Allergic rhinitis (AR) poses a significant global health burden, with the potential to progress to asthma, thereby impacting patients' quality of life. Immunotherapy has demonstrated effectiveness in mitigating clinical symptoms by altering the underlying disease mechanisms of AR. This article provides a thorough review of the current state of immunotherapy for AR, encompassing various facets of immunotherapeutic strategies, elucidating their mechanisms and clinical implications. By presenting a nuanced understanding of the present landscape of immunotherapy for AR, this review aims to serve as a valuable reference for informing clinical treatment strategies. The subsequent analysis of diverse immunotherapeutic pathways offers a comprehensive understanding of their mechanisms and clinical implications. A meticulous examination is conducted on subcutaneous immunotherapy, sublingual immunotherapy, oral immunotherapy, intralymphatic immunotherapy, and innovative intravenous gold-induced autologous serum injection therapy. Each pathway is systematically elucidated, with its distinctive features and potential contributions to managing AR emphasized. In conclusion, synthesizing epidemiological insights, immunotherapeutic nuances, and pathway-specific analyses encapsulates a profound understanding of immunotherapy for AR.

Allergic rhinitis (AR) is a prevalent chronic respiratory condition characterized by nasal inflammation, sneezing, congestion, and itching, significantly impacting quality of life. Over recent years, considerable advancements have been made in understanding the pathophysiology, diagnosis, and management of AR. This narrative review aims to synthesize these recent developments, providing a comprehensive overview of key areas. Emerging insights into AR pathophysiology have elucidated the complex interplay between genetic predisposition, environmental factors, and immune system dysregulation. Notably, the role of the epithelial barrier and the microbiome in AR pathogenesis has garnered increasing attention, offering potential targets for novel therapies. Advances in diagnostic technologies, such as component-resolved diagnostics and molecular allergology, have enhanced the precision of allergy identification, enabling more personalized treatment approaches. In terms of management, significant progress has been made in pharmacological and non-pharmacological treatments. Novel biologics targeting specific pathways involved in AR, including monoclonal antibodies against immunoglobulin (Ig)E and interleukin (IL)-4/13, have shown promise in reducing symptoms in refractory cases. Additionally, there has been a resurgence in interest in non-pharmacological strategies, including allergen avoidance, immunotherapy, and complementary therapies, which offer holistic options for patient care. The integration of digital health tools and mobile applications in AR management has further empowered patients, allowing for real-time symptom tracking and personalized treatment adjustments. Recent guidelines emphasize a multidisciplinary approach to AR management, promoting integrated care models that involve collaboration between allergists, primary care providers, and other specialists. These guidelines also highlight the importance of patient-centered care, advocating for shared decision-making and tailored treatment plans based on individual patient profiles. In conclusion, the landscape of allergic rhinitis management is rapidly evolving, with ongoing research and innovation paving the way for improved outcomes. This review underscores the importance of staying abreast of these advances to optimize the care and quality of life for individuals affected by allergic rhinitis.

Allergen immunotherapy (AIT) is a recognized key therapeutic modality for the treatment of allergic respiratory disease. Definitive studies have provided evidence-based data to demonstrate its effectiveness in allergic rhinitis and asthma due to the inhalation of proteinaceous allergic substances from specific seasonal pollens, dust mites, animal allergens, and certain mold spores. Over the ensuing decades, laboratory investigations have provided objective evidence to demonstrate immunologic changes, including production of protective IgG antibody, suppression of IgE antibody, upregulation of regulatory T cells, and induction of a state of immune tolerance to the offending allergen(s). Tangential to this work were carefully designed clinical studies that defined allergen dose and duration of treatment, established the importance of preparing extracts with standardized allergens (or well-defined extracts) based on major protein moieties, and used allergen provocation models to demonstrate efficacy superior to placebo. In the United States, the use of subcutaneous immunotherapy extracts for AIT was grandfathered in by the Food and Drug Administration based on expert literature review. In contrast, sublingual tablet immunotherapy underwent formal clinical development programs (phase I-III clinical trials) that provided the necessary clinical evidence for safety and efficacy that led to regulatory agency approvals for the treatment of allergic rhinitis in properly characterized patients with allergy. The allergy specialist's treatment options currently include traditional subcutaneous AIT and specific sublingual tablets approved for grass, ragweed, house dust mites, trees belonging to the birch-homologous group, and Japanese cedar. Tangential to this are sublingual drops that are increasingly being used off-label (albeit not approved by the Food and Drug Administration) in the United States. This article will review the evidence-based literature supporting the use of these forms of AIT, as well as focus on several current controversies and gaps in our knowledge base that have relevance for the appropriate selection of patients for treatment with specific AIT.

Up to a third of the world's population suffers from allergies, yet the effectiveness of available preventative measures remains, at large, poor. Consequently, the development of successful prophylactic strategies for the induction of tolerance against allergens is crucial. In proof-of-concept studies, our laboratory has previously shown that the transfer of autologous hematopoietic stem cells (HSC) or autologous B cells expressing a major grass pollen allergen, Phl p 5, induces robust tolerance in mice. However, eventual clinical translation would require safe allergen expression without the need for retroviral transduction. Therefore, we aimed to chemically couple Phl p 5 to the surface of leukocytes and tested their ability to induce tolerance. Phl p 5 was coupled by two separate techniques, either by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) or by linkage via a lipophilic anchor, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol)-maleimide (DSPE-PEG-Mal). The effectiveness was assessed in fresh and cultured Phl p 5-coupled cells by flow cytometry, image cytometry, and immunofluorescence microscopy. Chemical coupling of Phl p 5 using EDC was robust but was followed by rapid apoptosis. DSPE-PEG-Mal-mediated linkage was also strong, but antigen levels declined due to antigen internalization. Cells coupled with Phl p 5 by either method were transferred into autologous mice. While administration of EDC-coupled splenocytes together with short course immunosuppression initially reduced Phl p 5-specific antibody levels to a moderate degree, both methods did not induce sustained tolerance towards Phl p 5 upon several subcutaneous immunizations with the allergen. Overall, our results demonstrate the successful chemical linkage of an allergen to leukocytes using two separate techniques, eliminating the risks of genetic modifications. More durable surface expression still needs to be achieved for use in prophylactic cell therapy protocols.

Adherence is crucial for allergen immunotherapy (AIT) efficacy, and a long-term 3-year adherence is indispensable for the long-term benefits beyond AIT administration. Nonadherence causes should be analyzed not only at the patient level but from a broader perspective, including socioeconomic factors, health-care system factors, and disorder- and therapy-related factors. Subcutaneous immunotherapy (SCIT) adherence is ∼50% at best and, for sublingual immunotherapy, the numbers are even much worse in some regions. In this review, causes for AIT loss of adherence and strategies, published and from personal experience, to reduce nonadherence are presented. Although the broader picture of causes of nonadherence has to be taken into account, in all this, the patient-physician and patient-health care professional (AIT nurse, assistant) are still in the center, and, in SCIT, each clinic visit for a shot is an opportunity to exploit this interaction in a positive way and stimulate adherence. Patient factors of nonadherence are not so much forgetfulness but more perception of ineffectiveness and adverse effects. An explanation of what can be expected before starting AIT is crucial because most of those who drop out are seen during the first year. Adherence is especially under risk when administration is temporarily interrupted (lockdown, illness, disease flare, vacation, preseasonal AIT administration schedules). The pandemic has caused higher rates of nonadherence specifically due to a fear of getting infected with severe acute respiratory syndrome coronavirus 2, which can be mitigated with good hygiene techniques and strict sanitization protocols, which ensure the patients. Also, patient mobile discussion networks related to AIT can help encourage adherence and reduce fear of infection, even in these difficult times.

Subcutaneous immunotherapy (SCIT) is a widely used therapy for allergic rhinitis and asthma. It is a useful adjunct to standard medical management of these conditions that can lead to long-term benefits and possible resolution of symptoms. The benefits of SCIT, particularly for children, include avoiding prolonged use and side effects from medications, preventing new aeroallergen sensitizations, and reducing the risk of developing asthma. The primary risks of SCIT include local and systemic reactions. Standard schedules for SCIT include advancing through multiple doses usually in four vials (diluted to 1:1000) on a weekly basis; however, there are benefits of using accelerated schedules, especially for children who need to coordinate school and parent work schedules. Special considerations for pediatric patients include fear of needles, avoiding discomfort with injections, consent, optimal injection scheduling, and difficulty communicating about symptoms during reactions in very young children. Overall, SCIT can be a safe and beneficial therapy for children.

The administration of allergen immunotherapy, since its inception more than 100 years ago, remains a therapy unique to the field of allergy and immunology. The practicing, board-certified allergist is best equipped to evaluate and manage the allergic patient. The safety and efficacy of allergen immunotherapy is well established, and both are discussed in specific chapters in this primer. The practical application of each of these within the confines of the shot room (i.e., the places or places in the medical facility where injections are administered in the allergy clinic) are addressed in this chapter. In addition, practical suggestions are provided to enhance patient adherence with allergen immunotherapy while maximizing the practice management model as services are executed. The successful implementation of each of these areas (safety, efficacy, adherence, and profit margin) will allow the practicing allergist to optimize the clinical delivery of allergen immunotherapy within communities and to the patients being served. The optimization of allergen immunotherapy (AIT) depends on four specific defining factors: 1) safety; 2) efficacy; 3) adherence; and 4) profit margin. Identifying specific problems which could impede each of these four factors is necessary to ensure the success of AIT. The practical implications of these core concepts as they apply to AIT will be explored in this chapter.

It has been more than a decade since the most recent allergen immunotherapy (AIT) practice parameter was published and 5 years since a focused practice parameter on sublingual immunotherapy (SLIT) was issued. There is an unmet need, therefore, for a more up-to-date, concise summary of AIT to be published to provide allergy/immunology practitioners, allergy/immunology fellows-in-training, medical students, residents, and other health-care practitioners with the most current information available on AIT. The Allergen Immunotherapy Primer (AITP) is not intended to define a standard of care or to be inclusive of all proper methods of care, nor is it intended to replace or supplant established AIT practice parameters; rather, the goal of this AITP is to supplement the established practice parameters and to serve primarily as an updated tool for the practicing allergist/immunologist, allergy/immunology trainees, and health-care professionals seeking practical and concise information with regard to AIT. Primer topics include the history of AIT; descriptions of the mechanisms and biomarkers of subcutaneous immunotherapy (SCIT) and SLIT; the efficacy and safety of SCIT; the efficacy and safety of SLIT, pediatric SLIT, and SCIT; the long-term efficacy of SLIT and SCIT; long-term adherence strategies for AIT; the implications of real-world data for AIT; the role of AIT for asthma; patterns of cross-allergenicity among pollens; a practical implementation guide for optimized construction of AIT vaccines; standardization of allergen extracts; updated information on federal regulations about the United States Pharmacopeia and the compounding of allergenic extracts; an update on AIT venom immunotherapy; the advantages and disadvantages of accelerated immunotherapy regimens; the important role of shared decision-making in AIT and how it can be incorporated into the informed consent process; and a forecast of future directions in allergen immunotherapy.