Combination of omalizumab and specific immunotherapy is superior to immunotherapy in patients with seasonal allergic rhinoconjunctivitis and co-morbid seasonal allergic asthma

Background The treatment of allergic asthma by specific immunotherapy (SIT) is hampered by potential side-effects.
Objective The aim of this study was to study the effect of omalizumab, a monoclonal anti-IgE antibody, in combination with SIT in patients with seasonal allergic rhinoconjunctivitis (SAR) and co-morbid seasonal allergic asthma (SAA) incompletely controlled by conventional pharmacotherapy.
Methods A randomized, double-blind, placebo-controlled, multi-centre trial was performed to assess the efficacy and safety of omalizumab (Xolair^®) vs. placebo in combination with depigmented SIT (Depigoid^®) during the grass pollen season. Omalizumab or placebo was started 2 weeks before SIT; the whole treatment lasted 18 weeks. Primary endpoint was daily 'symptom load', the sum of daily scores for symptom severity and rescue medication use.
Results A total of 140 patients (age 11–46 years) were randomized; and a total of 130 finished the study. Combination therapy reduced the symptom load by 39% ( P =0.0464, Wilcoxon test) over SIT monotherapy. This difference was mainly due to reduced symptom severity ( P =0.0044), while rescue medication use did not change significantly. Combination therapy also improved asthma control (Asthma Control Questionnaire, P =0.0295) and quality of life in the case of asthma (Asthma Quality of Life Questionnaire, P =0.0293) and rhinoconjunctivitis (Rhinoconjunctivitis Quality of Life Questionnaire, P =0.0537). Numbers of patients with 'excellent or good' treatment efficacy according to ratings of investigators (75.0% vs. 36.9%) or patients (78.5% vs. 46.1%) were markedly higher in the combination group than under SIT alone.
Conclusion Combination of omalizumab with SIT for treatment of patients with SAR and co-morbid SAA was safe and reduced the symptom load in a statistically significant and clinically meaningful manner.     

Comparison of nasal immunohistology in patients with seasonal rhinoconjunctivitis treated with topical steroids or specific allergen immunotherapy

BACKGROUND: Specific allergen immunotherapy (SIT) and nasal steroids (NS) are considered effective anti-inflammatory treatments for allergic rhinitis, although their mechanism of action differs. OBJECTIVE: The aim of this study was to examine the effect of treatment with NS and SIT on different populations of inflammatory cells in the nasal mucosa and to compare cell numbers before and during the birch pollen season in patients with seasonal allergic rhinitis. METHODS: In a randomized, double-blind, double dummy comparative study, 41 patients with seasonal rhinoconjunctivitis were treated with birch SIT or NS (budesonide 400 microg daily). Treatment with NS started before the birch pollen season and at the same time SIT-treated patients reached the maintenance dose. Nasal biopsies for immunohistochemistry were obtained before the season and start of the treatments and at the peak of the pollen season during treatment. RESULTS: Symptoms of rhinoconjunctivitis increased significantly in both groups during the pollen season but less in the NS-treated group and the difference between the treatment groups was significant at the end of the season (P = 0.03). Immunohistochemistry of nasal biopsies from NS-treated patients showed significantly fewer CD1a+, IgE+ and Fc epsilonRI+ cells during the season compared with preseason (P = 0.02, P = 0.001 and P = 0.0004, respectively) and with seasonal values of the SIT-treated group (P = 0.002, P = 0.002 and P = 0.0004 respectively). CONCLUSION: Treatment with NS but not SIT decreased the numbers of CD1a+, IgE+ and Fc epsilonRI+ cells during the birch pollen season. Our data indicate that treatment with NS has a broader anti-inflammatory range than SIT.     

Cost-effectiveness of specific subcutaneous immunotherapy in patients with allergic rhinitis and allergic asthma

BACKGROUND: Specific immunotherapy is the only potentially curative treatment in patients with allergic rhinitis and allergic asthma. Health economic evaluations on this treatment, particularly in a German context, are sparse. OBJECTIVE: To evaluate the cost-effectiveness of specific subcutaneous immunotherapy (SCIT) in addition to symptomatic treatment (ST) compared with ST alone in a German health care setting. METHODS: The analysis was performed as a health economic model calculation based on Markov models. In addition, we performed a concomitant expert board composed of allergy experts in pediatrics, dermatology, pneumology, and otolaryngology. The primary perspective of the study was societal. Additional sensitivity analyses were performed to prove our results for robustness. RESULTS: The SCIT and ST combination was associated with annual cost savings of Euro140 per patient. After 10 years of disease duration, SCIT and ST reach the breakeven point. The overall incremental cost-effectiveness ratio (ICER) was Euro-19,787 per quality-adjusted life-year (QALY), with a range that depended on patient age (adults, Euro-22,196; adolescents, Euro-14,747; children, Euro-12,750). From a third-party payer's perspective, SCIT was associated with slightly additional costs. Thus, the resulting ICER was Euro8,308 per QALY for all patients. CONCLUSIONS: Additional SCIT was associated with improved medical outcomes and cost savings compared with symptomatic treatment alone according to a societal perspective. Taking a European accepted ICER threshold of up to Euro50,000 per QALY into account, additional SCIT is considered clearly cost-effective compared with routine care in Germany. The degree of cost-effectiveness is strongly affected by costs related to SCIT and the target population receiving such treatment.     

Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis

BACKGROUND: We wondered whether short-term coseasonal sublingual immunotherapy (SLIT) can reduce the development of asthma in children with hay fever in an open randomized study. OBJECTIVE: We sought to determine whether SLIT is as effective as subcutaneous immunotherapy in reducing hay fever symptoms and the development of asthma in children with hay fever. METHODS: One hundred thirteen children aged 5 to 14 years (mean age, 7.7 years) with hay fever limited to grass pollen and no other clinically important allergies were randomized in an open study involving 6 Italian pediatric allergy centers to receive specific SLIT for 3 years or standard symptomatic therapy. All of the subjects had hay fever symptoms, but at the time of study entry, none reported seasonal asthma with more than 3 episodes per season. Symptomatic treatment was limited to cetirizine, loratadine, nasal budesonide, and salbutamol on demand. The hay fever and asthma symptoms were quantified clinically. RESULTS: The actively treated children used less medication in the second and third years of therapy, and their symptom scores tended to be lower. From the second year of immunotherapy, subjective evaluation of overall allergy symptoms was favorable in the actively treated children. Development of asthma after 3 years was 3.8 times more frequent (95% confidence limits, 1.5-10.0) in the control subjects. CONCLUSIONS: Three years of coseasonal SLIT improves seasonal allergic rhinitis symptoms and reduces the development of seasonal asthma in children with hay fever.     

Cc-chemokine eotaxin as a marker of efficacy of specific immunotherapy in patients with intermittent IgE-mediated allergic rhinoconjunctivitis

BACKGROUND: Allergen-specific immunotherapy (SIT) is believed to be a valuable remedy in several allergic diseases; however, an accurate immunological marker of the efficacy of this treatment method has not been found yet. Cc-chemokine eotaxin, owing to its selective action on eosinophils, seems to play an important role in the pathophysiology of allergic response. The purpose of this study was to assess the usefulness of eotaxin in monitoring of SIT efficacy in patients with IgE-mediated allergic rhinoconjunctivitis. METHODS: One hundred and twenty-two patients with seasonal IgE-mediated allergic rhinoconjunctivitis due to tree- (birch, n = 42; hazel/alder, n = 14) or grass/cereal- (n = 66) pollen received allergen-specific immunotherapy.Serum eotaxin levels were determined four times in every patient, shortly before immunotherapy (Evaluation 0), immediately after the treatment (Evaluation 1), in the height of pollen season (Evaluation 2) and at least 2 weeks after the pollen season (Evaluation 3). Serum eotaxin levels were simultaneously measured in 59 healthy people from the control group. Changes in serum eotaxin levels were assessed in the healthy and allergic groups. Clinical symptoms of IgE-mediated rhinoconjunctivitis were evaluated and compared with serum eotaxin concentration changes. RESULTS: Mean values of eotaxin concentrations in serum during Evaluations 0-3 did not significantly differ in the healthy subjects and the patients with IgE-mediated rhinoconjunctivitis (P > 0.05). Moreover, no statistically significant differences in the serum eotaxin levels between the visits were observed in the patients who received immunotherapy (P > 0.05); however, immediately after immunotherapy (Evaluation 1) the mean serum level of eotaxin was lowest and closest to the serum eotaxin concentration in the control group at the same visit. No significant correlation between the mean value of the serum eotaxin level in the height of pollen season (r = -0.12, P > 0.05) or mean changes of the eotaxin levels between Evaluations 2 and 1 (r = -0.03, P > 0.05), on the one hand, and the cumulative score of symptoms and drug, on the other, were found. CONCLUSIONS: The results allow to conclude that although eotaxin plays a significant role in the mechanism of antigen-specific immunotherapy, its serum expression remains a poor marker of SIT efficacy.     

Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis

BACKGROUND: Specific immunotherapy is widely used to treat allergic rhinitis, but few large-scale clinical trials have been performed. OBJECTIVE: We sought to assess the efficacy and safety of specific immunotherapy with 2 doses of Alutard grass pollen in patients with moderately severe seasonal allergic rhinitis inadequately controlled with standard drug therapy. METHODS: We performed a double-blind, randomized, placebo-controlled study of 410 subjects (203 randomized to 100,000 standardized quality units [SQ-U] maintenance, 104 to 10,000 SQ-U, and 103 to placebo). Three hundred forty-seven (85%) completed treatment. Groups were well matched for demographics and symptoms. RESULTS: Across the whole pollen season, mean symptom and medication scores were 29% and 32% lower, respectively, in the 100,000-SQ-U group compared with those in the placebo group (both P < .001). Over the peak pollen season, mean symptom and medication scores were 32% and 41% lower, respectively, than those in the placebo group. The 10,000-SQ-U group had 22% less symptoms than the placebo group over the whole season (P < .01), but medication scores reduced by only 16% (P = .16). Quality-of-life measures confirmed the superiority of both doses to placebo. Local and delayed side effects were common but generally mild. Clinically significant early and delayed systemic side effects were confined to the 100,000-SQ-U group, but no life-threatening reactions occurred. CONCLUSIONS: One season of immunotherapy with Alutard grass pollen reduced symptoms and medication use and improved the quality of life of subjects with moderately severe hay fever. The 100,000-SQ-U regimen was more effective, but the 10,000-SQ-U regimen caused fewer side effects.     

Prevalence of asthma, allergic rhinoconjunctivitis and allergic sensitization in Mongolia

BACKGROUND: Studies in countries, such as Mongolia, which are in transition from farming to industrial society permit evaluation of the impact of environmental change on atopic diseases. METHODS: In the screening study, questionnaire data were obtained from 9453 subjects aged 10-60 years. In the clinical study, a subsample of 869 subjects (participation rate 50.0%) was examined. A questionnaire-based interview, clinical examination, skin prick tests, spirometry and bronchodilation test or methacholine challenge test were used to define the clinical diagnoses. The prevalences of atopic diseases were evaluated at the population level using two-phase data and sampling weights. RESULTS: The prevalences of asthma, allergic rhinoconjunctivitis and allergic sensitization with 95% confidence intervals were 1.1% (0.3-2.0%), 9.3% (4.0-14.6%) and 13.6% (7.4-19.9%) in Mongolian villages, 2.4% (1.4-3.5%), 12.9% (8.2-17.7%) and 25.3% (17.1-33.6%) in rural towns and 2.1% (1.3-3.0%), 18.4% (13.3-23.4%) and 31.0% (24.5-37.5%) in Ulaanbaatar city, respectively. The prevalence of allergic rhinoconjunctivitis (P = 0.02) and allergic sensitization (P = 0.003) increased significantly with increasing urbanization. CONCLUSIONS: The prevalences of atopic diseases were low in rural Mongolia and increased with increasing urbanization suggesting that rural living environment protects against atopy.     

特异性免疫治疗对变应性鼻炎合并哮喘患儿的影响

目的: 探讨屋尘螨变应原特异性免疫治疗对变应性鼻炎合并哮喘患儿血清白细胞介素 13(IL-13)、白细胞介素 4(IL-4)、干扰素 γ(IFN-γ)水平及鼻部症状和肺功能的影响。方法: 选择屋尘螨变应原阳性的变应性鼻炎合并支气管哮喘的患儿58例,其中35例接受屋尘螨特异性免疫治疗为免疫组,其余23例予局部糖皮质激素治疗为药物组。于治疗前及治疗1年后分别测定患儿血清IL-4、IFN-γ和IL-13水平,并评估鼻部症状和肺功能。结果: 经过1年治疗后,免疫组鼻部症状评分较治疗前明显减少(P<0.05),与药物组相比有显著差异(P<0.05);免疫组因哮喘急性发作而急诊就诊的频率明显少于药物组;与治疗前比较,免疫组血清IL-4和IL-13水平下降,IFN-γ水平及IFN-γ/IL-4升高 (P<0.05),肺功能改善明显(P<0.05);而药物组血清IL-4和IL-13水平较治疗前无明显下降 (P>0.05),肺功能无改善 (P>0.05)。结论: 特异性免疫治疗后患儿血清IL-4和IL-13下调, IFN-γ及IFN-γ/ IL-4上调,提示特异性免疫治疗可能调节体内T辅助细胞(Th)Th1/Th2细胞的平衡,从而改善患儿鼻部症状和肺功能。     

A comparison of topical levocabastine and oral terfenadine in the treatment of allergic rhinoconjunctivitis

This study was undertaken to compare the efficacy of twice-daily levocabastine, a new topical H₁-blocking antihistamine, with that of twice-daily oral terfenadine in the treatment of allergic rhinoconjunctivitis. A total of 128 adult patients with a history of birch-pollen-provoked allergic rhinoconjunctivitis participated in this double-blind, parallel-group study. Ocular and nasal symptoms, assessed by a 100-mm visual analog scale, were recorded daily on diary cards for a period of 8 weeks. Global assessments of treatment efficacy were also performed. Conventional statistical analysis detected no significant differences between the two treatment regimens. Similarly, there was no difference in the number or type of adverse reactions in each treatment group. Statistical analysis according to Hauck & Andersson confirmed equivalence between the two treatment regimens. Topical levocabastine appears to be as effective and well-tolerated as oral terfenadine in the treatment of allergic rhinoeonjunctivitis.
The Livostin Study Group. A comparison of topical levocabastine and oral terfenadine in the treatment of allergic rhinoconjunctivitis.     

Double-blind, placebo-controlled evaluation of sublingual immunotherapy with standardized olive pollen extract in pediatric patients with allergic rhinoconjunctivitis and mild asthma due to olive pollen sensitization

For evaluation of the efficacy and the safety of specific sublingual immunotherapy with high allergen dose, 66 children with seasonal asthma, rhinitis, and conjunctivitis due to sensitization to olive pollen were enrolled in a double-blind, randomized, placebo-controlled study between October 1994 and October 1996 in Greece. Thirty-four patients were randomly allocated to the active group, and 32 received placebo. Immunotherapy consisted of olive-allergen extracts (Stallergenes SA) administered sublingually pre- and coseasonally from January to July for 2 consecutive years. Serial concentrations from 1 to 300 IR were used up to the maintenance dose of 20 drops of 300 IR daily. The cumulative dose for each patient was 300 times higher than in parenteral immunotherapy, and the cumulative dose of the major allergen Ole e 1 was 8.1 mg/2 years. The patients were assessed by clinical parameters (symptom and medication scores from patients' daily diaries) and immunologic measurements (specific IgE. lgG4. eosinophil cationic protein [ECP]) were performed. The actively treated patients had a significantly lower score for dyspnea (P<0.04 during the first season; P<0.03 during the second season). At the poUinic peak during the second year, a lower score of conjunctivitis was recorded (P<0.05) in the actively treated patients. The analysis of intragroup evolution showed that the total score of rhinitis increased significantly during the pollinic peak in the group under placebo, whereas there was no symptomatic peak for the same period in the group under active treatment. However, the difference between the groups was not significant. The medication score did not differ significantly between the groups. Oral steroids were the only variables with a P value near the significance level (P=0.06) in favor of the actively treated group. A significant decrease in skin reactivity was recorded in the active group after 2 years of treatment. No significant variation in specific IgE and IgG4 was detected. A significantly lower level of serum ECP was observed at the pollinic peak in the actively treated patients during the first pollen season (P=0.01), but this was not confirmed the second year when the ECP levels doubled in both groups without correlation to the clinical findings. Tolerance was excellent with only a few minor side-effects reported. In conclusion, high-dose specific sublingual immunotherapy appears to be safe and effective in improving mild seasonal asthma and conjunctivitis linked to olive-pollen sensitization.     

儿童过敏性哮喘特异性免疫治疗中Foxp3和白细胞介素27 mRNA的表达变化研究

目的 探讨在过敏性哮喘尘螨特异性免疫治疗(SIT)过程中转录因子Foxp3、IL-27 p28和EBI3 mRNA在外周血单个核细胞中表达的变化.方法 根据进行抗原特异性免疫治疗的时间,采集过敏性哮喘患儿39例,分离其SIT治疗前、治疗一年后和治疗两年后的外周静脉血单个核细胞,提取总RNA,逆转录成cDNA,利用荧光定量PCR的方法检测Foxp3、IL-27 p28和EBI3 mRNA的表达情况,并观察患儿治疗前后的临床疗效.结果 随着SIT治疗的进行,患儿临床症状明显减轻,与SIT治疗前相比,治疗一年和两年后,外周血中Foxp3的mRNA表达水平明显升高,分别为治疗前的5.03倍和1.93倍,差异有统计学意义(P=0.0008,P =0.033);IL-27 EBI3的mRNA表达水平虽然有所升高,分别为治疗前的1.56倍和1.32倍,但差异并没有统计学意义(P =0.088,P=0.244);IL-27 p28的mRNA表达水平在治疗一年后明显升高,为治疗前的2.18倍,差异有统计学意义(P=0.027),治疗两年后又基本恢复至治疗前水平.结论 哮喘患儿特异性免疫治疗有效;Foxp3转录因子和IL-27在哮喘的发生和SIT治疗中起重要作用.     

Efficacy and safety of 5-grass pollen sublingual immunotherapy tablets in patients with different clinical profiles of allergic rhinoconjunctivitis

Background The optimal dose of grass pollen tablets for sublingual immunotherapy (SLIT) in allergic rhinoconjunctivitis patients was previously established in a multinational, randomized, double‐blind, placebo‐controlled study in 628 adults. Patients were randomized to receive once‐daily 5‐grass pollen sublingual tablets of 100 IR (index of reactivity), 300 IR or 500 IR, or placebo starting 4 months before the pollen season. Objective The aim of this complementary analysis was to determine whether 300 IR 5‐grass pollen SLIT‐tablets is effective in different subtypes of patients who are allergic to grass pollen. Methods Different subgroups could be identified regarding comorbidities (with or without asthma during the grass‐pollen season), sensitization (mono/polysensitization) and symptom severity. An additional exploratory analysis was performed within four subgroups based on pre‐treatment assessment: Group 1=high specific IgE; Group 2=high symptom scores; Group 3=high skin sensitivity; Group 4=any of Group 1, 2 or 3. Results Asthma and sensitization status were not significant covariates as the average Rhinoconjunctivitis Total Symptom Score (RTSS) was identical for patients with and without grass‐pollen asthma, as well as for mono‐ and polysensitized patients. Across the four subgroups, average RTSSs (± SD) for the optimal dosage (300 IR) were 3.91 ± 3.16, 3.83 ± 3.14, 2.55 ± 2.13 and 3.61 ± 2.97, for subgroups 1, 2, 3 and 4, respectively. ancova showed that in Group 1 average RTSS did not differ significantly with different doses of SLIT. In Groups 2, 3 and 4, doses of 300 IR and 500 IR were significantly more effective than 100 IR and placebo (P0.035). All doses of SLIT administered in this study can be considered safe in the patients investigated. Conclusions The risk–benefit ratio validates the use of 300 IR tablets in clinical practice in all of these patient subgroups, regardless of severity profile, sensitization status and presence of asthma.     

Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis

BACKGROUND: Allergen immunotherapy (desensitization) by injection is effective for seasonal allergic rhinitis and has been shown to induce long-term disease remission. The sublingual route also has potential, although definitive evidence from large randomized controlled trials has been lacking. OBJECTIVE: The aim was to confirm the efficacy of a rapidly dissolving grass allergen tablet (GRAZAX, ALK-Abelló, H?rsholm, Denmark) compared with placebo in patients with seasonal rhinoconjunctivitis. METHODS: A longitudinal, double-blind, placebo-controlled, parallel-group study that included 51 centers from 8 countries. Subjects were randomized (1:1) to receive a grass allergen tablet or placebo once daily. A total of 634 subjects with a history of grass pollen-induced rhinoconjunctivitis for at least 2 years and confirmation of IgE sensitivity (positive skin prick test and serum-specific IgE) were included in the study. Subjects commenced treatment at least 16 weeks before the grass pollen season, and treatment was continued throughout the entire season. RESULTS: The primary efficacy analysis showed a reduction of 30% in rhinoconjunctivitis symptom score (P < .0001) and a reduction of 38% in rhinoconjunctivitis medication score (P < .0001) compared with placebo. Side effects mainly comprised mild itching and swelling in the mouth that was in general well tolerated and led to treatment withdrawal in less than 4% of participants. There were no serious local side effects and no severe systemic adverse events. CONCLUSION: Sublingual immunotherapy with grass allergen tablets was effective in grass pollen-induced rhinoconjunctivitis. The tablet was well tolerated with minor local side effects. CLINICAL IMPLICATIONS: The grass allergen tablet represents a safe alternative to injection immunotherapy suitable for home use.     

The inverse association of salmonellosis in infancy with allergic rhinoconjunctivitis and asthma at school-age: a longitudinal study

BACKGROUND: Respiratory allergies are inversely related to early acquisition of food-borne and fecal-oral infections, consumption of unpasteurized milk, early exposure to stables and high endotoxin concentrations in a farming environment. We tested therefore if infection by Salmonella in early life can protect from development of respiratory allergies later in life. METHODS: During 2003, we studied two groups of Sardinian children (age 6-18 years) who had been hospitalized before 4 years of age (during 1989-2001) with non-typhoid salmonellosis (n = 148) or acute enteritis of nonbacterial etiology (NB-enteritis) (n = 167). Allergic rhinoconjunctivitis (AR) and asthma were evaluated by telephonic interview with a ISAAC questionnaire; participants reporting AR and/or asthma were further examined through a complete diagnostic work-up to objectively confirm or exclude current disease. Kaplan-Meier curves and Cox proportional hazard models were used to analyze the role of different types of enteritis on the risk of developing allergic rhinoconjunctivitis or asthma over time. RESULTS: Children who had been hospitalized with salmonellosis had a lower prevalence of allergic rhinoconjunctivitis (eight of 148, 5.4%vs 23 of 167, 13.8%; P = 0.019) or asthma (five of 148, 3.4% vs 21 of 167, 12.6%; P = 0.006) than those who had been hospitalized with NB-enteritis. The proportional hazard of salmonellosis for asthma was 0.23 (95% CI: 0.08-0.67; P < 0.01) and for allergic rhinoconjunctivitis was 0.40 (95% CI: 0.17-0.95; P = 0.04), after adjusting for confounders. DISCUSSION: The strength of the observed associations suggests that Salmonella may contribute to shape the natural history of respiratory allergies. However, further studies are needed to test in other settings the association observed in Sardinian children. We speculate that clinical or subclinical infection by Salmonella may contribute to the atopy protective influence of a traditional farming environment or of areas endemic for food-borne and fecal-oral infections. Food hygiene and prevention of salmonellosis must remain however a public health priority.