Long-term follow-up of nasal immunotherapy to Parietaria: clinical and local immunological effects

Background Local nasal immunotherapy (LNIT) with extracts in powder has been detnonstrated clinically effective and devoid of side-effects in several controlled trials; nevertheless, no data concerning the long-term effects of LNIT are presently available. Methods In a recent double-blind, placebo-controlled study of LNIT to Parietaria pollen we observed, by means of specific nasal provocation test (SNPT) that LNIT is able to modify the local allergic inflammatory response. In the present study we followed up the same patients in open fashion for 2 further years. Results The results confirmed the clinical efficacy of LNIT and showed that it is strictly dependent on pre-seasonal administration: in fact, after LNIT discontinuation a clinical relapse was observed. A certain long-lasting protective effect on SNPT parameters (nasal symptoms and neutrophils infiltration) was also observed, whereas an increase of eosinophils count and ICAM-1 expression on nasal epithelial cells appeared as possible markers of clinical relapse. Conclusion The present study suggests that pre-seasonal LNIT can be taken in consideration in selected subjects as prophylactic treatment for pollen-induced rhinitis. In addition, the results obtained provide informations about the duration of clinical efficacy and add data about the local allergic inflammation and its modulation.     

Low-dose local nasal immunotherapy in children with perennial allergic rhinitis due to Dermatophagoides

BACKGROUND: Allergen specific immunotherapy was known to be useful in the treatment of respiratory allergic disease. Local nasal immunotherapy (LNIT) offers advantages such as a good efficacy/safety ratio and a more convenient allergen delivery. The aim of this study was to assess the safety and clinical efficacy of a modified scheduling of LNIT in 32 children with allergic rhinitis due to Dermatophagoides. METHODS: A multicentre, randomized, double-blind placebo controlled study carried out for two years, with a modified schedule of LNIT treatment: a build-up phase at increasing dosages from 2.5 AU to 80 AU and a maintenance period at low dosage (80 AU) once a week. Symptom and medication scores. threshold dose with specific nasal provocation test (NPT) and immunological parameters (IgE and IgG4) were evaluated. RESULTS: No important local or systemic side-effects were observed in children who completed the study. Compared to placebo, the active treatment group showed significant improvement in rhinitis symptoms and a reduction of drug consumption after 18 months of LNIT. These results were confirmed by a significant reduction of allergen specific nasal reactivity. Serum and nasal specific IgE and IgG4 did not show any difference in the two groups. CONCLUSIONS: The safety and clinical efficacy of low-dose LNIT suggests that this therapy may be useful in the treatment of allergic rhinitis disease in children.     

Clinical and immunological effects of immunotherapy with alum-absorbed grass allergoid in grass-pollen-induced hay fever

A double-blind, placebo-controlled study of immunotherapy was conducted in 19 patients with grass-pollen hay fever to evaluate the efficacy and safety of a formalinized depot grass allergoid. The patients were assessed before and during IT by clinical (symptom-medication scores during the grass- pollen season, specific nasal and skin reactivity) and immunological (specific IgE, IgG, IgG₁ and IgG₄ antibodies) parameters. High doses of grass allergoid, corresponding to a cumulative pre-seasonal dosage of 46050 PNU, were administered, with only one systemic reaction. The actively treated patients had significantly lower symptom-medication scores than placebo ( p < 0.01) during the month of May and showed a significant decrease in specific skin ( p < 0.01) and nasal ( p < 0.05) reactivity, and a significant early increase in specific IgE ( p < 0.01), IgG ( p < 0.0005), IgG₁ ( p < 0.001) and IgG₄ ( p < 0.05), with a subsequent decrease of IgE and IgG₁. No differences were detected in any of these parameters in the placebo group. A correlation was found between high IgG₄/IgG₁ ratio and the specific skin reactivity decrease (r = 0.691, p < 0.05), whereas a high IgG₄/IgG₁, ratio was associated with higher symptom-medication scores (r = 0.654, p < 0.05). Possible explanations of these apparent discrepancies are proposed.     

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.     

Efficacy and safety of preseasonal-specific immunotherapy with an aluminium-adsorbed six-grass pollen allergoid

BACKGROUND: The clinical efficacy and safety of a six-grass pollen allergoid has been studied. The advent of more exacting clinical guidelines and a better appreciation of the possible mechanisms of treatment prompted this reappraisal. METHODS: A 2-year double-blind multicentre placebo-controlled phase 3 clinical trial was undertaken in 154 patients suffering symptoms of rhinoconjunctivitis with or without asthma (GINA I or II). Therapy comprised two consecutive preseasonal short-courses of subcutaneous injections using a grass pollen allergoid adsorbed to aluminium hydroxide. RESULTS: A combined symptom and medication score (SMS) was used as the primary end-point for clinical efficacy. SMS from the first year showed a significant difference of 26.6% between the two study groups (P=0.026) and this was improved after the second year when there was a 48.4% difference in SMS between active and placebo treatment in favour of the allergoid (P = 0.018). Highly significant increases in grass pollen allergen-specific IgG1 and IgG4 antibody concentrations were measured in association with active treatment. Allergen tolerance was increased as judged by a conjunctival provocation test and significant improvements in quality of life were documented using a standardized questionnaire. The allergoid was well tolerated. CONCLUSIONS: The grass pollen allergoid was shown to be safe and clinically efficacious in the management of hay fever with or without asthma (GINA I or II).     

Sublingual tryptase and ECP in children treated with grass pollen sublingual immunotherapy (SLIT): safety and immunologic implications

BACKGROUND: The clinical safety of sublingual immunotherapy (SLIT) has been repeatedly confirmed; nevertheless, the possible onset of local oral symptoms is still a concern, and nothing is known about the pathogenesis of this effect. We aimed to determine whether the administration of SLIT in allergic children can evoke an IgE-mediated reaction, by measuring the levels of sublingual tryptase and ECP. METHODS: Thirty children (7-12 years old) with allergic rhinitis/asthma due to grass pollen were prescribed SLIT. In these children, an allergen-specific nasal challenge was performed, and nasal tryptase and ECP were measured before and after. Sublingual ECP and tryptase were also assessed before the SLIT, after 1 month, and after 6 months of treatment. Ten matched allergic children and 10 healthy ones served as controls for the baseline levels of sublingual ECP and tryptase. RESULTS: The levels of nasal tryptase and ECP significantly increased after nasal challenge (P<0.001), whereas no change during the SLIT course (at the beginning, after 1 month, and after 6 months) could be detected in sublingual tryptase either before or after SLIT administration. The sublingual ECP significantly decreased after 6 months of SLIT. The baseline levels of nasal tryptase and ECP were significantly higher in allergic subjects than in healthy controls, as was the level of sublingual ECP. CONCLUSIONS: In the presence of an IgE-mediated reaction (ASNC), a significant increase of tryptase and ECP can be seen. When SLIT is administered, such a phenomenon does not occur; therefore, SLIT does not elicit any IgE reaction in the mouth. It is noteworthy that allergic subjects display higher levels of nasal ECP and tryptase than healthy subjects, even when symptom-free, and these observations may indicate the presence of subclinical inflammation.     

Clinical efficacy and immunological mechanisms of sublingual and subcutaneous immunotherapy in asthmatic/rhinitis children sensitized to house dust mite: an open randomized controlled trial

Background In children, the clinical efficacy and immunological mechanisms of sublingual immunotherapy (SLIT) compared with subcutaneous immunotherapy (SCIT) is still to be elucidated. Objectives To compare SLIT, SCIT and pharmacotherapy in relation to clinical efficacy and immunological mechanisms that govern its effect in asthmatic/rhinitis children who were sensitized to house dust mite (HDM). Methods In this single centre, prospective, randomized, controlled, open labelled, three parallel group trial, 48 patients mono‐sensitized to HDM were randomized to receive either SLIT (n=16), SCIT (n=16) or pharmacotherapy alone (n=16). Symptom, medication and visual analogue score (VAS) were collected and bronchial‐nasal hyper‐reactivity, skin prick tests, total‐specific IgE were performed at baseline and 12 months after treatment. In addition, peripheral blood mononuclear cells were cultured with recombinant Der p 1 and Bet v 1 extracts and allergen‐specific IL‐4, IL‐5, IL‐13, IFN‐γ, IL‐10, and TGF‐β secretions were measured. Results SLIT and SCIT demonstrated a significant reduction of total rhinitis and asthma symptom score, total medication score, VAS and skin reactivity to HDM (P<0.05) when compared with pharmacotherapy. A significant reduction of serum‐specific HDM‐IgE in SCIT and SLIT were observed. Moreover, titrated nasal provocative dose significantly increased in both immunotherapy groups when compared with the pharmacotherapy group. No adverse effects were reported in SLIT, while two patients demonstrated serious adverse events in SCIT. After 1 year of treatment, Der p 1‐driven IL‐10 significantly increased in SLIT compared with pharmacotherapy, whereas Bet v 1‐driven TGF‐β (negative control) increased significantly in SLIT only. No changes were observed for Th1–Th2 cytokines. Conclusion Both SLIT and SCIT demonstrated clinical improvement compared with pharmacotherapy in asthma/rhinitis children sensitized to HDM.     

Sublingual immunotherapy with Dermatophagoides monomeric allergoid down-regulates allergen-specific immunoglobulin E and increases both interferon-γ- and interleukin-10-production

BACKGROUND: The clinical efficacy and safety of sublingual immunotherapy (SLIT) for aeroallergens has been demonstrated in several trials, whereas the immunological changes induced by this treatment, which may account for the clinical improvement, are still unclear. OBJECTIVE: To investigate the effects of a successful SLIT on the in vitro allergen-driven T cell response and cytokine secretion as well as on the serum levels of chemokines and of IgE, IgG1 and IgG4 antibodies (Abs). MATERIALS AND METHODS: Twenty-five Dermatophagoides pteronyssinus (Dp)-sensitive patients with perennial rhinitic and/or rhinitic and asthmatic symptoms were randomized into two groups (13 untreated (UT) and 12 SLIT-treated) for a 1 year and half study. The proliferative response of peripheral blood mononuclear cell (PBMC) to purified Der p1 allergen, their cytokines (IFN-gamma, IL-4, IL-10 and TGF-beta) production and serum levels of chemokines associated with T helper type 1 (Th1) (CXCL10) or T helper type 2 (Th2) (CCL22) responses and of Dp-specific IgE, IgG1 and IgG4 Abs were evaluated before and after 6 months of treatment. RESULTS: SLIT induced a significant reduction of symptom medication scores after 6, 12 and 18 months of treatment in comparison with UT patients. SLIT-treated patients showed a significant decrease in serum levels of DP-specific IgE Abs, whereas total IgE, and specific IgG1 and IgG4 Abs remained unchanged. The proliferative response of allergen-specific T cells to Der p1 in vitro after 6 months of treatment was reduced, while no effect was observed on T cell proliferation to recall antigen (streptokinase). Moreover, Der p1-driven IFN-gamma and IL-10 were significantly increased in culture supernatants of PBMC from 6 month-treated patients in comparison with those detected at the beginning of therapy. CONCLUSIONS: These data suggest that the allergen-driven enhancement of IL-10- and IFN-gamma-producing T cells precedes and associates with SLIT-induced down-regulation of specific IgE, thus providing a rationale to explain the clinical benefit of SLIT in allergic patients.     

A prospective, randomized, double-blind, placebo-controlled multi-centre study on the efficacy and safety of sublingual immunotherapy (SLIT) in children with seasonal allergic rhinoconjunctivitis to grass pollen

BACKGROUND: Especially in childhood, sublingual immunotherapy (SLIT) could offer advantages over subcutaneous therapy. However, limited data on its efficacy is available. METHODS: In four German centres 97 children (age 3-14 years) with allergic rhinoconjunctivitis to grass pollen were enrolled in a prospective, double-blind trial comparing SLIT (Pangramin SLIT; ALK-SCHERAX, 0.5 microg major allergens, three times per week, 32 months) with placebo. Primary endpoint was a multiple symptom-medication score for changes in seasonal diary entries between the first and third year of the study (SLIT n=39; placebo n=38). RESULTS: The multiple symptom-medication score was significantly reduced by SLIT to 77.3% of the placebo group (P=0.0498). The subsequent analysis of the single endpoints did not reveal significant differences for symptom scores in favour of SLIT (85.1% of placebo group; P=0.22). However, the medication score improved significantly (67.1% of placebo group; P=0.0025). Furthermore, secondary endpoints assessing in vivo immune responses did not differ significantly between the groups. However, retrospective analysis showed some inhomogeneity for clinical and in vitro parameters at the beginning of the study. Allergic side effects with possible relation to the study drug were reported in both groups (SLIT 49%, placebo 27%, P=0.026). CONCLUSION: Our study indicates that SLIT had a positive effect on the reduction of a multiple symptom-medication score, mainly by significantly reducing rescue medication use, but had no significant effect on symptoms alone in children with rhinoconjunctivitis to grass pollen compared with a placebo.     

腕管综合征类固醇腕管局部注射的临床和电生理评估

目的：运用临床评分和神经传导检测（NCS）评估类固醇腕管局部注射对腕管综合征（CTS）的疗效。方法：2009年4月至2010年1月间就诊的CTS患者共66例,符合纳入标准者41例（64只腕）。进行症状严重程度评分（SSS）、功能状态评分（FSS）以及常规NCS,记录腕-拇短展肌末端运动潜伏期（DML）、拇短展肌复合肌肉动作电位（CMAP）波幅,腕-食指／环指感觉传导速度（SCV）、正中／尺神经感觉潜伏期差（△DSL）和感觉神经动作电位（SNAP）波幅。嘱患者改变生活方式且行夜间腕部夹板,2周后症状无好转者行类固醇腕管局部注射。紧挨掌长肌腱尺侧、腕皱褶近侧,用25号针头以30。角朝向腕管进针,注射利多卡因1ml（20mg）和甲基强的松龙1ml（40mg）。注射前、注射（3．23±0．56）个月后分别进行临床评分和NCS。结果：①18例（28只腕）进行了注射,12例（19只腕）完成随访。与注射前比较,注射后SSS和FSS减少、DML缩短、△DSL减小、腕-环指SCV增快、SNAPCMAP波幅增高。注射前、注射后SSS分别为（2．31±0．45）、（1．89±0．46）（t=5．82,P=0．000：FSS为（2．29±0．64）、（1．79±0．59）（t=5．21,P=0．000）;DML（ms）为（5．08±1．58）、（4．66±1．76）（t=2．81,P=0．012）;△DSL（ms）为（1．25±40．67）、（0．93±0．67）（t=3．90,P=0．002）;SCV（m／s）为（40．55±11．48）、（44．70±13．66）（t=-2．55,P=0．029）;SNAP波幅（uV）为（12．72±10．83）、（15．07±11．00）（t=-2．17,P=0．048）;CMAP波幅（mV）为（5．31±3．37）、（6．13±3．04）（t=-2．42,P=0．026）;3例（4只腕、21％）注射后临床评分无改善。②SSS、FSS与NCS各参数之间均无相关性（P均〉0．05）。结论：CTS患者类固醇腕管局部注射治疗至少在短期内有效;临床评分与NCS无相关性,两者共同评估疗效更有意义。     

Safety of immunotherapy with therapeutic vaccines containing depigmented and polymerized allergen extracts

BACKGROUND: The major complication of allergen immunotherapy is a severe reaction. OBJECTIVE: To evaluate the safety of depigmented and glutaraldehyde-modified allergen extracts in a large group of patients undergoing immunotherapy treatment. MATERIAL AND METHODS: Seven hundred sixty-six patients, having rhinoconjunctivitis and/or asthma, were entered in a prospective, multi-centre, observational cohort study, to evaluate the safety of immunotherapy with modified allergen vaccines. Patients were sensitized to mites and/or pollen and received a therapeutic vaccine containing depigmented and polymerized allergen extracts of mites and/or pollens adsorbed onto aluminium hydroxide. The schedule of administration consisted of a build-up phase of 4- to 6-weekly injections, followed by 12-monthly injections of the maintenance dose. Tolerance was assessed by recording all side reactions related to immunotherapy. RESULTS: All patients completed the study. Fifty-four clinically relevant local reactions (43 immediate and 11 delayed) were observed (0.4% of injections). The systemic reactions were 34 in 12 patients. Six reactions were immediate (all of grade 2) and 28 delayed (18 of grade 1 in two patients, nine of grade 2 and one of grade 3). The systemic reactions of grade 2 or 3 occurred in 0.12% of the injections. All systemic reactions were mild and resolved spontaneously without the need for medication. CONCLUSION: Specific immunotherapy using modified allergen vaccines is safe to treat allergic patients. The percentage of adverse reactions detected is lower than those reported in the literature with native-unmodified allergen extracts.     

Seasonal idiopathic rhinitis with local inflammatory response and specific IgE in absence of systemic response

Background: Patients with idiopathic rhinitis (IR) are considered to be nonallergic because they have a negative skin prick test (SPT) and allergen specific‐IgE in serum. The concept of localized mucosal allergy in the absence of atopy has recently been proposed. The immunological mechanisms involved in seasonal IR have not been sufficiently studied. We examined nasal mucosa inflammation, the presence of nasal specific‐IgE and the response to nasal allergen provocation test (NAPT) in patients with seasonal IR who presented symptoms only in spring. Methods: We evaluated 32 patients with seasonal IR and 35 with persistent allergic rhinitis to pollen (PAR‐P) and compared these with healthy controls and persons with PAR to house dust mite during the pollen season, as well as by NAPT out‐of‐season with grass and Olea europea. We measured the nasal leukocyte–lymphocyte phenotype (CD45, CD33, CD16, CD3, CD4 and CD8), eosinophil‐cationic‐protein, and total and specific‐IgE to grass and olive pollen in serum and nasal lavage and performed NAPT. Results: In the IR group, 62.5% had a positive NAPT (IR‐PosNAPT), 20/32 to grass, with four of these having a positive NAPT to olive pollen as well. IR‐PosNAPT patients showed a similar nasal leukocyte–lymphocyte profile to the PAR‐P patients and different to controls. We detected nasal specific‐IgE in 35% of IR‐PosNAPT patients. Conclusions: These results support the hypothesis that a subgroup of patients with IR have seasonal symptoms with evidence of a nasal allergic immune reaction in the absence of a positive SPT or serum specific IgE.     

Nasal and Skin Sensitivity during Immunotherapy with Two Major Allergens 19, 25 and Partially Purified Extract of Timothy Grass Pollen

In a double blind 3-year prospective study 40 grass pollen allergic patients were allocated to specific immunotherapy (hyposensitization) with two timothy major allergens, 19, 25, or partially purified timothy extract. The extracts were biologically standardized and coupled to aluminium hydroxide for treatment.
Efficacy of hyposensitization was evaluated by titrated nasal provocations and skin prick tests with the two treatment extracts and a five-grass mixture. The threshold dose for skin prick test (skin (threholds) produced reactions identical to histamine chloride 5.43 mmol/l, and the threshold dose for nasal provocations (nasal thresholds) produced two of the three reactions: at least 0.5 ml of nasal secretion, at least five sneezes, and/or at least a 20 % fall in nasal peak flow.
Nasal thresholds showed highest efficacy from partially purified timothy extract but equal protection against timothy and I he five -grass mixture. Nasal thresholds of 14 untreated patients corresponded to treatment with the two major allergens.
Changes in skin and nasal thresholds after 12 and after 64 weeks of treatment predicted the severity of hay fever. Increase in nasal thresholds coincided with a marked effect on asthma. Nasal thresholds below 1 HEP before treatment predicted major systemic side effects.     

Polymeric microparticles for sustained and local delivery of antiCD40 and antiCTLA-4 in immunotherapy of cancer

This study investigated the feasibility of the use of polymeric microparticles for sustained and local delivery of immunomodulatory antibodies in immunotherapy of cancer. Local delivery of potent immunomodulatory antibodies avoids unwanted systemic side effects while retaining their anti-tumor effects. Microparticles based on poly(lactic-co-hydroxymethyl-glycolic acid) (pLHMGA) and loaded with two distinct types of immunomodulatory antibodies (CTLA-4 antibody blocking inhibitory receptors on T cells or CD40 agonistic antibody stimulating dendritic cells) were prepared by double emulsion solvent evaporation technique. The obtained particles had a diameter of 12–15 μm to avoid engulfment by phagocytes and were slightly porous as shown by SEM analysis. The loading efficiency of the antibodies in the microparticles was >85%. The in vitro release profile of antiCD40 and antiCTLA-4 from microparticles showed a burst release of about 20% followed by a sustained release of the content up to 80% of the loading in around 30 days. The therapeutic efficacy of the microparticulate formulations was studied in colon carcinoma tumor model (MC-38). Mice bearing subcutaneous MC-38 tumors were treated with the same dose of immunomodulatory antibodies formulated either in incomplete Freund's adjuvant (IFA) or in microparticles. The antibody-loaded microparticles showed comparable therapeutic efficacy to the IFA formulation with no local adverse effects. The biodegradable microparticles were fully resorbed in vivo and no remnants of inflammatory depots as observed with IFA were present in the cured mice. Moreover the microparticles exhibited lower antibody serum levels in comparison with IFA formulations which lowers the probability of systemic adverse effects. In conclusion, pLHMGA microparticles are excellent delivery systems in providing long-lasting and non-toxic antibody therapy for immunotherapy of cancer.     

Three years of specific immunotherapy with house-dust-mite extracts in patients with rhinitis and asthma: significant improvement of allergen-specific parameters and of nonspecific bronchial hyperreactivity

Twenty-seven patients with allergy to house-dust mite and the clinical symptoms of perennial rhinitis and/or mild asthma were treated with specific immunotherapy (SIT) with standardized extracts of house-dust mite for 3 years. The success of therapy was evaluated in yearly intervals by 1) subjective rhinitis and asthma scores. 2) allergen-specific skin and conjunctival tests. 3) nonspecific bronchial hyperreactivity to methacholine. 4) medication scores of rhinitis and asthma. SIT induced a significant improvement of all parameters already after 1 year, with further improvement in the follow-up measurements at 2 and 3 years. We found a constant improvement of the rhinitis and asthma symptom scores, a reduced reactivity in the skin prick and conjunctival provocation tests, and a constantly increasing reduction of bronchial hyperreactivity to methacholine. Concomitantly, the use of medication (topical corticosteroids, beta2-mimetics, and antihistamines) was reduced. Our data support the concept that SIT with standardized extracts of house-dust mite results in an improvement of allergen-specific parameters in patients with perennial rhinitis and intermittent asthma. This beneficial effect of SIT on allergen-specific immune parameters seems to induce also a diminution of nonspecific bronchial hyperreactivity and enables reduction of symptomatic treatment.