalence of coeliac disease in diabetic children and adolescents in Sweden.

The aim of this study was to determine the minimum prevalence of coeliac disease in a group of 459 diabetic children and adolescents. Six patients were already known to have coeliac disease. A total of 436 patients with type 1 diabetes mellitus aged 2-21 years and with age at onset at 2 months to 17 years at three paediatric departments agreed to participate in the study. All patients were tested for gliadin IgA antibodies with a commercial kit (Pharmacia Gluten IgA EIA). Later, serum was tested for reticulin IgA/IgG antibodies. Nineteen patients had elevated gliadin IgA levels (> 25 AU). Eighteen underwent jejunal biopsy. Ten had total or subtotal villous atrophy. These 10 patients were reticulin IgA-positive. Of 417 gliadin IgA-negative patients, 408 were reticulin IgA/IgG-negative. Of 6 reticulin IgA-positive patients, 3 had total or subtotal villous atrophy. All 3 had become gliadin IgA-positive at the time of biopsy. Among 3 reticulin IgG-positive patients with IgA deficiency, 2 had total villous atrophy: 1 was not willing to be biopsied. Patients with total or subtotal villous atrophy were judged as having coeliac disease and were recommended a gluten-free diet. Within 2 months, gliadin IgA levels were normal in patients adhering to the diet. Five patients have gone through a second jejunal biopsy to date with normal histology in all 5. The 15 newly diagnosed patients with coeliac disease plus 6 already known patients with coeliac disease and type 1 diabetes mellitus gave a minimum prevalence of coeliac disease in diabetic children and adolescents of 21/459 = 4.6%.

Total blood eosinophils, serum eosinophil cationic protein and eosinophil protein X in childhood asthma: relation to disease status and therapy.

Blood eosinophils, and serum levels of the eosinophil proteins, eosinophil cationic protein (ECP) and eosinophil protein X (EPX) were measured in childhood asthma. Seventeen patients mean age 11.9 years who were symptomatic with asthma, were enrolled in a study examining the eosinophil counts and eosinophil proteins at the onset of study and after treatment in relation to changes in their baseline forced expiratory volume at 1 second (FEV1) and % predicted FEV1. The patients with symptomatic asthma were compared with 17 patients mean age 12.0 years with asymptomatic asthma maintained on daily inhaled steroid and 13 patients, mean age 12.0 years, without asthma but with urticaria who served as non-asthma controls. Patients with symptomatic asthma did not have significantly higher initial eosinophil counts compared with those with asymptomatic asthma (0.43 x 10(9)/l vs 0.26 x 10(9)/l, P = 0.09) but had higher serum ECP levels (28.9 micrograms/l vs 18.5 micrograms/l). Both asthma patient groups had significantly higher serum ECP levels (P < 0.01) than the controls (9.8 micrograms/l). After therapy consisting of increased dose of inhaled steroids and/or oral steroids, patients in the symptomatic asthma group demonstrated a significant rise in FEV1 (1.67 l/sec at Visit 1 vs 2.08 l/sec at Visit 2, P < 0.001). A similar rise was seen for % predicted FEV1.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of the extended Phadebas RAST panel in the diagnosis of mould allergy in asthmatic children.

The clinical significance of mould allergens in Phadebas RAST panel was investigated in 121 asthmatic children. They were selected from a total population of 1649 patients. The patients were distributed into four groups, based on the combination of positive or negative skin prick tests (SPT) together with symptoms suggestive or not of mould sensitivity. Mould-specific IgE antibodies were investigated using the original RAST panel (Alternaria, Aspergillus, Candida, Cladosporium, Mucor and Penicillium) and a set of 10 additional mould-allergen discs (Aureobasidium, Botrytis, Curvularia, Epicoccum, Fusarium, Helminthosporium, Phoma, Rhizopus, Stemphylium and Trichoderma). The set of additional RAST discs revealed patients with mould-reaginic antibodies not found with the original RAST panel. This occurred in four of 49 (8.2%) RAST positive (class greater than or equal to 2) patients. The allergens most frequently positive were Cladosporium (in 28% of the patients), Candida (28%) and Helminthosporium (26%). A remarkable degree of simultaneous reactivity to almost all moulds tested was observed. Patients with multiple (greater than or equal to 7) mould sensitization were effectively pinpointed using any duplicate combination of Aureobasidium, Botrytis, Candida, Cladosporium, Helminthosporium, Penicillium and Stemphylium.

A new laboratory kit for anti-gliadin IgA at diagnosis and follow-up of childhood celiac disease.

A new laboratory kit measuring anti-gliadin IgA level by enzyme immunoassay has been evaluated to assess the test's potential for screening children with suspected celiac disease for small intestinal biopsy and predicting mucosal relapse after gluten challenge. One hundred thirty children were tested, and the results were related to the histopathologic findings of the intestinal mucosa and the final diagnosis. The sensitivity of the test was 97% and the specificity was 92% in the studied population. Forty-five children with celiac disease on different diets were observed. All had reduced anti-gliadin IgA levels on a gluten-free diet, and 91% had normal levels after 1 year. Two of four patients with increased values had an insufficient diet. During gluten challenge, 38 of 45 children showed increased anti-gliadin IgA levels. Of the remaining seven, five reacted either with immediate and strong symptoms or had spontaneously reduced gluten intake, or had an acquired IgA deficiency. In two cases, there was no explanation. In five children without relapse on gluten challenge, the anti-gliadin IgA level remained normal. Provided that IgA deficiency is ruled out and the gluten intake is sufficient, the test is reliable for screening and has a potential to replace the third biopsy.

Airway opioid receptors mediate inhibition of cough and reflex bronchoconstriction in guinea pigs.

Effects of opioids and opioid antagonists on citric acid-induced cough and reflex bronchoconstriction have been examined in conscious guinea pigs. Airway reflexes produced by inhaled citric acid are mediated by capsaicin sensitive sensory neurons, and we examined particularly the possibility that inhibitory effects of opioids can be exerted locally in the airway. As expected, systemically administered codeine (1-10 mg/kg), meperidine (3-30 mg/kg) and morphine (1-10 mg/kg) dose-dependently inhibited cough and bronchoconstriction. However, inhalations of nebulized codeine (10-100 mg/ml) and morphine (10-30 mg/ml) also produced these effects. The potency and rapid onset of action of inhaled codeine suggest that it exerted its effects without first being metabolized to morphine. The opioid receptor antagonist naloxone completely (10-100 micrograms/kg), and nalorphine (a mixed agonist/antagonist) (1-3 mg/kg) partly, inhibited codeine's antitussive and antibronchoconstrictor effects. Nalorphine alone (3-30 mg/kg) inhibited citric acid induced reflexes, whereas naloxone was without effect. Prior inhalation of a quaternary opioid receptor antagonist, levallorphan methyl iodide (10 mg/ml), abolished the inhibitory effects of inhaled codeine (30 mg/ml). The present data suggest that inhibition of cough and reflex bronchoconstriction can be produced by opioids, acting on mu and kappa receptors located in the guinea pig tracheobronchial tree. The possible existence in the airways of a unique opioid receptor mediating inhibition of cough (as described in the central nervous system) cannot be excluded.

Specific IgE, IgG, and IgA antibody response to oral immunotherapy in birch pollinosis.

Thirty-nine patients with birch pollinosis participated in a double-blind, placebo-controlled trial of oral immunotherapy (OIT) for 18 months. They were treated with increasing doses of freeze-dried birch-pollen antigens for 16 months, reaching a cumulative dose of 280 x 10(6) biologic units. This is about 200 times more than the dose used in conventional subcutaneous immunotherapy (IT). In the placebo-treated group, but not in the actively treated group, there was a rise in postseasonal birch-specific IgE antibody levels. A significant decline in postseasonal values after 1 year of treatment was recorded in the actively treated, but not in the placebo-treated, group. Compared to the placebo treatment, there was a significant rise in birch-specific IgG antibodies in patients administered active treatment; however, the rise was less than that usually observed during subcutaneous IT. No significant change in birch-specific serum IgA was found in either group. The changes in IgE and IgG antibody levels demonstrate that OIT affects the immune system. This supports our recent findings that OIT demonstrates a beneficial effect in the treatment of birch pollinosis in adults. But, as with subcutaneous IT, there was no clear relationship between antibody response and clinical findings in the patients. The underlying mechanisms responsible for the relief of symptoms thus remain unknown.

Low specific IgE, IgG and lymphocyte reactivity in a group of patients developing anaphylaxis following a honey-bee sting.

Ten patients who developed severe generalized reactions following a honey-bee sting were investigated for the presence of specific IgE and IgG antibodies, and for lymphocyte reactivity following in-vitro honey-bee venom (HBV) stimulation. Five of the patients (high responders) showed high HBV-specific IgE and IgG levels, whereas the other five patients (low responders) showed low HBV-specific IgE and IgG levels. Mononuclear cells from the high responder group incorporated significant amounts of 3H-thymidine when activated with pure bee venom, whereas insignificant lymphocyte proliferation was observed in the low-responder group. It is concluded that, amongst HBV-sensitive patients, a group of low responders exists in whom the mechanism of anaphylaxis cannot be explained.

A double-blind study comparing monomethoxy polyethylene glycol-modified honeybee venom and unmodified honeybee venom for immunotherapy. I. Clinical results.

Thirty-five patients were allocated at random to immunotherapy (IT) in a double-blind way with either monomethoxy polyethylene glycol (mPEG)-modified honeybee venom (HBV) or HBV. The two groups were well matched regarding age, sex, skin sensitivity, HBV-specific serum IgE and IgG antibodies, and history of reactions after a field sting; mPEG-HBV-treated patients received doses that increased more steeply than doses of the HBV-treated patients. The maintenance dose of the former group (200 micrograms) was greater than that of the latter group (100 micrograms). During IT, both groups had the same frequency of local swellings after injections. Four patients receiving mPEG-HBV developed one mild systemic reaction (SR) during dose increase, whereas 10 patients receiving HBV demonstrated one or more of these reactions, compelling two patients to stop therapy. Following challenge with a honeybee sting after about 14 weeks of IT, six patients with SR were observed, four in the mPEG-HBV-treated group and two in the HBV-treated group. In the HBV-treated group, three patients were not challenged, one because of an insufficient IgG increase and two other patients because they dropped out of IT before reaching maintenance dose because of repeated SRs. Since the mPEG-HBV is extremely well tolerated during IT and the success rate is not significantly lower than with unmodified HBV, we suggest it as an attractive alternative to HBV for the treatment of HBV hypersensitivity. Increase of the maintenance dose may result in an even better clinical efficacy.

Oral immunotherapy in birch pollen hay fever.

Previous controlled trials with oral administration of allergen have not demonstrated any treatment effect in patients with allergic rhinoconjunctivitis or asthma. In the present double-blind, placebo-controlled trial, we have tested the effect of oral immunotherapy in adult patients with birch pollinosis. Thirty-nine patients completed this 18-month study comprising two birch pollen seasons. The patients received enterosoluble capsules daily, and the actively treated patients reached a cumulated dose of 280 times 10(6) biologic units of birch pollen extract, which is about 200 times higher than the dose used in conventional subcutaneous immunotherapy. We found a significant decrease in eye symptom scores and conjunctival sensitivity to birch pollen, as determined by conjunctival provocation test, as well as a numerical but nonsignificant decrease in nasal symptom scores, nasal sensitivity as determined by nasal provocation test, and antiallergic medication. The treatment was safe, and only a few slight side effects were observed. We thus conclude that our study demonstrates a clinical effect of oral immunotherapy in birch pollinosis.

Clinical and immunological effects of oral immunotherapy with a standardized birch pollen extract.

Oral immunotherapy (IT) was evaluated in a pilot study in two centres in children aged 8-15 years with allergic rhinoconjunctivitis. High doses (up to 20 X 10(6) BU monthly) of a defined freeze-dried birch pollen extract administered in enteric-coated gelatine capsules were given either daily for seven consecutive days every month or once weekly. Symptom scores, as assessed by sneezing, dripping and blockage of the nose, and redness, itching and swelling of the eyes, were significantly lower in treated patients compared to untreated, or placebo treated controls after 3 to 5 months of therapy. In all the 16 treated, but only in three of eight untreated patients, the scores were lower during the pollen season 1982 than during the pollen season preceding the treatment period, despite comparable pollen counts during the two seasons. One year after beginning treatment the reactivity in conjunctival provocation tests was decreased about 10-fold (P less than 0.001) in the patients receiving more than 2 X 10(5) BU monthly compared to about two-fold in patients receiving lower doses, or placebo. Increased levels of IgE antibodies directed against birch pollen were recorded in the serum and saliva of most patients after 3-4 months of active IT. In contrast, IgG antibody responses were poor in most of the patients. Side effects, particularly from the gastrointestinal tract, appeared in all treated children. In one of them a systemic reaction occurred during IT. The study indicates that properly performed oral IT with a potent birch allergen extract in enteric-coated capsules may be effective.

Oral immunotherapy of children with rhinoconjunctivitis due to birch pollen allergy. A double blind study.

Thirty children with rhinoconjunctivitis due to birch pollinosis were treated in a double blind manner for 10 months with enteric-coated capsules containing either a birch pollen preparation (n = 14) with doses up to 1.4 X 10(6) biologic units per day or placebo (n = 16). Compared with the placebo group the actively treated children had less symptoms during the birch pollen season after 3 months of therapy (P = 0.035). Skin prick reactions decreased significantly more in the active group than in the placebo group after 10 months (P = 0.01). Conjunctival sensitivity was lower in the active group than in the placebo group after 3 months of treatment (P = 0.01) but not after 10 months. Compared with the placebo group the treated children more often increased their levels of IgG (P = 0.007) and pre-seasonal IgE (P = 0.001) against birch. There was a seasonal increase of IgE antibody level against birch in the placebo but not in the treatment group (P less than 0.001). None of the treated children developed asthma, compared with five of the untreated children. No general reactions occurred and few side effects were seen during the treatment period. We conclude that in children with birch pollinosis oral immunotherapy with high doses of a biologically potent preparation in enteric-coated capsules is effective, easy to perform, economic and safe.

A preliminary study of immunotherapy with a monomethoxy polyethylene glycol modified honey bee venom preparation.

Monomethoxy polyethylene glycol (mPEG) modified honey bee venom (HBV) immunotherapy (IT) has been studied in 14 patients allergic to honey bee venom. Doses could be increased more rapidly and higher doses were reached compared to regular venom immunotherapy. No general side effects were seen, although large local swellings were found somewhat more often than with regular HBV. Most patients could easily be switched from the modified to the unmodified venom. Eight patients experienced and tolerated field stings. Skin testing showed a decreased allergenicity of the mPEG-HBV. The mean HBV-specific IgE level was below pre-treatment level already after only 6 weeks of IT. The HBV-specific IgG response was very good.

IgG and IgE antibody patterns after immunotherapy with monomethoxy polyethyleneglycol modified honey bee venom.

Antibody responses to honey bee venom (HBV) were studied in 13 patients during a 4-month course of immunotherapy with monomethoxy polyethyleneglycol (mPEG) modified venom. There was a rise of HBV-specific IgG antibodies as measured by IgG-RAST in all patients and a slight decrease of IgE antibody in most of them. The IgG-antibody responses during mPEG-HBV treatment as examined by crossed radioimmunoelectrophoresis were directed to phospholipase A, hyaluronidase, acid phosphatase and to another allergen, antigen 1. Thus, despite a high degree of mPEG-modification of HBV, the immunogenicity of the most important HBV allergens was retained.

Reproducibility of histamine skin prick test. Inter- and intravariation using histamine dihydrochloride 1, 5, and 10 mg/ml.

The reproducibility of skin prick test using histamine dihydrochloride 1, 5, and 10 mg/ml was tested by three nurses in five non-atopics in a double-blind trial. The variations day-to-day, within-day, between and for the same tester were calculated. Seventy-five percent of wheal reactions obtained by histamine 1 mg/ml were less than 15 mm2. With histamine 5 mg/ml there were only a few wheals less than 15 mm2 and none at all with histamine 10 mg/ml. The mean coefficient of variation of wheals greater than 15 mm2 was between 20-30%, in contrast to figures between 30-60% with wheals less than 15 mm2. No significant day-to-day or within-day variation was shown concerning histamine wheal areas. It is suggested that histamine dihydrochloride 10 mg/ml should replace histamine dihydrochloride 1 mg/ml as the positive reference in routine skin prick tests and biological standardization.

A double blind study on immunotherapy with chemically modified honey bee venom: monomethoxy polyethylene glycol-coupled versus crude honey bee venom.

24 patients with honey bee sting allergy were treated with either honey bee venom (HBV) or monomethoxy polyethylene glycol-coupled HBV (PEG-HBV) in a double blind trial. Both treatments induced a strong increase in HBV-specific IgG antibodies in most patients. Immunotherapy with PEG-HBV was much better tolerated than that with HBV. Conversely, patients on HBV did considerably better during a sting challenge with a living honey bee. Only 4 developed a large local and one a mild systemic reaction compared to 7 large local and 3 moderate to severe systemic reactions in the PEG-HBV-group. A higher maintenance dose of PEG-HBV may still be well tolerated but prove more effective at reexposure.

Venom immunotherapy in hymenoptera sting allergy. Comparison of rush and conventional hyposensitization and observations during long-term treatment.

42 patients with confirmed hypersensitivity to honey bee (HBV) and/or yellow jacket (YJV) were treated with the respective venoms (7 with HBV, 5 with VJV and 30 with both venoms). Treatment tolerance, skin tests (ST), specific IgE- and specific IgG-antibodies were monitored before, after 3, 6, 12, 24 and 36 months. 21 patients had a rush and 21 a conventional treatment schedule. Maintenance dose was 100 micrograms. Adverse effects occurred as large local (8 patients), slight systemic (12 patients) and moderate to severe systemic reactions (4 patients). Of 24 re-exposed patients 17 had no reaction at all, six a markedly decreased and one an unchanged reaction. After 3 years of treatment ST became negative in nine of 31 patients on HBV and in seven of 26 patients on YJV. RAST became negative in three of 30 patients on HBV and 17 of 29 patients on YJV treatment. Both ST and RAST became negative in five HBV- and 10 YJV-treated patients. Loss of venom hypersensitivity according to diagnostic tests may correspond to actual desensitization and enable discontinuation of immunotherapy.

Clinical studies of a purified timothy pollen extract: desensitization therapy with a purified timothy pollen preparation compared to a crude timothy pollen extract. II. Results of the tests in vitro and their relation to symptoms and tests in vivo.

Perennial desensitization therapy was given during a period of 3.5 years to 40 children allergic to grass pollen allergens. 20 patients were treated with a crude and another 20 with a purified timothy pollen extract. 8 children served as untreated controls. The concentration of total and specific IgE in the treated groups covaried with those in the control group. Neither a suppression of the seasonal booster effect nor a suppression of IgE synthesis attributable to the treatment was found. The rise of timothy-specific "blocking' IgG antibodies was more pronounced in the group treated with the purified extract than in the group treated with the crude extract. A significant difference was found only after 3.5 years of treatment. The amplitude of rise of IgG antibodies correlated significantly with the effect of the treatment as judged by repeated conjunctival titration test. The results suggest that a good IgG response is an indication of successful therapy and that a better IgG response may be achieved with purified allergen extracts.

[Antibody response pattern (specific IgE and IgG) of insect sting allergic patients in immunotherapy with venom preparations]. / Antikörper-Antwortmuster (spezifische IgE und IgG) von Insektenstich-Allergikern unter Immuntherapie mit Giftpräparaten.

The concentrations of venom specific IgE (Phadebas-RAST) and IgG (Phadebas IgG-RAST) were monitored in sera of 22 patients with histories of systemic anaphylactic reactions following insect stings who underwent immunotherapy with venom extracts (bee venom and/or yellow jacket venom). Analysis of the immunological parameters during immunotherapy revealed great individual variation in the degree of response concerning both specific IgE and IgG antibodies. Nevertheless, four typical patterns of immune response could be found. The majority of the patients were able to produce high titers of IgG "blocking" antibodies without an IgE increase. Another group of patients had a marked rise in both specific IgG and IgE following the initial phase of hyposensitization. In contrast, one patient received venom injections without a significant IgG or IgE response. Finally, a small group of patients has a marked increase in specific IgE while synthesis of IgG was not observed. This IgE rise was the cause of systemic reactions in this group after the venom injections. Regular monitoring of venom specific IgE and IgG is useful in evaluating the degree of protection for the patient. Since an increasing IgG/IgE ratio must be obtained during immunotherapy, a knowledge of this relationship serves to adapt the individual treatment schedule.

Hyposensitization in childhood hay fever. A comparison of refined and whole timothy extracts.

Thirty-six children with well-defined criteria for hay fever (mean age 8 and range 4-15 years) were allocated at random for hyposensitization (HS) with a refined (R) or whole (W) timothy pollen extract during 3-4 years. HS was performed as rush HS with the patients hospitalized for about 1 week and thereafter with monthly injections. Scores for symptoms and antihistamine use were recorded during the season before HS and all seasons during HS. Skin and conjunctival tests were made at the start of HS and postseasonally. Blood samples for IgE and IgG measurements were drawn before and during rush HS and pre- and postseasonally each year. The R-group patients tolerated a higher allergen dose at the end of the rush HS than the W-group ones. They also demonstrated a higher, significant increase in total and specific IgE levels within 7 days and specific IgG levels within 60 days after the start of HS. In both groups postseasonal increases in total and specific IgE levels were seen. The IgG levels increased successively during the treatment. The most remarkable difference between the groups was in scores for symptoms and antihistamine use, which in group R decreased significantly while they increased significantly in group W. Based on these data we recommended that HS, if indicated, should be performed with purified allergen extracts.