Immunotherapy with cat- and dog-dander extracts. V. Effects of 3 years of treatment

The effect of a 3-year course of cat or dog immunotherapy (IT) was evaluated in 32 patients with a history of asthma on exposure to cat or dog. Twenty-one subjects (14 children and seven adults) received cat IT and 11 subjects (six children and five adults) received dog IT. Bronchial challenges with allergen and histamine were performed once a year. Specific IgE, IgG1, and IgG4 were measured, and skin prick tests were done in connection with the challenges. Allergen sensitivity decreased significantly in both treated groups (p less than 0.001 and p less than 0.05 in the cat-allergen and dog-allergen treated groups, respectively). Bronchial hyperreactivity measured by the provocative concentration of histamine causing a 20% decrease in peak expiratory flow in the cat-allergen treated patients (p less than 0.001) but not in the dog-allergen treated patients. Skin sensitivity decreased in both groups (p less than 0.01 and p less than 0.05), whereas specific IgE increased initially but dropped to the pretreatment level during the second year. Specific IgG1 and IgG4 increased during the first and second year in the cat-allergen treated group (p less than 0.01 and p less than 0.001), whereas only IgG4 increased in the dog-allergen treated group (p less than 0.01). Five cat-allergen treated children and one of the adults who completed 3 years of therapy had mild systemic reactions. We conclude that cat IT ameliorated bronchial allergen sensitivity and bronchial hyperreactivity and resulted in an adequate antibody response. Dog IT was less efficacious but led to attenuation of bronchial allergen sensitivity.     

Immunotherapy with cat- and dog-dander extracts. III. Allergen-specific immunoglobulin responses in a 1-year double-blind placebo study

An investigation was made of the specific antibody response to individual antigens in 40 patients taking part in a double-blind placebo study of immunotherapy with cat- or dog-dander extracts. Antigen-specific IgE levels were measured by means of CRIE, and the results were expressed as scores. The patients demonstrated IgE specificities toward 1 to 5 antigens. Cat-dander antigens Nos. 4 (cat Ag 1) and 7, and dog antigens Nos. 6 and 13, produced the highest scores, but high IgE binding was also found for dog albumin. After 1 year of treatment, the IgE responses of the two treatment groups (allergen and placebo) were statistically indistinguishable from those before the start of treatment. There was a tendency toward a reduction in score for two of the dander antigens (cat Ag 1 and dog Ag No. 13), and no new IgE specificities appeared. Antigen-specific IgG levels were measured by means of CIE with patient serum incorporated in an intermediate gel, and the results were expressed as plus/minus precipitins. Only two patients had precipitating antibodies before the start of treatment (one against cat albumin and one against cat Ag 1). During the course of treatment, the production of antigen-specific IgGs was observed in 18/22 allergen- and 1/18 placebo-treated patients. For the cat allergen-treated group, the specificities were directed against cat antigens Nos. 2, 3 (cat albumin), 4 (cat Ag 1), and 7, and for the dog allergen-treated group, against dog antigens Nos. 2 (dog albumin), 13, and 20.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunotherapy with cat- and dog-dander extracts. II. In vivo and in vitro immunologic effects observed in a 1-year double-blind placebo study

The effects of immunotherapy on the skin prick test, allergen-specific IgE, and IgG in 39 patients (19 adults and 20 children), treated with partially purified cat- or dog-dander extracts or placebo for 1 year, were studied by use of a double-blind protocol. IgG levels were measured by three different assays: IgG RAST, IgG4 RAST, and Staph A IgG1, 2, and 4. The skin prick test reaction decreased continuously in the allergen-treated patients, the decrease being the first sign of an immunologic effect of the therapy. Allergen-specific IgE levels increased during the first 9 months in both children and adults. The RAST activity during the last 3 months continued to rise for the children, whereas it declined for the adults. IgG levels measured by all three methods demonstrated an increase in the allergen-treated patients and no increase in the placebo-treated patients. The children developed higher values on IgG RAST and IgG4 RAST than the adults. IgG RAST correlated negatively with IgE levels in the cat allergen-treated group. No correlation between skin prick test results, IgE levels, and IgG levels was found, nor was there any correlation between these parameters and the patients' own subjective evaluation or the allergen bronchial challenge test. In summary, the expected change in skin prick test reaction and allergen-specific IgE and IgG levels was found. The children tended to be more immunologically active than the adults.     

Immunotherapy with partially purified and standardized tree pollen extracts. IV. Results from long-term (6-year) follow-up

The long-term effect of tree pollen extract immunotherapy was investigated 6 years after termination of the treatment. Subjective symptom evaluation of 36 patients 6 years after a 3-year period of immunotherapy showed that rhinitis and asthma symptoms remained at the improved level reached just after termination of the treatment. Some 86% of the rhinitis patients and 68% of the asthma patients maintained improvement. None of the rhinitis patients developed asthma in the study period. Skin prick tests reflected the outcome of the subjective symptom assessment. The skin sensitivity of the patients decreased significantly during immunotherapy, and the skin reactions 6 years after specific immunotherapy were still significantly lower than the pretreatment levels. Total IgE and birch-specific IgE levels were constant throughout the study period, and both the affinity and epitope specificity of the IgE antibodies of the patients were the same before, during, and 6 years after treatment. In conclusion, specific immunotherapy reduces symptoms in patients suffering from rhinitis and asthma, and the effect is maintained 6 years after termination of the treatment. Specific immunotherapy seems to prevent long-term development of asthma in rhinitis patients. IgE measurements do not reflect the overall status of the patients.     

Immunotherapy with dog and cat extracts in children

Hypersensitivity to dogs and cats causes asthma in many children. In this open controlled clinical study we wanted to establish whether immunotherapy can be recommended as a supplement to conventional medical therapy in dog- and cat-induced asthma in children. Twenty-seven children with mean age 10 7/12 years and with allergy to dog or cat according to anamnesis, skin prick test (SPT), specific IgE (RAST) and bronchial provocation test (BPT) entered the study. On the basis of age and bronchial sensitivity they were randomly allocated to either immunotherapy with dog or cat extract (active group, n = 14) or conventional medical therapy (control group, n = 13). Immunotherapy comprised subcutaneous injections with an alum-adsorbed depot extract (Alutard-SQ), and a maintenance dose of 100,000 SQ-U or the maximum tolerated dose. Before entering the study and after 9 months' therapy the patients were evaluated by BPT, SPT, RAST - and IgG4 analyses. The active group showed statistically significant change in bronchial tolerance (P less than 0.02), whereas no such change was found in the control group (P greater than 0.05). The change in skin sensitivity was significantly greater in the active group than in the control group (P less than 0.05), whereas no significant differences were found in RAST and IgG4. However, a significant (P = 0.05) increase in IgG4 was seen in the active but not in the control group. Frequency and degree of side effects in this study were acceptable.     

Immunotherapy with partially purified and standardized tree pollen extracts

Patients allergic to pollen from alder, birch and hazel were hyposensitized during a 3-year period with either birch pollen extract alone (n = 24) or a mixture of one or more of alder, birch and hazel pollen extracts (n = 27). The effect of the treatment was evaluated by RAST and tandem crossed-radioimmunoelectrophoresis (tandem-CRIE). The patient' specific IgE response to the major allergens of alder (Aln g I), birch (Bet v I) and hazel (Cor a I and Cor a II), as measured by tandem-CRIE, and the total specific IgE response, measured by RAST, decreased significantly (Pc less than 0.05) during immunotherapy, irrespective of the extract used during the treatment. There was no significant difference (Pc less than 0.05) between the two treatment groups. The results obtained indicate either that birch pollen extract alone is adequate in the treatment of the studied patient group or the patients had been sensitized towards birch pollen alone.     

Immunotherapy with partially purified and standardized tree pollen extracts

Patients allergic to tree pollen entered a 3-year course of immunotherapy (1980-83) with either birch pollen extracts alone (n = 26) or patient-tailored extracts of birch, alder and hazel pollen (n = 27). The clinical and immunological results of this study are published elsewhere. This paper contains an evaluation of skin prick test and nasal provocation test results. There were no significant differences between the two treatment groups concerning these two parameters. In both groups the allergen-specific sensitivity in the skin showed seasonal variations but a significant decrease. During the years of treatment there was also a significant decrease in the specific sensitivity of the nasal mucosa. With the present demands for purification and standardization of allergen extracts it is of practical and economic interest to know that tree pollen-allergic patients showing positive reactions to birch, alder and hazel extracts can be effectively treated using birch pollen extract alone.     

Immunotherapy with partially purified and standardized tree pollen extracts

Fifty-four adult patients with tree pollen-induced rhinitis (28), asthma (1), or rhinitis and asthma (25) were selected for immunotherapy with standardized and partly purified tree pollen extracts using a double blind protocol. The selection was based on clinical history, results of nasal or bronchial challenge, skin prick tests and RAST. Further, based on crossed radio-immunoelectrophoresis, sex, age and severity of symptoms, the patients were allocated in matched pairs and the treatment alternatives were randomly distributed within the pairs. Twenty-three patients treated with extracts composed of any combination of alder, birch and hazel pollen which matched their IgE response in CRIE (Group 1 (ABC)) and 22 patients receiving birch pollen extracts (Group 2 (B)) completed all 3 years of treatment. The in vivo results comprising symptom and medicine consumption scores are given here. Changes in specific skin and nasal reactivity as well as in immunological parameters are presented separately. No significant differences were demonstrated between the treatment groups in the two parameters. Both extracts were effective and reduced in general the symptom scores to one tenth of the starting level. Expressed another way, at the end of the study, the patients tolerated 30 times more pollen until symptoms of the same severity were elicited, compared to before. In the Nordic countries, spring-time asthma and rhino-conjunctivitis caused by pollen from deciduous trees can be effectively treated with an extract of birch pollen alone.     

Immunotherapy with depigmented glutaraldehyde-polymerized extracts: changes in quality of life

BACKGROUND: Immunotherapy (IT) with modified allergens reduces allergic rhinitis (AR) symptoms and medications requirements. Improvement of quality of life (QOL) is a key point in the treatment of AR. The aim of this study was to provide evidence of changes related to the patient's QOL (well-being) induced by a modified (depigmented glutaraldehyde-polymerized) therapeutic vaccine and of its safety. MATERIAL AND METHODS: Fifty-three patients with a well-documented clinical history of seasonal AR sensitized to Dactylis glomerata and Olea europaea pollens were included in a randomized clinical trial. Twenty-five patients (Group-A) received a mixture of D. glomerata and O. europaea pollen extracts and 28 patients received placebo (group-C). Any adverse event was recorded and graded in accordance with EAACI guidelines. RQLQ was recorded before the treatment (pollen season 2000) and after 1 year of treatment (pollen season 2001). Dose-response skin prick test with each allergen extract was conducted at baseline and at the end of the study. RESULTS: Each patient received 17 injections during this period. All patients completed the trial and no systemic adverse reactions were recorded. Symptom scores (P<0.001) and medication requirements (P<0.001) were significantly reduced in the IT group during the pollen season. This patient group also experienced greater and statistically significant improvement in overall RQLQ score and in five of the seven domains, all of them surpassing the threshold of 'minimal important difference' of 0.5 points. CONCLUSIONS: Results of this study provided evidence that IT with depigmented, glutaraldehyde-modified allergen extracts was well-tolerated and added beneficial effects to AR treatment in pollen allergic patients eliciting an improvement in QOL enough to justify a change in the patient's treatment.     

Short-term dynamic psychotherapy. IV. Comparison of recorded changes in 33 neurotic patients 2 and 5 years after end of treatment

Changes for 33 neurotic patients treated with short-term dynamic psychotherapy were compared as measured at 2 and 5 years after end of treatment. There were changes both in symptoms and in degree of insight as measured by a dynamic variable between the two follow-up points. Some of these changes could be due to spontaneous remission and further therapy, but this could not explain all changes. Dynamic changes measured at 2-year follow-up persisted throughout the whole follow-up period. Some patients with mere symptom relief at 2-year follow-up got their symptoms back while others changed dynamically. Thus effect of short-term dynamic psychotherapy may occur even after 2 years after the end of treatment.     

Immunotherapy with aluminum hydroxide adsorbed insect venom extracts (Alutard SQ): immunologic and clinical results of a prospective study over 3 years

This prospective study over 3 years investigated the safety, immunogenicity, and effectiveness of immunotherapy (IT) with aluminum hydroxide adsorbed insect venom extracts (Alutard SQ, ALK Laboratories) m patients with previous, severe, systemic, IgE-mediated, anaphylactic reactions to Hymenoptera stings. Seventeen patients were treated with honeybee venom (BV), 13 with yellow-jacket venom (YJV), and 5 with both. No severe reactions to IT were noted. Only 3 BV-allergic patients experienced mild systemic reactions of grades I or II (1 per 139 injections) during the increase phase.
As for the immunologic data, there was a significant decrease in specific IgE antibodies after 1 year, and a significant increase in specific IgG and IgG4 antibodies on reaching the maintenance dose, with a further rise after 1, 2, and 3 years. Moreover, a significant decrease in anti-IgE autoantibodies was observed in the BV group. Out of the 11 patients that were occasionally restung by the relevant insect (totaling 19 stings in all), only one patient developed mild systemic allergic symptoms after a third sting.
In view of these results, we consider IT with aluminium hydroxide adsorbed insect venom extracts to safe, immunogenic, and effective. The low rate of side-effects may be due to the slow release of the venom in the aluminium hydroxide adsorbed form.     

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.     

Immunotherapy with partially purified and standardized animal dander extracts. I. Clinical results from a double-blind study on patients with animal dander asthma

Forty-one patients (21 adults and 20 children) with cat dander-or dog dander-induced asthma were selected for immunotherapy with standardized and partially purified cat- or dog-dander extracts by use of a double-blind protocol. Based on sex, age, clinical history, results of bronchial challenge, and crossed radioimmunoelectrophoresis studies, the patients were stratified in matched pairs, and the treatment alternatives were distributed randomly among the pairs. Twenty-two patients treated with allergen (15 with cat allergen and seven with dog allergen) and 17 patients receiving placebo therapy completed the first year of treatment. In the cat allergen-treated group, the bronchial sensitivity toward cat and histamine decreased (p less than 0.001 and p less than 0.05, respectively). Measured by bronchial challenge, the cat allergen-treated patients could tolerate 11 times more allergen at the end than at the start of the study, and they also demonstrated a tendency toward less pronounced symptoms after exposure to cat and dog allergens. No significant changes were observed in the dog allergen treated- or placebo-treated groups. The adverse effects in general were negligible except for some systemic side effects during rush hyposensitization, especially among the children, but these were mild and responded promptly to treatment.     

Allergens in Hymenoptera venoms: IV. Comparison of venom and venom sac extracts

Honeybee venom sac extract is compared with pure venom. All five known allergens of venom are present in venom sac extract. Enzyme analyses indicate that the sac extracts contain 11% to 16% venom. At least 10 additional components, several of which are proteins, are present in venom sac extract. Radioallergosorbent test (RAST) studies of yellow jacket venom and venom sac extract yielded a correlation of r = 0.94, with only some weakly reactive sera positive to only one preparation. A few sera were substantially more reactive with venom sac extract. Venom sac extracts appear to be suitable for in vitro diagnostic use, but the extraneous proteins and peptides may make them less suitable than pure venoms for use in immunotherapy.     

Side Effects during Immunotherapy with Purified Grass Pollen Extracts

In a 3-year prospective double blind study, grass pollen allergic patients were allocated to perennial hyposensitization with the timothy major allergens Nos. 19 and 25 (2-component extract) or a 20-component timothy extract. The extracts were biologically standardized and adsorbed to aluminium hydroxide for treatment.
Systemic side effects (SSE) had début after 1 1/2–5 h and lasted without treatment 1/2–10 h. Treatment with the 2-component extract showed preponderance of minor SSE (arthralgia, rhinitis, tiredness, headache, conjunctivitis, nausea, flu-like symptoms), but major SSE (urticaria, angioedetma, asthma) were equally distributed between treatment with the two timothy extracts.
Major SSE comiplicated the treatment before the first grass pollen season in 33% of the patients vs. only in 3% during the subsequent perentiial therapy, and developed (92%) at high single dose of ≥1,000 biological units. The majority (69%) were later able to reach the same or higher dose without relapse. Most (62%) patients with major SSE were predicted by high nasal sensitivity before treatment.
Only 18% of the patients had immediate local skin reactions of ≥2 cm, but delayed local side effects of ≥10 cm were recorded in 70%. Immediate skin reactions did not correlate with delayed skin reactions or with SSE, but delayed local side effects tended towards negative correlation with major SSE. A mean area reduction of 50% of the delayed skin reactions was recorded by repetition of a single dose.
Subcutaneous nodules appeared at single doses of ≥5,000 biological units. Only 5% of the patients contracted nodules during initial preseasonal therapy compared with 38% during subsequent perennial dosage. The nodules contained typical benign granulomas, and the frequency in the two groups was proporitonate to the quantity of aluminium in the two extracts.     

Post-consolidation Immunotherapy with Histamine Dihydrochloride and Interleukin-2 in AML

The initial chemotherapy in acute myeloid leukaemia (AML) comprises a first phase of induction and a second phase of consolidation. In the majority of patients, the induction treatment leads to complete remission (CR), defined as microscopic disappearance of leukaemic disease along with the return of normal haematopoiesis. However, despite the introduction of more efficacious consolidation regimens, a worryingly large proportion of AML patients in CR will subsequently experience relapses with poor prospects of long-term survival. A relapse is assumed to be the result of expansion of residual leukaemic cells that have escaped the initial chemotherapy. The anti-leukaemic functions of T cells and natural killer (NK) cells has formed the background to the use of interleukin-2 (IL-2), a T- and NK cell-activating cytokine, with the aim to eliminate residual leukaemia and hence reduce the relapse rate in AML, but the clinical trials using IL-2 monotherapy have yielded disappointment. A recent phase III study has demonstrated that post-consolidation treatment with the combination of histamine dihydrochloride (HDC) and IL-2 significantly prevents relapse in AML patients. Here we account for the preclinical background to the use of HDC/IL-2 in AML along with a review of clinical results.