Intralymphatic immunotherapy (ILIT) is a potential treatment option for allergic rhinitis (AR). We aimed to determine the efficacy (primary outcomes) and safety (secondary outcomes) of ILIT in treating patients with AR.

An electronic literature search was performed using MEDLINE and Cochrane Central Register of Controlled Trials CENTRAL (from their inception to December 2020). A random-effects model was used to estimate the pooled prevalence with 95% confidence intervals. This study is registered with PROSPERO (CRD42019126271).

We retrieved a total of 285 articles, of which 11 satisfied our inclusion criteria. There were 452 participants with age ranged from 15 to 58 years old. Intralymphatic immunotherapy was given in three doses with intervals of four weeks between doses in 10 trials. One trial gave three and six doses with an interval of two weeks. Both primary and secondary outcomes showed no difference between ILIT and placebo for all trials. There was no difference in the combined symptoms and medication score (SMD -0.51, 95% CI -1.31 to 0.28), symptoms score (SMD -0.27, 95% CI -0.91 to 0.38), medication score (SMD -6.56, 95% CI -21.48 to 8.37), rescue medication (RR 12.32, 95% CI 0.72-211.79) and the overall improvement score (MD -0.07, 95% CI -2.28 to 2.14) between ILIT and placebo. No major adverse events noted.

Intralymphatic immunotherapy possibly has a role in the treatment of AR patients. This review found it is safe but not effective, which could be contributed by the high variation amongst the trials. Future trials should involve larger numbers of participants and report standardized administration of ILIT and outcome measures.

Subcutaneous immunotherapy (SCIT) has been proven as an effective therapy against some allergens for seasonal allergic rhinitis (SAR) patients unresponsive to intranasal corticosteroids and/or antihistamines but carries risk of systemic allergic reactions. Dupilumab blocks the shared receptor component for interleukin-4 and interleukin 13, key and central drivers of type 2 inflammation in multiple diseases.

To evaluate the efficacy and safety of SCIT+dupilumab vs SCIT alone.

This phase 2a, multicenter, double-blind, placebo-controlled parallel-group study conducted in 103 adults with grass pollen-induced SAR (NCT03558997) randomized patients 1:1:1:1 to SCIT, dupilumab (300 mg every 2 weeks), SCIT+dupilumab, or placebo. SCIT was administered using an 8-week cluster protocol followed by 8 weeks of maintenance injections. Primary endpoint was change from pre-treatment baseline in area under the curve (AUC) in total nasal symptom score (TNSS) 0-1 h following nasal allergen challenge (NAC) with timothy grass extract at Week 17.

Although 16 weeks of treatment with SCIT+dupilumab did not significantly improve TNSS AUC (0-1 h) following NAC at Week 17 vs SCIT (least squares mean -56.76% vs -52.03%), a higher proportion of SCIT+dupilumab treated patients (61.5%) achieved SCIT maintenance dose vs SCIT (46.2%). A lower proportion of SCIT+dupilumab-treated patients (7.7%) required epinephrine rescue treatment vs SCIT (19.2%). There were significantly fewer withdrawals in the SCIT+dupilumab group than in the SCIT group (n = 2 [7.7%] vs n = 8 [30.8%]; P = 0.0216); the majority of SCIT group withdrawals were due to SCIT-related intolerability, compared with no discontinuations from the SCIT+dupilumab group.

In SAR patients, 16 weeks of SCIT+dupilumab may improve SCIT tolerability but did not incrementally reduce post-allergen challenge nasal symptoms compared with SCIT alone.

Meta-analyses comparing the efficacy of sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) for house dust mite (HDM) allergy are lacking.

To compare the efficacy of SLIT drops, SLIT tablets, and SCIT in patients with perennial allergic rhinitis (AR) through network analysis.

Frequentist network meta-analyses estimated the standardized mean difference (SMD) across the three immunotherapy modalities on AR symptom and medication score data from double-blind randomized clinical trials (DBRCTs). Random effects models were investigated.

Twenty-six DBRCTs were included in this meta-analysis for the symptom score, and 18 DBRCTs were included for the medication score. In the direct pairwise meta-analysis, significant reduction of the symptom score was observed for all immunotherapy modalities as compared to the placebo: pooled SMDs of -0.461 (95% CI, -0.795 to -0.127) for SLIT-drop, -0.329 (95% CI, -0.426 to -0.231) for SLIT-tablet, and -1.669 (95% CI, -2.753 to -0.585) for SCIT. For the medication score, significant reduction was observed for all the modalities. In network meta-analysis, the clinical efficacy of SCIT based on the symptom score was greater than SLIT-drop or SLITtablet (SMD: -0.697, 95% CI, -1.105 to -0.288 and SMD: -0.819, 95% CI, -1.242 to -0.397). However, there was no significant difference in the symptom score between SLIT-drop and SLIT-tablet.

This study demonstrated the clinical efficacy of all HDM immunotherapy modalities and suggested that SCIT may be more effective than SLIT drop or tablet in controlling symptoms of allergic rhinitis.

The same dosing schedule, 1000 SQ-U times three, with one-month intervals, have been evaluated in most trials of intralymphatic immunotherapy (ILIT) for the treatment of allergic rhinitis (AR). The present studies evaluated if a dose escalation in ILIT can enhance the clinical and immunological effects, without compromising safety.

Two randomized double-blind placebo-controlled trials of ILIT for grass pollen-induced AR were performed. The first included 29 patients that had recently ended 3 years of SCIT and the second contained 39 not previously vaccinated patients. An up-dosage of 1000-3000-10,000 (5000 + 5000 with 30 minutes apart) SQ-U with 1 month in between was evaluated.

Doses up to 10,000 SQ-U were safe after recent SCIT. The combined symptom-medication scores (CSMS) were reduced by 31% and the grass-specific IgG4 levels in blood were doubled. In ILIT de novo, the two first patients that received active treatment developed serious adverse reactions at 5000 SQ-U. A modified updosing schedule; 1000 3000-3000 SQ-U appeared to be safe but failed to improve the CSMS. Flow cytometry analyses showed increased activation of lymph nodederived dendritic but not T cells. Quality of life and nasal provocation response did not improve in any study.

Intralymphatic immunotherapy in high doses after SCIT appears to further reduce grass pollen-induced seasonal symptoms and may be considered as an add-on treatment for patients that do not reach full symptom control after SCIT. Up-dosing schedules de novo with three monthly injections that exceeds 3000 SQ-U should be avoided.

House dust mite (HDM) is a main perennial allergen causing allergic rhinitis (AR). It has been shown that HDM cross-reacts with a variety of other allergens. Presently, allergen-specific immunotherapy (AIT) is an effective way for management of mono-sensitized HDM+ AR patients. However, management approaches to polysensitized HDM-sensitized AR patients are not standardized yet.

This article reviews the data available in the literature for cross-reactivity between HDM and inhalant or food allergens, the diagnosis of cross reactivity in HDM-sensitized AR patients, and the effect of immunotherapy on cross-reactivity in HDM-sensitized AR patients; which may help to develop effective therapeutic strategies for management of polysensitized HDM-sensitized AR patients in the future.

Pan-allergen proteins such as tropomyosin, arginine kinase (AK), glutathione S-transferase (GST), and hemocyanin are responsible for cross-reactivity between HDM and other allergens. To distinguish genuine or cross-reactive sensitization, molecular- or component resolved diagnosis is suggested to apply in HDMsensitized AR patients. The effect of HDM immunotherapy to treat the associated cross reactivity in HDM-sensitized AR patients is still contradictory, and might be dependent on the degree of homology between two allergens. Furthermore, targeting tropomyosin might be a promising way to treat HDM patients with allergen crossreactivity.

AIT: allergen specific immunotherapy; AK: arginine kinase; AR: allergic rhinitis; CRD: component-resolved diagnostics; Der f: Dermatophagoides farina; Derp: Dermatophagoides pteronyssinus; EAACI: European Academy of Allergy and Clinical Immunology; GST: glutathione S-transferase; GWAS: genomewide association study; HDM: house dust mite; IgE: immunoglobulin E; RAST: radioallergosorbent test; sIgE: specific IgE; SIT: specific immunotherapy; SCIT: subcutaneous immunotherapy; SLIT: sublingual immunotherapy; SPT: skin prick test.

Real-life (or real-world) studies can provide information that cannot be derived from randomized controlled trials. This approach is currently becoming of relevance for many treatments. In recent years, the real-life method has been applied also to allergen immunotherapy, providing new insights on it. We reviewed herein the available literature on the argument.

Several prospective and retrospective studies on allergen immunotherapy in the real-world setting have been published, mostly in the last 5 years. Most of them focused on adverse events, compliance, and the long term/preventive effects, and evidenced an overall favorable profile for different products and different allergens.

Real life study provided novel information and evidenced those aspects of immunotherapy that worth a more detailed approach, without the strict limitations usually imposed by controlled randomized trials.

Allergic rhinitis (AR) is a growing public health, medical and economic problem worldwide. The current review describes the major discoveries related to AR during the past 2 years, including risk factors for the prevalence of AR, the corresponding diagnostic strategy, precise underlying immunological mechanisms, and efficient therapies for AR during the ongoing global "coronavirus disease 2019 (COVID-19) pandemic. The review further attempts to highlight future research perspectives. Increasing evidence suggests that environmental exposures, climate changes, and lifestyle are important risk factors for AR. Consequently, detailed investigation of the exposome and the connection between environmental exposures and health in the future should provide better risk profiles instead of single predictors, and also help mitigate adverse health outcomes in allergic diseases. Although patients with dual AR, a newly defined AR phenotype, display perennial and seasonal allergens-related nasal symptoms, they are only allergic to seasonal allergens, indicating the importance of measuring inflammation at the local sites. Herein, we suggest that a combination of precise diagnosis in local sites and traditional diagnostic methods may enhance the precision medicine-based approach for management of AR; however, this awaits further investigations. Apart from traditional treatments, social distancing, washing hands, and disinfection are also required to better manage AR patients in the ongoing global COVID-19 pandemic. Despite recent advances in understanding the immune mechanisms underlying the effects of allergen immunotherapy (AIT), further understanding changes of cell profiles after AIT and accurately evaluate the efficacy of AIT are required.

Local allergic rhinitis(LAR) is a clinical rhinitis phenotype characterized by the presence of nasal symptoms of AR in nonatopic patients with a negative skin prick test and undetectable specific IgE(sIgE) in serum against inhalant allergens but with a positive nasal allergen provocation test. This study evaluated the effectiveness of a 12- month course of sublingual immunotherapy(SLIT) for house dust mite (HDM) allergies in adult patients with confirmed LAR and concomitant asthma.Methods. The study was a prospective, double-blind, placebo-controlled trial with patients diagnosed with LAR to HDMs and with concomitant asthma who underwent a 12-month treatment course of SLIT for HDM allergies. Seventeen patients were randomized to SLIT with the use of allergen extracts of D.pteronyssinus and D.farinae (50/50%) in SQ-HDM SLIT tablets and 15 patients were randomized to the placebo group. The total rhinitis score (TRSS), total asthma symptom score (TASS), combined total symptom score (TSS), total medication score (TMS), and FEV1 were analyzed.Results & conclusion: In the final analysis, 16 patients who received SLIT and 14 who received placebo who completed the study protocol were included. Significant reductions in TRSS, TASS, TSS, and TMS after 12 months of treatment were observed in patients after SLIT (p < 0.05). A significant increase in the mean FEV1 between baseline and after 12 months of therapy was observed in the study, with p = 0.03 in the study group. SLIT can improve nasal and bronchial symptoms and reduce symptomatic treatment in patients with LAR and asthma and with hyperresponsiveness to HDMs.

Treatment options for seasonal and perennial allergic rhinitis (SAR/PAR) include pharmacotherapies and allergy immunotherapy. These meta analyses evaluated the efficacy of pharmacotherapies and sublingual immunotherapy tablets (SLIT-tablets) versus placebo on nasal symptoms associated with SAR and PAR.

Randomized, double-blind, placebo-controlled trials were identified from systematic PubMED/EMBASE searches through 7/18/2019 (PROSPERO protocol CRD42018105632). The primary outcome was mean numerical difference in total nasal symptom score (TNSS; 0-12) between active treatment and placebo at the end of the assessment period. Random-effects meta-analyses estimated the mean difference for each medication group weighted by the inverse of the trial variance. Publication bias assessments and sensitivity analyses were conducted.

Rescue symptom-relieving pharmacotherapy was prohibited in most pharmacotherapy trials but was allowed in all SLIT-tablet trials. For adult/adolescent SAR, the mean numerical difference (95% CI) in TNSS versus placebo was: intranasal corticosteroids (INCS)=1.38 (1.18, 1.58; 39 trials); combination intranasal antihistamine/INCS=1.34 (1.15, 1.54; 4 trials); intranasal antihistamines=0.72 (0.56, 0.89; 13 trials); oral antihistamine=0.62 (0.35, 0.90; 18 trials); SLIT-tablets=0.57 (0.41, 0.73; 4 trials); and montelukast=0.48 (0.36, 0.60; 10 trials). For adult/adolescent PAR, mean difference in TNSS versus placebo (95% CI) was: INCS=0.82 (0.66, 0.97; 14 trials); SLIT-tablets=0.65 (0.42, 0.88; 3 trials); and oral antihistamine=0.27 (0.11, 0.42; 3 trials). The number of eligible trials limited meta-analyses for pediatric SAR/PAR.

All treatments significantly improved nasal symptoms versus placebo. SLIT-tablets provided improvement in TNSS despite access to rescue symptomrelieving pharmacotherapy. Extensive trial heterogeneity and strong indications of publication bias preclude the comparison of treatment effects among treatment classes.

As the number of allergic sensitizations increases the severity of allergic respiratory diseases worsens. Multiple monoallergen immunotherapy can be accompanied by poor treatment adherence and high costs, single multiallergen immunotherapy needs to prove efficacy whilst maintaining a good safety profile.

Observational, retrospective, multicenter study using a 2 pollen single undiluted multiallergen subcutaneous immunotherapy (SCIT) in routine clinical practice in Spain. Patients with rhinoconjunctivitis, with/without controlled asthma, sensitized to grass, olive, Parietaria, Cupressus, plane tree and/or Salsola pollen were included. Primary and secondary clinical efficacy endpoints were quality of life (mini Rhinitis Quality of Life Questionnaire (miniRQLQ)) and visual analogue scale (VAS) respectively. All adverse events were documented.

Ten centers included 97 patients, median age 32 years. SCIT treatment included combinations of grass mix with olive, Parietaria, Cupressus, plane tree or Salsola or olive with Parietaria, Cupressus or Salsola. The mean duration of SCIT was 1.8 years with a high treatment adherence (73%). Significant improvement in quality of life, nasal and ocular symptoms, activity limitations and practical problems (p< 0.0001) and other symptoms (p= 0.024) was observed. Most patients did not develop asthma-like symptoms and a significant improvement of all allergic symptom severity was perceived. VAS showed a significant improvement in rhinoconjunctivitis and asthma by patients and physicians. Twenty-nine patients experienced adverse reactions, 25 had local and 6 had systemic reactions.

Single undiluted multiallergen SCIT treatment of two different pollens is efficacious and safe in both children and adults, showing that it is a suitable option for the treatment of polyallergic patients.