Subcutaneous immunotherapy with depigmented-polymerized allergen extracts: a systematic review and meta-analysis.

BACKGROUND: Double-blind, placebo-controlled trials (DBPCTs) have confirmed the efficacy of allergen-specific immunotherapy (AIT) with depigmented-polymerized allergen extracts (DPAEs). This systematic review evaluates the efficacy of AIT using different allergens in different severity stages of rhinoconjunctivitis with or without asthma in the pollen studies and asthma and rhinitis in the house dust mite studies in comparison to placebo. METHODS: We used MEDLINE, Embase, CENTRAL and LILACS databases to review DBPCTs published until July 2016. The combined symptom and medication score (cSMS) served as primary endpoint. The total rhinoconjunctivitis symptom score (RCSS) and total score in Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) were secondary efficacy endpoints. Solicited local and systemic adverse events were secondary safety endpoints. We assumed a random effects model with standardized mean differences (SMDs) or mean differences as summary statistics. In a subgroup analysis, we classified the studies following the GINA (Global Initiative for Asthma) and ARIA (Allergic Rhinitis and its Impact on Asthma) guidelines for rhinoconjunctivitis and asthma severity. RESULTS: Six DBPCTs in pollen and 2 trials in house dust mites (HDM) were selected. Patients (N = 915) with intermittent or mild persistent asthma were included in 3 (37.5%) and 5 (62.5%) trials, respectively. Two (25%) HDM studies included patients with moderate persistent asthma, 4 trials patients with moderate-to-severe rhinoconjunctivitis. Treatment periods ranged from 12 to 24 months. AIT with DPAEs yielded significantly lower cSMS (SMD: 1.9, 95% CI: 0.9-2.8) and RQLQ (SMD: 0.3, 95% CI: 0.1-0.5) values than did placebo. An exploratory analysis of cSMS and RCSS suggested that the efficacy of AIT treatment with DPAEs was higher in trials including patients with more severe rhinoconjunctivitis and asthma. A publication bias was not detected. Heterogeneity between individual studies was explained by differences in severity. Patients receiving DPAEs did not experience a significantly higher risk of local (OR: 1.55, 95% CI: 0.86-2.79) or systemic reactions (OR: 1.94, 95% CI: 0.98-3.84). CONCLUSIONS: Compared to placebo, AIT with DPAEs is effective in patients with pollen- or HDM-induced rhinoconjunctivitis with or without allergic asthma and improves health-related quality of life. It does not differ significantly in safety and tolerability.

Liposomal Eye Spray Is as Effective as Antihistamine Eye Drops in Patients with Allergic Rhinoconjunctivitis Induced by Conjunctival Provocation Testing.

BACKGROUND: Liposomal eye spray (LS) has been introduced for the treatment of dry eye. Whether LS can also relieve symptoms due to allergic rhinoconjunctivitis (ARC) has not yet been sufficiently investigated. OBJECTIVES: The aim of this study was to assess the onset of action, the reduction of allergy symptoms, and the safety of LS - a nonpharmacological treatment option - compared with those of antihistamine eye drops (AD). METHODS: In this open, prospective, controlled, monocenter noninterventional study, adults with ARC received either LS or AD for the relief of eye irritation after a positive conjunctival provocation test (CPT). All patients completed a questionnaire before and after the CPT. Eye irritation was rated on a visual analogue scale (VAS) at 6 time points. Conjunctival redness was analyzed using objective digital analysis based on images taken during the study visit. RESULTS: Data were collected from 40 patients (20 per group). In both groups, 80% of patients perceived an onset of action within 0-2 min after application of LS or AD following the CPT. Relief of eye irritation (as determined by VAS) increased throughout the visit for both groups. In the digital analysis, the mean proportion of redness of the eye decreased from 10.3 to 7.0% for LS and from 10.4 to 6.5% for AD, with the largest difference observed 10 min after application (LS: 8.9%; AD: 6.0%; p = 0.094). CONCLUSIONS: LS is a nonpharmacological treatment option for ARC, showing no significant difference or relevant numerical inferiority to AD in any parameter studied. It was generally safe and well tolerated.

Early nonreactivity in the conjunctival provocation test predicts beneficial outcome of sublingual immunotherapy.

BACKGROUND: Clinical practice needs a common parameter that can provide an early, reliable estimation of the outcome of sublingual immunotherapy (SLIT) in an upcoming pollen season. We investigated whether the conjunctival provocation test (CPT) can predict the beneficial outcome of SLIT in patients with allergic rhinoconjunctivitis after 4 weeks of treatment. METHODS: We conducted two separate prospective, randomized, double-blind, placebo-controlled, multicenter trials. Adults 18-75 years of age received placebo or SLIT tablets containing tree or grass pollen allergoids and underwent CPTs. Participants receiving SLIT were divided into two groups (reactive, nonreactive) according to their CPT reactions after 4 weeks of treatment. These two groups were compared with regard to clinical outcome parameters (total combined score, rhinoconjunctivitis total symptom score, total rescue medication score, well days) assessed during the pollen season for the 14-day (tree) or 30-day (tree/grass) peaks and for the entire 60-day seasons. Participants' global evaluations of therapy after completing treatment were also compared. RESULTS: The tree pollen trial randomized 188 participants; 182 participants were evaluable, 76 of whom received SLIT and were suitable for this post hoc analysis. The grass pollen trial included 90 participants; 82 participants were evaluable, 44 of whom underwent SLIT. Comparing SLIT participants who reacted to the CPT after 4 weeks (tree: 77.6%; grass: 79.5%) with those who ceased to show a reaction (tree: 22.4%; grass: 20.5%) (tree: P = 0.0001; grass: P = 0.003), the total combined score for the 14-day (P = 0.017) and 30-day peaks (P = 0.042) as well as the rhinoconjunctivitis total symptom score assessed for the 14-day peak (P = 0.024) were significantly lower in the nonreactive group of the tree pollen trial. In the grass pollen trial, the nonreactive group rated their SLIT treatment significantly better (P = 0.019). CONCLUSIONS: Using clinically meaningful outcome parameters during the pollen season, both trials independently led to similar results when comparing participants' reactions to the CPT 4 weeks after beginning SLIT. These results suggest that CPT allows an early estimation of allergic rhinoconjunctivitis symptoms before an upcoming season. Thus, the CPT can be used as a valuable parameter to predict the beneficial outcome of ongoing SLIT. TRIAL REGISTRATION: Both trials registered with the Medical Ethics Committee of the North Rhine Medical Council (EudraCT numbers 2012-004916-79 (grass pollen trial) and 2013-002129-43 (tree pollen trial)) and the German Federal Ministry of Health (Paul-Ehrlich-Institut).

Reliability of a New Symptom Score in a Titrated Quantitative Conjunctival Provocation Test Supported by an Objective Photodocumentation.

BACKGROUND: Allergen provocation tests are useful methods for proving the clinical relevance of an allergen-specific sensitization. Among these methods, the conjunctival provocation test (CPT) represents an easy-to-use tool. However, its readout parameters have not yet been internationally standardized or validated. Photodocumentation has been shown as a good option for objectifying a CPT reaction, supporting the local investigator assessment. Based on test-retest reliability of the score and an objective digital photoanalysis of the conjunctival redness, this study aimed to prove the reproducibility of a new CPT scoring system for use in clinical trials (ClinicalTrials.gov identifier: NCT02690740). METHODS: A titrated quantitative CPT was conducted outside of the pollen season in a final cohort of 23 adult patients with birch or grass pollen-induced allergic rhinoconjunctivitis. Conjunctival symptoms were analyzed using a standardized symptom score. Conjunctival redness was also evaluated by an external observer and correlated with a digital photoanalysis using MATLAB software. RESULTS: A test-retest correlation of 0.6 (p < 0.01) was found for the symptom score results. Likewise, a correlation of 0.65 (p < 0.01) was observed in the digital photoanalysis. The total symptom score showed a decrease in the mean value of 0.48 score points in the retest. CONCLUSIONS: This study reveals both a valuable test-retest correlation of the proposed score as well as a good correlation of eye redness with the (objective) photodocumentation. Based on our results, we can recommend the use of this scoring system as a valuable clinical protocol for future clinical trials.

Specific Characteristics in Digital Assessment of Conjunctival Redness.

Photodocumentation of allergic hyperemia induced during the conjunctival provocation test (CPT) is analyzed by digital imaging and by assessment from an external observer. Selected specific characteristics, derived from the measured conjunctival redness values, represent the relevance of digital imaging and reproducibility of the CPT. The characteristics discussed here are: the area under the ROC curve and Pearson's product-moment correlation coefficient.

Photodocumentation of Allergic Severity under Conjunctival Provocation.

The aim of this work was to evaluate conjunctival redness as an objective allergy symptom during the conjunctival provocation test (CPT). The CPT is an instillation of ophthalmic solution containing an allergen into the ocular mucosa. Allergic severity using the CPT was evaluated in the multicenter, randomized, controlled, double-blind, dose-finding study of 159 patients with birch pollen allergy where the mucosal sensitivity of the eye was assessed based on subjective and objective symptoms such as itching and redness, respectively. High-resolution digital photos were taken, arranged in image matrices, and analyzed by an external central observer to assess conjunctival redness. The photodocumentation method described here was successfully applied in a dose-finding study using the CPT. The evaluations of allergic severity carried out by an external observer agreed with the investigators' assessments.

Image-Based Assessment of Allergic Inflammation under Conjunctival Provocation.

Conjunctival redness is an objective allergy symptom which can be analyzed using objective computer imaging methods. To evaluate allergic inflammation of the eyes, a robust and precise image-based method was developed and applied to analyze allergic hyperemia under the conjunctival provocation test (CPT). High-resolution digital photos were taken and analyzed via digital analysis software to obtain and document conjunctival redness. The evaluations made using this newly developed image-based method concurred with the study investigators' assessments: the therapeutic effects of the highest doses were superior to the lowest dose.

Digitally Analyzed Conjunctival Redness: Does Repeated Conjunctival Provocation Intrinsically Cause Local Desensitization of the Eye?

BACKGROUND: Allergic reactions in patients with seasonal or perennial rhinoconjunctivitis mediated by airborne allergens can be effectively assessed with the conjunctival provocation test (CPT). The CPT is a fast and easy diagnostic procedure that challenges the ocular mucosa with instillations of allergen solutions into the conjunctival region. This paper aimed to investigate the possible influence of repeated diagnostic CPT procedures on the patient's clinical presentation, i.e. to analyze desensitization effects caused by diagnostic solutions and to show the reproducibility of CPT results. METHODS: Treatment progress in 120 placebo-treated patients from 2 immunotherapeutic dose-finding studies was estimated and documented, as based on the CPT which was applied at 4 visits with intervals of 4, 8 and 16 weeks. High-resolution digital photos collected as part of the CPT documentation were analyzed by an external observer and by digital analysis software to determine conjunctival redness, completely independent of the subjectivity of investigators and patients. RESULTS: Two extremal scenarios of the redness changes were considered after provocation with 10,000 standard quality units/ml. A maximal decrease of about 3% (t test: p = 0.0002; U test: p = 0.001) and a minimal decrease of about 1% (t test: p = 0.254; U test: p = 0.431) were found. CONCLUSIONS: The observed decrease in conjunctival hyperemia can be explained by local desensitization or by placebo effect. Due to the setup of both studies considered, we could not ascertain how these factors influence the decrease in redness. In order to attribute the observed effects to local conjunctival desensitization with certainty, further pilot studies are needed.