Effects of local treatment with salmeterol and terbutaline on anti-IgE-induced wheal, flare, and late induration in human skin

The capacity of terbutaline and the long-acting β₂-agonist salmetcrol to suppress wheal-and-flare reactions (WFRs) to intradermal antihuman IgE and to histamine was evaluated in 36 healthy volunteers. We also exaniined effects of the two drugs on the subsequent late cutaneous reaction (LCR) to anti-IgE. Salmeterol (10^-10 10^-6 M) and terbutaline (10^-10 10^-5 M), injected intradermally 2 or 15 min before anti-IgE challenge, produced a dose-dependent inhibition of the WFRs to anti-IgE (liter 1:10000) with a maximal effect of ?60% (wheal) and ??75% (flare) by both drugs. On a molar basis, salmctcrol was approximately 10–100 times more potent than terbutaline in inhibiting the WFRs. Moreover, the wheal response to histamine (4 nmol) was antagonized by ?40% after prctrcatment with either salmeterol (10^-5 M) or terbutaline (10^-4 M). We found that both salmeterol and terbutaline exhibited anti-WFR activity for up to 24 h, salmeterol being significantly more potent in this regard. When selecting a 15-min pretreatment interval with equieffective anti-WFR doses from the first dose-response experiments (i.e., a salmetcrol: terbutaline ratio of 1:10), the WFRs to high-dose anti-IgE (titer 1:100) were inhibited by terbutaline (10^-5 M) by 25–30%, but not by salmeterol (10^-4). On the other hand. salmeterol attenuated (by up to ?35%) the subsequent LCR more effectively than terbutaline. As compared to the prctrcatment procedure, infiltration of the drugs (single doses) into the wheals 30 min after challenge with anti-IgE (titer 1:100) proved to be less effective on the development of LCRs. Taken together, salmeterol was found to express higher potency and have longer duration of action than terbutaline in inhibition of IgE-mediated inflammation in human skin.     

Late cutaneous reactions in patients with delayed pressure urticaria

Late cutaneous reactions ( LCRs ) have been described in patients after allergen skin testing, skin testing with heterologous anti-human IgE, autologous skin-blister fluid, and, variably, after 48/80 injection. We report our results of skin testing patients with delayed pressure urticaria ( DPU ), chronic urticaria, and normal volunteers with histamine and 48/80. All patients with DPU had LCRs after 48/80. No patients in either of the other groups developed LCRs . This may be a clue to pathogenic mechanisms involved in DPU .     

Suppression of Immediate and Late Anti-IgE-Induced Skin Reactions by Topically Applied Alcohol/Onion Extract

In a double blind study, alcohol/onion extract (5% ethanol) was injected simultaneously with 20 IU and 200 IU rabbit anti-human-IgE intradermally in 12 adult volunteers (6 atopics, 6 non-atopics). Diameters of wheals and flares were measured 10 min after and compared with control sites challenged with 20 IU and 200 IU anti-IgE in a 5% ethanol solution. The skin sites were then treated epidermally with 45% alcohol/onion extract and 45% ethanol under occlusion. Diameters of late cutaneous reactions were measured hourly. Oedema formation was clinically estimated according to an arbitrary scale and skin thickness measured with a calliper. In the onion-treated skin sites the wheal areas were significantly reduced (20 IU: control: 108 +/- 53 mm2; onion 69 +/- 42 mm2, P less than 0.05; 200 IU anti-IgE: control: 152 +/- 25 mm2, onion: 138 +/- 26 mm2, P less than 0.02). The oedema formation during the late phase skin reaction was markedly depressed (P less than 0.005 at 2 h, P less than 0.01 at 4 and 6 h, P less than 0.02 at 8 h). The extent of late skin reactions was slightly, but not significantly reduced. Obviously, onions contain pharmacologically active substances with anti-inflammatory and/or allergic properties.     

Treatment of ragweed hay fever with urea-denatured antigen E

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

Induction of late cutaneous reactions by skin-blister fluid from allergen-tested and normal skin

Ten healthy volunteers (five atopic, five nonatopic) and seven patients suffering from allergic bronchial asthma and rhinitis/conjunctivitis as well as showing dual reactions after intradermal or bronchial allergen challenge were investigated. Using the suction blister technique, we obtained skin-blister fluid (SBF) from dual skin reactions 30, 60, 180, and 300 min after allergen injection and from normal untested skin. The biologic activity of SBF was tested by intradermal reinjection of the fluid into the donor. SBF taken from dual skin reactions 30 or 60 min after allergen injection produced late cutaneous reactions (LCRs) quite similar to those induced by the allergen. SBF taken from LCR areas 180 or 300 min after antigen testing had much weaker effects, similar to SBF from untested skin. A possible content of allergen extract in SBF from allergen-tested skin areas was not responsible for the observed effects as demonstrated in passive cutaneous anaphylaxis experiments in monkeys. High doses of SBF from untested skin were able to induce LCRs similar to but weaker than LCRs produced by SBF taken at early phases from dual skin reactions. Similar volumes of autologous heparin-plasma or serum did not induce LCRs. It is concluded that during the initial phase of dual skin reactions, factors are formed that are able to induce LCRs. The generation of these mediators seems to be caused at least in part by the extravasation of plasma.     

IgE against ethylene oxide-altered human serum albumin in patients with anaphylactic reactions to dialysis

We have measured total antibody and IgE directed against ethylene oxide-altered human serum albumin (ETO-HSA) in the sera of 24 patients who have experienced anaphylaxis during hemodialysis and of 41 patients who have not had such episodes during hemodialysis. ETO is used to sterilize dialyzers and other medical equipment. The geometric mean level of IgE to ETO-HSA in patients with reactions (0.9 ng ETO-HSA bound to IgE per milliliter of serum) is significantly higher than in nonreacting patients (0.1 ng/ml, p less than 0.0001). Sixteen of 24 patients with reactions had detectable levels of IgE to ETO-HSA, whereas only three of 41 nonreacting patients had detectable levels (p less than 0.0001 chi-square). The geometric mean level of total antibody to ETO-HSA is also significantly higher in patients with reactions (270 ng ETO-HSA bound per milliliter) than in nonreacting patients (31 ng/ml, p less than 0.0001). Fourteen of 24 patients with reactions but only four of 39 nonreacting patients had total antibody binding of ETO-HSA (p less than 0.0001 chi-square). These data extend our previous observations on a small group of 13 patients receiving hemodialysis (seven patients with reactions, and six nonreacting patients) and clearly demonstrate an association between the presence of IgE or total antibody to ETO-HSA and immediate anaphylactic reactions in this group of 65 patients receiving hemodialysis.     

Association of protamine IgE and IgG antibodies with life-threatening reactions to intravenous protamine

Life-threatening reactions to intravenous protamine, administered to reverse heparin anticoagulation, have been reported with increasing frequency as a consequence of the escalating use of cardiac catheterization and coronary bypass surgery. Retrospective studies have shown that such reactions are more common in diabetic patients receiving daily subcutaneous injections of protamine-insulin preparations. To determine whether anti-protamine IgE or IgG antibodies might explain the increased risk for protamine reactions among patients with protamine-insulin-dependent diabetes, we conducted a case-control study of 27 patients (diabetic and nondiabetic) who had acute reactions to intravenous protamine and 43 diabetic patients who tolerated protamine without a reaction during diagnostic or surgical procedures. Cases and controls were grouped according to previous exposure to protamine-insulin preparations. In diabetic patients who had received protamine-insulin injections, the presence of serum antiprotamine IgE antibody was a significant risk factor for acute protamine reactions (relative risk, 95; P = 1.0 X 10(-5), as was antiprotamine IgG (relative risk, 38; P = 1.2 X 10(-5). No patients without previous exposure to protamine-insulin injections had serum protamine IgE antibodies. In this group, anti-protamine IgG antibody was a risk factor for protamine reactions (relative risk, 25; P = 0.0062). We conclude that in protamine-insulin-dependent diabetics, the increased risk of serious reactions when intravenous protamine was given appeared to be caused largely by antibody-mediated mechanisms. In nondiabetic subjects, the presence of protamine IgG was significantly associated with an increased risk of acute protamine reactions, although many nondiabetic subjects who had reactions had no IgG antibodies.     

Positive skin tests to fern spore extracts in atopic patients

Thirty-six atopic and eight non-atopic adult volunteers who had been exposed to ferns in their homes, were skin tested with extracts obtained from seven species of house ferns. Out of the 36 atopic patients, 18 had positive skin reactions to at least one out of seven species of the most common house ferns, whereas none of the non-atopic, healthy controls had positive reactions to any of the ferns.     

Evaluation of neutralizing antibodies to type A, B, E, and F botulinum toxins in sera from human recipients of botulinum pentavalent (ABCDE) toxoid.

Twenty-five serum specimens from personnel immunized with botulinum pentavalent toxoid (ABCDE) had titers of neutralizing antibodies to type A (5.7 to 51.6 IU/ml), type B (0.75 to 18 IU/ml), and type E (0.61 to 10 IU/ml) botulinum toxins. Titers for one type could not be used to predict titers for another type in individuals receiving the toxoid. Cross-neutralizing antibodies to type F botulinum toxin were not detected (less than 0.0125 IU/ml).     

Induction of late cutaneous reaction by kallikrein injection: comparison with allergic-like late response to compound 48/80

Although IgE antibody is able to provoke a late cutaneous allergic response (LCAR), the mechanism of its development is not clear. It seems to involve vasoactive and clotting mediators released from mast cells and basophils. Substances biologically similar to plasma kallikrein (KK), a Hageman factor activator, have been shown to be released by basophils in the course of an IgE-dependent reaction. Because compound 48/80 induces LCAR-like responses in the skin, we compared the ability of tissue KK and compound 48/80 to induce late cutaneous reactions (LCRs). All 40 test subjects showed an immediate wheal and flare reaction (WF) after both KK and 48/80. The WF was followed by an LCR characterized by diffuse edema, pain, and erythema in 36 of 40 subjects with 48/80 and 26 of 40 with KK. The LCRs evoked by the two agents did not differ in their appearance or in their time of development. These reactions increased until the 5 hr mark, began to decrease at the 10 hr mark, and were gone after 24 hr. Histologic study showed edema and a mixed cell infiltration with fibrin deposition. Challenge of the original injection site and a new site after 1 or 2 wk showed a local refractory state lasting 2 wk. Prednisone almost totally suppressed the LCRs induced by both KK and 48/80.     

Late and immediate systemic-allergic reactions to inhalant allergen immunotherapy

Systemic-allergic reactions to allergen immunotherapy were prospectively studied in four allergy treatment centers to assess frequency and specific attributes of these episodes relative to several variables. A total of 20,588 extract injections were administered to 628 patients. Forty-two patients experienced a systemic reaction (7%). Fifty-two systemic reactions occurred in total. Eight patients accounted for 18 of the reactions. Late systemic reactions, occurring from 35 minutes to 6 hours after injection, accounted for 38% of all reactions. Extracts containing only pollen antigens were more commonly associated with immediate and late systemic reactions relative to other extracts (p less than 0.001 and p less than 0.01, respectively). There were no significant reaction-rate differences whether immunotherapy was at maintenance or increasing doses or if the time of injection was during a pollinating or nonpollinating season. The most common clinical manifestations of the systemic reactions were generalized pruritus and urticaria. We conclude that patients receiving extracts containing only pollen antigens have increased systemic-allergic reaction rates. A subgroup of patients are at risk for recurrent reactions. Finally, late systemic reactions to immunotherapy are not rare events and pose a definite risk to the individual patient.     

Cutaneous reactivity to mosquito bites: effect of cetirizine and development of anti-mosquito antibodies

Cutaneous reactivity to mosquito bites was examined in 27 adult volunteers exposed to Aedes communis mosquitoes. Twenty-three subjects showed a combination of immediate wealing and delayed bite-papules, two subjects each experienced only immediate or delayed cutaneous reactions and two were non-responsive to the bites. The mean size of wealing and the mean score of pruritus was similar in 19 non-atopic and in eight atopic volunteers. These results confirm that normal subjects exhibit different stages of sensitization to mosquito bites. At the onset of the mosquito season, immunoblotting showed that four of 21 subjects (19%) had IgG-class antibodies to a recently described 21.5 kD Aedes communis mosquito antigen. After a 10-day exposure to a mean of 47 mosquito bites, these antibodies were found in 10 subjects (48%) who exhibited both strong and weak cutaneous bite-lesions. A placebo-controlled, double-blind study with cetirizine 10 mg was performed to examine the effect of this non-sedating antihistamine on mosquito bites. The bite lesions were measured and pruritus scored at 15 min, 60 min, 12 hr, and 24 hr. Cetirizine decreased significantly immediate wealing and pruritus (P less than 0.01), but had no effect on the delayed symptoms. This result supports the view that immediate mosquito-bite reactions are histamine-mediated.     

A prospective Italian survey on the safety of subcutaneous immunotherapy for respiratory allergy

Background Subcutaneous immunotherapy is effective for the treatment of respiratory allergy, and it is largely used in Italy, but no systematic safety assessment has been carried out so far.
Objective To assess prospectively the safety of injection immunotherapy in a multicentre, real-life survey.
Methods Eleven Italian allergy departments recorded the clinical characteristics of systemic reactions (SRs) due to immunotherapy. Vaccines were prescribed according to guidelines; only standardized depot extracts were used. SRs were graded according to the EAACI recommendations, and were classified as immediate or delayed.
Results One thousand seven hundred and thirty-eight patients (847 males, age range 5–71) received immunotherapy from eight different manufacturers, for a total of 2038 courses (300 patients received two extracts). A total of 60 785 injections were given over a mean immunotherapy duration of 3 years. Overall, 95 reactions were observed in 57 patients (3.28%), corresponding to 4.7% of the courses and 1.56/1000 injections. Twenty-five patients experienced more than one adverse event. There were 34 grade 2, 60 grade 3 and one grade 4 reactions and no fatality. SRs occurred more frequently in patients with asthma than in patients with rhinitis alone (4.1% vs. 1.1%), and were equally distributed between the build-up and the maintenance phase. Ragweed and grass extracts caused significantly more side effects than other allergens.
Conclusion In this large prospective study, the rate of SRs was low, thus confirming that injection immunotherapy has an acceptable risk/benefit ratio when prescribed and carried out according to recommendations.     

Immunotherapy for cat asthma

In 22 patients with cat asthma who were highly sensitive to cat, we compared, double-blind, the effects of immunotherapy with cat-hair and dander extract (11 patients) with effects of placebo (11 patients). Patients were matched by the dose of the cat extract expressed in Food and Drug Administration (FDA) units of Fel d I (previously called cat allergen 1) required for end point reaction in intradermal skin test end point titration (STEPT), for in vitro leukocyte histamine release (LHR), and for the dose of cat extract producing a 20% fall in FEV1 (cat-extract PD20) in bronchoprovocation test. Patients were matched also for bronchoprovocation dose of methacholine producing a 20% fall in FEV1 (methacholine PD20). Patients were randomly assigned to one of two treatment groups. During immunotherapy, doses were increased to maintenance dose of 4.56 FDA units of Fel d I, or, if this were less, to the highest tolerated dose. Systemic reactions to cat-extract immunotherapy were mild and infrequent. Before and during immunotherapy, we measured (in FDA units of Fel d I) cat-extract PD20, cat-extract intradermal STEPT, cat-extract in vitro LHR, serum levels of cat IgG and cat IgE, and methacholine PD20. After they had received 1 year of immunotherapy, patients receiving cat extract, in comparison to patients receiving placebo, had decreased cat-extract PD20 (p less than 0.01), diminished responses to cat-extract intradermal STEPT (p less than 0.025), increased IgE antibodies toward cat extract (p less than 0.01), increased IgG antibodies toward cat extract, Fel d I, and cat albumin (p less than 0.001), but no significant change in cat-extract in vitro LHR or in methacholine PD20. We conclude that cat-extract immunotherapy was well tolerated, significantly decreased skin and bronchial responses to cat extract, and significantly increased IgE antibodies to cat extract and IgG antibodies to cat extract, Fel d I, and cat albumin.     

Immunotherapy with honeybee venom and yellow jacket venom is different regarding efficacy and safety.

Venom immunotherapy (VIT) for Hymenoptera allergy is accepted as safe and effective. However, widely varying success rates and frequencies of side effects are reported. Differences between various Hymenoptera species could account for these diverging results. We therefore analyzed 205 patients with a history of systemic allergic reactions to either honeybee (148 patients) or yellow jacket stings (57 patients) during VIT. All patients had a positive skin test to the respective venom before VIT, were monitored for side effects of VIT, and submitted to a sting challenge while they were receiving VIT. Patients with honeybee-venom allergy had a higher sensitivity in both skin tests (p less than 0.05) and RAST (p less than 0.001) than patients with yellow jacket-venom allergy. They developed systemic side effects to VIT injections significantly more often (41% versus 25%; p less than 0.01) and also reacted more frequently to the sting challenge (23% versus 9%; p less than 0.01) than patients with yellow jacket-venom allergy. We conclude that results obtained from studies on the allergy to one Hymenoptera venom cannot be extrapolated to allergies to other Hymenoptera venoms.     

Dose response of A/Alaska/6/77 (H3N2) cold-adapted reassortant vaccine virus in adult volunteers: role of local antibody in resistance to infection with vaccine virus.

An attenuated influenza A candidate vaccine virus, derived from the A/Ann Arbor/6/60 (H2N2) cold-adapted (ca) donor virus and the A/Alaska/6/77 (H3N2) wild-type virus, was evaluated in adult seronegative volunteers (serum hemagglutination-inhibiting antibody titer, less than or equal to 1:8) for level of attenuation, infectivity, antigenicity, and genetic stability. Four groups with similar preinoculation mean titers of serum and nasal wash antibodies were inoculated intranasally with 10(4.5), 10(5.5), 10(6.5), or 10(7.5) 50% tissue culture infectious doses (TCID50) of the ca reassortant virus, and eight other seronegative adult volunteers received the wild-type virus. Only 2 of 66 vaccinees developed fever or mild and brief systemic or upper respiratory tract illness or both. Both volunteers with vaccine-related reactions received the highest dose (10(7.5) TCID50) of ca virus, which indicates that the vaccine retains some mild reactogenicity at a high dosage. In contrast, four of eight volunteers infected with the wild-type virus became ill. Each of the 54 isolates tested retained the temperature-sensitive phenotype of the vaccine virus. Thus, the ca reassortant was genetically stable and attenuated at 10(4.5) to 10(7.5) TCID50 for seronegative adults. The 50% human infective dose of ca virus was approximately 10(5.3) TCID50. Ten and one hundred 50% human infectious doses infected 73 and 83% of vaccinees, respectively, and approximately 75% developed an immunological response at these doses. The failure of the vaccine virus to infect some volunteers was correlated with the presence of pre-inoculation nasal wash immunoglobulin A hemagglutinin antibody.     

A review of the hospital course of asthmatic children and adults

We reviewed 82 consecutive hospital admitted patients treated for acute severe asthma over a seven-month period at a University medical center and an additional 25 patients at an affiliated community hospital. Those asthmatics treated on the adult medical service had a significantly longer length of hospitalization when compared to those treated on the pediatric service (t = 5.12; p less than 0.005). In addition, longer hospitalization periods were noted for those asthmatics who smoked (t = 2.98; p less than 0.005) and for those with a history of chronic bronchitis (t = 2.32; p less than 0.025). Drug regimens were frequently suboptimal; 30% of the patients reviewed were receiving no therapeutic agents prior to admission. Of those patients receiving theophylline 53% had serum levels of less than 10 mcg/ml on their post admission assessment. Although frequently suboptimal, inadequate drug regimens prior to admission did not lengthen hospital stay. Poor compliance with medications was recorded as a major cause of decompensation in nine patients whose mean age was 13 years. Finally, occupational exposure to airway irritants was elicited from 24% of the adult population at the University medical center. Increased length of stay in the hospital for adult asthmatics may reflect relatively fixed airway disease among these patients since a significant proportion of them related a history compatible with chronic bronchitis or were smokers. Occupational histories should be evaluated in adult asthmatics to rule out workplace exposures as a cause for severe decompensation. In addition, the importance of educational efforts addressing therapeutic non-compliance is evident from this study.     

E-rosette forming cells and humoral antibody titres in humans after vaccination with three different inactivated influenza virus vaccines A/USSR/92/77 (H1N1)

The number of E-rosette forming cells and the serum haemagglutination inhibition (HI) antibody titres were examined in 37 volunteers immediately before and 14, 28, 35 and 63 days after immunization with three inactivated influenza virus vaccines A/USSR/92/77 (H1N1)--NIB 6 and in 11 non-vaccinated controls. From the former, 10 volunteers were immunized with 1000 haemagglutinin (HA) IU per dose, 11 volunteers with the NIB 6 adsorbate vaccine (340 HA IU/dose) and 16 volunteers with a bivalent vaccine composed of 180 HA IU/dose NIB 6 and 180 HA IU/dose of influenza virus A/Bangkok X-73 (H3N2). The percentage of E-rosette forming cells was decreased in all vaccinated volunteers 14 days after vaccination; later on the values reached normal level of non-vaccinated controls or of subjects before vaccination. The number of E-rosette forming cells was in correlation with the applied virus vaccine dose, i.e. for the 1000 HA IU/dose: 29.95 +/- 11.74%, p less than 0.001 and for the 340 HA IU/dose: 47.75 +/- 11.15%, p less than 0.005; however, after administration of 180 HA IU/dose of NIB 6 in the bivalent vaccine, the value 58.65 +/- 11.5% was not significantly decreased in comparison to non-vaccinated donors. The serum HI antibody titres reached the highest level 14 days after vaccination and remained constant during the next 6 weeks. There was a correlation between decreased E-rosette values and increased serum antibody titres (p less than 0.05). The current study indicates that the number of E-rosette forming cells may serve as a further laboratory criterion for controlling the effect of inactivated influenza virus vaccines on the immune system of man.     

The existence of specific antibodies to cobalt in hard metal asthma

Twelve workers with hard metal asthma diagnosed on the basis of peak flow diaries and positive bronchial reactions to cobalt chloride (CoCl₂) were studied for sensitization by detection of specific antibodies to radioactive cobalt (⁵⁷Co), cobalt-conjugated human serum albumin (Co-HSA) and cobalt-conjugated exchange resin (Co-resin). Their IgE titres ranged from 73 to 1500 IU/ml and eight were atopic individuals. Sixty serum samples from asthmatic patients with IgE titres of 14–4300 IU/ml were studied as controls in all tests. Eleven of twelve subject sera that selectively bound to ⁵⁷Co after incubation with saturated ammonium sulphate (>232 c.p.m., P <0.01) were divided into three groups: (1) six sera showing evidence of specific IgE antibodies to Co-HSA (>673 c.p.m., P <0.01) without those to Co-resin; (2) one serum giving a positive radio-allergosorbent test (RAST) only to Co-resin (>417 c.p.m., P <0.01), and (3) four sera that were negative for two antigenic agents (Co-HSA, Co-resin). These results suggest that the subjects had occupational asthma due to hard metal exposure from cobalt sensitivity. An immuno-allergic mechanism mediated by specific IgE antibodies to cobalt was confirmed to be responsible for the development of hard metal asthma, with the possibility of some role of the reaction without reagins.     

IgG4 antibodies in patients with house-dust-mite-sensitive bronchial asthma: relationship with antigen-specific immunotherapy

Sera from 40 patients with house-dust-mite (Dermatophagoides farinae)-sensitive bronchial asthma were evaluated by solid-phase radioimmunoassay for their mite-specific IgG4 antibody levels. Asthmatic patients undergoing specific immunotherapy possessed a significantly higher mean value of IgG4 antibodies than normal controls and asthmatics without immunotherapy (p less than 0.01 and p less than 0.05, respectively). Moreover, evaluation of 11 patients before and after immunotherapy showed that IgG4 antibodies tend to increase during immunotherapy. The clinical significance of the IgG4 subclass as blocking antibodies in immediate allergic reactions is also briefly discussed.