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Creticos PS, Gunaydin FE, Nolte H, Damask C, Durham SR. Allergen Immunotherapy: The Evidence Supporting the Efficacy and Safety of Subcutaneous Immunotherapy and Sublingual Forms of Immunotherapy for Allergic Rhinitis/Conjunctivitis and Asthma. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2024; 12:1415-1427. [PMID: 38685477 DOI: 10.1016/j.jaip.2024.04.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 04/23/2024] [Accepted: 04/23/2024] [Indexed: 05/02/2024]
Abstract
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.
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Affiliation(s)
- Peter Socrates Creticos
- Johns Hopkins Division of Allergy & Clinical Immunology, Baltimore, Md; Creticos Research Group, Crownsville, MD.
| | - Fatma E Gunaydin
- Department of Immunology & Allergy, Ordu University Education & Research Hospital, Ordu, Türkiye
| | | | - Cecilia Damask
- Department of Otolaryngology, Central Florida College of Medicine, Orlando, Fla
| | - Stephen R Durham
- Allergy & Clinical Immunology, Division of Respiratory Science, National Heart and Lung Institute, Imperial College London, Royal Brompton Hospital, London, United Kingdom
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Di Bona D, Carlucci P, Spataro F, Paoletti G, Cognet-Sicé J, Scurati S, Canonica GW. IR (index of reactivity)-house dust mite sublingual immunotherapy liquid formulation for allergic rhinoconjunctivitis: Systematic review and meta-analysis of randomized and nonrandomized studies. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. GLOBAL 2024; 3:100208. [PMID: 38328804 PMCID: PMC10847924 DOI: 10.1016/j.jacig.2024.100208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 11/10/2023] [Accepted: 11/10/2023] [Indexed: 02/09/2024]
Abstract
Background Although randomized controlled trials (RCT) are the reference standard of evidence in allergen immunotherapy (AIT), nonrandomized studies (NRS) are needed to confirm their results in more representative populations, particularly for treatment duration and persistence. However, when discrepancies are observed between RCT and NRS, NRS reliability decreases because these discrepant results are generally attributed to the methodologic flaws of NRS. Objective We compared the benefit of sublingual AIT (SLIT) for allergic rhinoconjunctivitis in NRS versus RCT focusing on a single product/allergen to reduce heterogeneity. Methods For meta-analysis, house dust mite (HDM) SLIT liquid formulation studies were sourced from computerized (Medline, Web of Science, and LILACS databases, to January 2023) and manual literature searches. Populations, treatments, and outcome data were combined (DerSimonian-Laird method). Noncomparative NRS were compared to RCT' SLIT arm before and after treatment. Efficacy was determined as the standardized mean difference (SMD) in symptom score (SS) and medication score (MS). Results Data from 12 NRS (682 patients) and 8 RCT (176 patients) were analyzed. The benefit with index of reactivity (IR)-HDM SLIT liquid formulation was found significant for, first, SS in both NRS (SMD = -1.27; 95% confidence interval [CI], -1.64, -0.90) and RCT (SMD = -0.56; 95% CI, -0.90, -0.21), and second, MS with SMD equal to -1.35 (95% CI, -1.77, -0.93) and -0.46 (95% CI, -0.67, -0.25), respectively. Metaregression showed that symptom improvement was correlated with treatment duration with consistent results in NRS and RCT with 12-month SS data: -0.87 (interquartile range, -1.02, -0.77) and -0.75 (interquartile range, -0.93, -0.41), respectively. Conclusion This meta-analysis showed comparable clinical benefit of IR-HDM SLIT liquid formulation increasing over time in both NRS and RCT, suggesting that NRS may reliably integrate RCT results and be considered for guidelines.
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Affiliation(s)
- Danilo Di Bona
- Department of Precision and Regenerative Medicine and Jonic Area, Unit of Allergology, University of Bari Aldo Moro, Bari, Italy
| | - Palma Carlucci
- Department of Precision and Regenerative Medicine and Jonic Area, Unit of Allergology, University of Bari Aldo Moro, Bari, Italy
| | - Federico Spataro
- Department of Precision and Regenerative Medicine and Jonic Area, Unit of Allergology, University of Bari Aldo Moro, Bari, Italy
| | - Giovanni Paoletti
- Personalized Medicine, Asthma and Allergy, Humanitas Clinical and Research Center, IRCCS, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | | | | | - Giorgio Walter Canonica
- Personalized Medicine, Asthma and Allergy, Humanitas Clinical and Research Center, IRCCS, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
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Gurgel RK, Baroody FM, Damask CC, Mims J“W, Ishman SL, Baker DP, Contrera KJ, Farid FS, Fornadley JA, Gardner DD, Henry LR, Kim J, Levy JM, Reger CM, Ritz HJ, Stachler RJ, Valdez TA, Reyes J, Dhepyasuwan N. Clinical Practice Guideline: Immunotherapy for Inhalant Allergy. Otolaryngol Head Neck Surg 2024; 170 Suppl 1:S1-S42. [PMID: 38408152 PMCID: PMC11788925 DOI: 10.1002/ohn.648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 01/02/2024] [Indexed: 02/28/2024]
Abstract
OBJECTIVE Allergen immunotherapy (AIT) is the therapeutic exposure to an allergen or allergens selected by clinical assessment and allergy testing to decrease allergic symptoms and induce immunologic tolerance. Inhalant AIT is administered to millions of patients for allergic rhinitis (AR) and allergic asthma (AA) and is most commonly delivered as subcutaneous immunotherapy (SCIT) or sublingual immunotherapy (SLIT). Despite its widespread use, there is variability in the initiation and delivery of safe and effective immunotherapy, and there are opportunities for evidence-based recommendations for improved patient care. PURPOSE The purpose of this clinical practice guideline (CPG) is to identify quality improvement opportunities and provide clinicians trustworthy, evidence-based recommendations regarding the management of inhaled allergies with immunotherapy. Specific goals of the guideline are to optimize patient care, promote safe and effective therapy, reduce unjustified variations in care, and reduce the risk of harm. The target patients for the guideline are any individuals aged 5 years and older with AR, with or without AA, who are either candidates for immunotherapy or treated with immunotherapy for their inhalant allergies. The target audience is all clinicians involved in the administration of immunotherapy. This guideline is intended to focus on evidence-based quality improvement opportunities judged most important by the guideline development group (GDG). It is not intended to be a comprehensive, general guide regarding the management of inhaled allergies with immunotherapy. The statements in this guideline are not intended to limit or restrict care provided by clinicians based on their experience and assessment of individual patients. ACTION STATEMENTS The GDG made a strong recommendation that (Key Action Statement [KAS] 10) the clinician performing allergy skin testing or administering AIT must be able to diagnose and manage anaphylaxis. The GDG made recommendations for the following KASs: (KAS 1) Clinicians should offer or refer to a clinician who can offer immunotherapy for patients with AR with or without AA if their patients' symptoms are inadequately controlled with medical therapy, allergen avoidance, or both, or have a preference for immunomodulation. (KAS 2A) Clinicians should not initiate AIT for patients who are pregnant, have uncontrolled asthma, or are unable to tolerate injectable epinephrine. (KAS 3) Clinicians should evaluate the patient or refer the patient to a clinician who can evaluate for signs and symptoms of asthma before initiating AIT and for signs and symptoms of uncontrolled asthma before administering subsequent AIT. (KAS 4) Clinicians should educate patients who are immunotherapy candidates regarding the differences between SCIT and SLIT (aqueous and tablet) including risks, benefits, convenience, and costs. (KAS 5) Clinicians should educate patients about the potential benefits of AIT in (1) preventing new allergen sensitizations, (2) reducing the risk of developing AA, and (3) altering the natural history of the disease with continued benefit after discontinuation of therapy. (KAS 6) Clinicians who administer SLIT to patients with seasonal AR should offer pre- and co-seasonal immunotherapy. (KAS 7) Clinicians prescribing AIT should limit treatment to only those clinically relevant allergens that correlate with the patient's history and are confirmed by testing. (KAS 9) Clinicians administering AIT should continue escalation or maintenance dosing when patients have local reactions (LRs) to AIT. (KAS 11) Clinicians should avoid repeat allergy testing as an assessment of the efficacy of ongoing AIT unless there is a change in environmental exposures or a loss of control of symptoms. (KAS 12) For patients who are experiencing symptomatic control from AIT, clinicians should treat for a minimum duration of 3 years, with ongoing treatment duration based on patient response to treatment. The GDG offered the following KASs as options: (KAS 2B) Clinicians may choose not to initiate AIT for patients who use concomitant beta-blockers, have a history of anaphylaxis, have systemic immunosuppression, or have eosinophilic esophagitis (SLIT only). (KAS 8) Clinicians may treat polysensitized patients with a limited number of allergens.
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Affiliation(s)
| | | | | | | | | | - Dole P. Baker
- Anderson ENT & Facial Plastics, Anderson, South Carolina, USA
| | | | | | | | | | | | - Jean Kim
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Joshua M. Levy
- National Institute on Deafness and Other Communication Disorders, Bethesda, Maryland, USA
| | - Christine M. Reger
- University of Pennsylvania, Otolaryngology–Head and Neck Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | | | | | | | - Joe Reyes
- American Academy of Otolaryngology–Head and Neck Surgery Foundation, Alexandria, Virginia, USA
| | - Nui Dhepyasuwan
- American Academy of Otolaryngology–Head and Neck Surgery Foundation, Alexandria, Virginia, USA
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Park DY, Lee YJ, Kim DK, Kim SW, Yang HJ, Kim DH, Jun YJ, Park SC, Kim BS, Yang SI, Lee IH, Kim M, Ryu G, Kang SY, Kim MA, Lee SM, Kim HJ, Choi GS, Chung SJ, Lee HJ, Kim HB, Choi JH. KAAACI Allergic Rhinitis Guidelines: Part 2. Update in Non-pharmacological Management. ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH 2023; 15:145-159. [PMID: 37021502 PMCID: PMC10079515 DOI: 10.4168/aair.2023.15.2.145] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 01/05/2023] [Accepted: 01/09/2023] [Indexed: 04/07/2023]
Abstract
Allergic rhinitis is the most common chronic disease worldwide. Various upper airway symptoms lower quality of life, and due to the recurrent symptoms, multiple treatments are usually attempted rather than one definitive treatment. There are alternatives to medical (medication-based) and non-medical treatments. A guideline is needed to understand allergic rhinitis and develop an appropriate treatment plan. We have developed guidelines for medical treatment based on previous reports. The current guidelines herein are associated with the "KAAACI Evidence-Based Guidelines for Allergic Rhinitis in Korea, Part 1: Update in pharmacotherapy" in which we aimed to provide evidence-based recommendations for the medical treatment of allergic rhinitis. Part 2 focuses on non-pharmacological management, including allergen-specific immunotherapy, subcutaneous or sublingual immunotherapy, nasal saline irrigation, environmental management strategies, companion animal management, and nasal turbinate surgery. The evidence to support the treatment efficacy, safety, and selection has been systematically reviewed. However, larger controlled studies are needed to elevate the level of evidence to select rational non-medical therapeutic options for patients with allergic rhinitis.
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Affiliation(s)
- Do-Yang Park
- Department of Otolaryngology, Ajou University School of Medicine, Suwon, Korea
| | - Yong Ju Lee
- Department of Pediatrics, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea
| | - Dong-Kyu Kim
- Institute of New Frontier Research, Division of Big Data and Artificial Intelligence, Hallym University College of Medicine, Chuncheon, Korea
- Department of Otorhinolaryngology-Head and Neck Surgery, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon, Korea.
| | - Soo Whan Kim
- Department of Otolaryngology-Head and Neck Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
| | - Hyeon-Jong Yang
- Department of Pediatrics, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Do Hyun Kim
- Department of Otolaryngology-Head and Neck Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Young Joon Jun
- Department of Otorhinolaryngology-Head and Neck surgery, Uijeongbu Eulji Medical Center, Eulji University, Uijeongbu, Korea
| | - Sang Chul Park
- Department of Otorhinolaryngology-Head and Neck surgery, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Bong-Seong Kim
- Department of Pediatrics, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea
| | - Song-I Yang
- Department of Pediatrics, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea
| | - Il Hwan Lee
- Department of Otorhinolaryngology-Head and Neck Surgery, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon, Korea
| | - Minji Kim
- Department of Pediatrics, Chungnam National University Sejong Hospital, Sejong, Korea
| | - Gwanghui Ryu
- Department of Otorhinolaryngology-Head and Neck Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung-Yoon Kang
- Division of Pulmonology and Allergy, Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Mi-Ae Kim
- Department of Pulmonology, Allergy and Critical Care Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Sang Min Lee
- Division of Pulmonology and Allergy, Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Hyun-Jung Kim
- Department of Preventive Medicine, College of Medicine, Korea University, Seoul, Korea
| | - Gil-Soon Choi
- Division of Allergy and Clinical Immunology, Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea
| | - Soo Jie Chung
- Department of Pulmonology and Allergy, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Korea
- Allergy and Clinical Immunology Research Center, Hallym University College of Medicine, Chuncheon, Korea
| | - Hyun Jong Lee
- Lee and Hong ENT Sleep and Cosmetic Center, Seongnam, Korea
| | - Hyo-Bin Kim
- Department of Pediatrics, Asthma and Allergy Center, Inje University Sanggye Paik Hospital, Seoul, Korea
| | - Jeong-Hee Choi
- Department of Pulmonology and Allergy, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Korea
- Allergy and Clinical Immunology Research Center, Hallym University College of Medicine, Chuncheon, Korea
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Maeda H, Ichimizu S, Watanabe H, Hamasaki K, Chikamatsu M, Murata R, Yumoto N, Seki T, Katsuki H, Otagiri M, Maruyama T. Cell-penetrating albumin enhances the sublingual delivery of antigens through macropinocytosis. Int J Biol Macromol 2022; 221:1439-1452. [PMID: 36126807 DOI: 10.1016/j.ijbiomac.2022.09.132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 09/15/2022] [Indexed: 11/26/2022]
Abstract
Innovations in oral immunotherapy have greatly advanced the therapeutic control of allergies. However, these therapeutic effects suffer from the fact that the amount of antigen delivered to antigen-presenting cells is limited given the formulations that are currently available. We recently designed a cell-penetrating albumin and found that this modified albumin enters cells via the induction of macropinocytosis. Herein, we report on a novel system for delivering antigens based on cell-penetrating albumin-inducible macropinocytosis that allows larger amounts of antigens to be delivered to antigen-presenting cells. A treatment with cell-penetrating albumin significantly increased the permeability of ovalbumin (45 kDa) or dextran (2000 kDa) on monolayers derived from human oral squamous carcinoma cells. Flow cytometric analyses showed that the cell-penetrating albumin treatment resulted in a significant elevation in the amount of dextran that was delivered to two types of antigen-presenting cells. Finally, mice that had been sensitized by Japanese cedar pollen extract (JCPE) and cell-penetrating albumin showed a decline in the frequency of nose-rubbing against a subsequent intranasal administration of JCPE. These findings suggest that the sublingual administration of cell-penetrating albumin efficiently delivers antigens to antigen-presenting cells via the induction of macropinocytosis, resulting in an enhancement in the therapeutic effect of sublingual immunotherapy.
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Affiliation(s)
- Hitoshi Maeda
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Shota Ichimizu
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Hiroshi Watanabe
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
| | - Keisuke Hamasaki
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Mayuko Chikamatsu
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Ryota Murata
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Nao Yumoto
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Takahiro Seki
- Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Hiroshi Katsuki
- Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Masaki Otagiri
- Faculty of Pharmaceutical Sciences, Sojo University, 1-22-4 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan
| | - Toru Maruyama
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
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Allergen Immunotherapy in Pediatric Respiratory Allergy. CURRENT TREATMENT OPTIONS IN ALLERGY 2021. [DOI: 10.1007/s40521-021-00280-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Abstract
Purpose of Review
Atopic diseases such as asthma and allergic rhinitis are highly prevalent in children. Common triggers include tree and grass pollens, house dust mites, molds, and animal dander. These diseases are most often treated symptomatically; however, many patients show partial or poor response and require long-term medication use. Allergen immunotherapy (AIT) stands as the only treatment modality that can alter the underlying disease process and potentially offer a cure. In this review article, we discuss the merits of AIT with particular emphasis on its efficacy and safety in pediatric patients. We also discuss the challenges for AIT implementation and present an overview of current research that aims at improving its applicability for the treatment of allergic diseases.
Recent Findings
Subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are both safe and efficacious treatment options in children with allergic rhinitis and allergic asthma. Additionally, AIT has efficacy in preventing the development of asthma in children. Although there are clear advantages with AIT, there are challenges to overcome to optimize treatment. Solutions include improved diagnostics with pre-treatment biomarkers and molecular multiplex assays, biomarkers for prediction of response (e.g., basophil activation markers), improved allergen immunogenicity with the use of recombinant AIT, adjuvants, and allergoids, and lastly improved safety with the concurrent use of omalizumab.
Summary
AIT has shown safety and efficacy in major clinical trials for the treatment of allergic rhinitis and allergic asthma in children. AIT provides a curative treatment option for atopic disorders and should be considered in children with allergic rhinitis and allergic asthma. There are many continued advances being made in the field of allergy to further improve the safety and efficacy profile and shorten the duration of AIT treatment.
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Tie K, Miller C, Zanation AM, Ebert CS. Subcutaneous Versus Sublingual Immunotherapy for Adults with Allergic Rhinitis: A Systematic Review with Meta-Analyses. Laryngoscope 2021; 132:499-508. [PMID: 33929726 DOI: 10.1002/lary.29586] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/13/2021] [Accepted: 04/14/2021] [Indexed: 11/11/2022]
Abstract
OBJECTIVES To determine whether subcutaneous immunotherapy (SCIT) or sublingual immunotherapy (SLIT) better improves patient outcomes and quality of life for adults with allergic rhinitis or rhinoconjunctivitis (AR/C) with or without mild to moderate asthma. METHODS Systematic review methodology was based on the Cochrane Collaboration handbook and Preferred Reporting Items for Systematic Reviews and Meta-analyses. Four databases (PubMed, Cochrane Library, EMBASE, and Web of Science) were queried from inception to July 30, 2020. Two independent reviewers screened potentially relevant studies and assessed risk of bias. Outcomes of interest were symptom score (SS), medication score (MS), combined symptom medication score (CSMS), and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). Meta-analyses with an adjusted indirect comparison were conducted in RevMan 5.4.1. RESULTS Seven SCIT versus SLIT randomized controlled trials (RCTs) demonstrated no significant differences for any outcomes, but insufficient data precluded direct meta-analysis. For the adjusted indirect comparison, 46 RCTs over 39 studies were included for SCIT versus placebo (n = 13) and SLIT versus placebo (n = 33). Statistically significant results favoring SCIT were found for SS (standardized mean difference [SMD] = 0.40; 95% confidence interval [CI] = 0.31-0.49), MS (SMD = 0.26; 95% CI = 0.14-0.39), CSMS (SMD = 0.42; 95% CI = 0.17-0.67), and RQLQ (MD = 0.24; 95% CI = 0.04-0.44). Statistically significant results favoring SLIT were found for SS (SMD = 0.42; 95% CI = 0.32-0.53), MS (SMD = 0.40; 95% CI = 0.28-0.53), CSMS (SMD = 0.37; 95% CI = 0.29-0.45), and RQLQ (MD = 0.32; 95% CI = 0.20-0.43). No significant differences were found between SCIT and SLIT for SS (SMD = -0.02; 95% CI = -0.15 to 0.11), MS (SMD = -0.14; 95% CI = -0.31 to 0.03), CSMS (SMD = 0.05; 95% CI = -0.21 to 0.31), or RQLQ (MD = -0.08; 95% CI = -0.31 to 0.15). CONCLUSION SCIT and SLIT are comparably effective treatments for adults with AR/C. More RCTs analyzing SCIT versus SLIT are needed to directly compare the two. Laryngoscope, 2021.
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Affiliation(s)
- Kevin Tie
- University of North Carolina School of Medicine, Chapel Hill, North Carolina, U.S.A
| | - Craig Miller
- Department of Otolaryngology-Head & Neck Surgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina, U.S.A
| | - Adam M Zanation
- Department of Otolaryngology-Head & Neck Surgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina, U.S.A
| | - Charles S Ebert
- Department of Otolaryngology-Head & Neck Surgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina, U.S.A
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León B, Ballesteros-Tato A. Modulating Th2 Cell Immunity for the Treatment of Asthma. Front Immunol 2021; 12:637948. [PMID: 33643321 PMCID: PMC7902894 DOI: 10.3389/fimmu.2021.637948] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 01/21/2021] [Indexed: 12/14/2022] Open
Abstract
It is estimated that more than 339 million people worldwide suffer from asthma. The leading cause of asthma development is the breakdown of immune tolerance to inhaled allergens, prompting the immune system's aberrant activation. During the early phase, also known as the sensitization phase, allergen-specific T cells are activated and become central players in orchestrating the subsequent development of allergic asthma following secondary exposure to the same allergens. It is well-established that allergen-specific T helper 2 (Th2) cells play central roles in developing allergic asthma. As such, 80% of children and 60% of adult asthma cases are linked to an unwarranted Th2 cell response against respiratory allergens. Thus, targeting essential components of Th2-type inflammation using neutralizing antibodies against key Th2 modulators has recently become an attractive option for asthmatic patients with moderate to severe symptoms. In addition to directly targeting Th2 mediators, allergen immunotherapy, also known as desensitization, is focused on redirecting the allergen-specific T cells response from a Th2-type profile to a tolerogenic one. This review highlights the current understanding of the heterogeneity of the Th2 cell compartment, their contribution to allergen-induced airway inflammation, and the therapies targeting the Th2 cell pathway in asthma. Further, we discuss available new leads for successful targeting pulmonary Th2 cell responses for future therapeutics.
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Affiliation(s)
- Beatriz León
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Andre Ballesteros-Tato
- Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
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Abstract
BACKGROUND Asthma is a common long-term respiratory disease affecting approximately 300 million people worldwide. Approximately half of people with asthma have an important allergic component to their disease, which may provide an opportunity for targeted treatment. Sublingual immunotherapy (SLIT) aims to reduce asthma symptoms by delivering increasing doses of an allergen (e.g. house dust mite, pollen extract) under the tongue to induce immune tolerance. Fifty-two studies were identified and synthesised in the original Cochrane Review in 2015, but questions remained about the safety and efficacy of sublingual immunotherapy for people with asthma. OBJECTIVES To assess the efficacy and safety of sublingual immunotherapy compared with placebo or standard care for adults and children with asthma. SEARCH METHODS The original searches for trials from the Cochrane Airways Group Specialised Register (CAGR), ClinicalTrials.gov, WHO ICTRP, and reference lists of all primary studies and review articles found trials up to 25 March 2015. The most recent search for trials for the current update was conducted on 29 October 2019. SELECTION CRITERIA We included parallel randomised controlled trials, irrespective of blinding or duration, that evaluated sublingual immunotherapy versus placebo or as an add-on to standard asthma management. We included both adults and children with asthma of any severity and with any allergen-sensitisation pattern. We included studies that recruited participants with asthma, rhinitis, or both, providing at least 80% of trial participants had a diagnosis of asthma. We selected outcomes to reflect recommended outcomes for asthma clinical trials and those most important to people with asthma. Primary outcomes were asthma exacerbations requiring a visit to the emergency department (ED) or admission to hospital, validated measures of quality of life, and all-cause serious adverse events (SAEs). Secondary outcomes were asthma symptom scores, exacerbations requiring systemic corticosteroids, response to provocation tests, and dose of inhaled corticosteroids (ICS). DATA COLLECTION AND ANALYSIS Two review authors independently screened the search results for included trials, extracted numerical data, and assessed risk of bias, all of which were cross-checked for accuracy. Any disagreements were resolved by discussion. We analysed dichotomous data as odds ratios (ORs) or risk differences (RDs) using study participants as the unit of analysis; we analysed continuous data as mean differences (MDs) or standardised mean differences (SMDs) using random-effects models. We considered the strength of evidence for all primary and secondary outcomes using the GRADE approach. MAIN RESULTS Sixty-six studies met the inclusion criteria for this update, including 52 studies from the original review. Most studies were double-blind and placebo-controlled, varied in duration from one day to three years, and recruited participants with mild or intermittent asthma, often with comorbid allergic rhinitis. Twenty-three studies recruited adults and teenagers; 31 recruited only children; three recruited both; and nine did not specify. The pattern of reporting and results remained largely unchanged from the original review despite 14 further studies and a 50% increase in participants studied (5077 to 7944). Reporting of primary efficacy outcomes to measure the impact of SLIT on asthma exacerbations and quality of life was infrequent, and selective reporting may have had a serious effect on the completeness of the evidence; 16 studies did not contribute any data, and a further six studies could only be included in a post hoc analysis of all adverse events. Allocation procedures were generally not well described; about a quarter of the studies were at high risk of performance or detection bias (or both); and participant attrition was high or unknown in around half of the studies. The primary outcome in most studies did not align with those of interest to the review (mostly asthma or rhinitis symptoms), and only two small studies reported our primary outcome of exacerbations requiring an ED or hospital visit; the pooled estimate from these studies suggests SLIT may reduce exacerbations compared with placebo or usual care, but the evidence is very uncertain (OR 0.35, 95% confidence interval (CI) 0.10 to 1.20; n = 108; very low-certainty evidence). Nine studies reporting quality of life could not be combined in a meta-analysis and, whilst the direction of effect mostly favoured SLIT, the effects were often uncertain and small. SLIT likely does not increase SAEs compared with placebo or usual care, and analysis by risk difference suggests no more than 1 in 100 people taking SLIT will have a serious adverse event (RD -0.0004, 95% CI -0.0072 to 0.0064; participants = 4810; studies = 29; moderate-certainty evidence). Regarding secondary outcomes, asthma symptom and medication scores were mostly measured with non-validated scales, which precluded meaningful meta-analysis or interpretation, but there was a general trend of SLIT benefit over placebo. Changes in ICS use (MD -17.13 µg/d, 95% CI -61.19 to 26.93; low-certainty evidence), exacerbations requiring oral steroids (studies = 2; no events), and bronchial provocation (SMD 0.99, 95% CI 0.17 to 1.82; low-certainty evidence) were not often reported. Results were imprecise and included the possibility of important benefit or little effect and, in some cases, potential harm from SLIT. More people taking SLIT had adverse events of any kind compared with control (OR 1.99, 95% CI 1.49 to 2.67; high-certainty evidence; participants = 4251; studies = 27), but events were usually reported to be transient and mild. Lack of data prevented most of the planned subgroup and sensitivity analyses. AUTHORS' CONCLUSIONS Despite continued study in the field, the evidence for important outcomes such as exacerbations and quality of life remains too limited to draw clinically useful conclusions about the efficacy of SLIT for people with asthma. Trials mostly recruited mixed populations with mild and intermittent asthma and/or rhinitis and focused on non-validated symptom and medication scores. The review findings suggest that SLIT may be a safe option for people with well-controlled mild-to-moderate asthma and rhinitis who are likely to be at low risk of serious harm, but the role of SLIT for people with uncontrolled asthma requires further evaluation.
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Affiliation(s)
- Rebecca Fortescue
- Cochrane Airways, Population Health Research Institute, St George's, University of London, London, UK
| | - Kayleigh M Kew
- Cochrane Editorial and Methods Department, Cochrane, London, UK
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Alvaro-Lozano M, Akdis CA, Akdis M, Alviani C, Angier E, Arasi S, Arzt-Gradwohl L, Barber D, Bazire R, Cavkaytar O, Comberiati P, Dramburg S, Durham SR, Eifan AO, Forchert L, Halken S, Kirtland M, Kucuksezer UC, Layhadi JA, Matricardi PM, Muraro A, Ozdemir C, Pajno GB, Pfaar O, Potapova E, Riggioni C, Roberts G, Rodríguez Del Río P, Shamji MH, Sturm GJ, Vazquez-Ortiz M. EAACI Allergen Immunotherapy User's Guide. Pediatr Allergy Immunol 2020; 31 Suppl 25:1-101. [PMID: 32436290 PMCID: PMC7317851 DOI: 10.1111/pai.13189] [Citation(s) in RCA: 178] [Impact Index Per Article: 35.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Allergen immunotherapy is a cornerstone in the treatment of allergic children. The clinical efficiency relies on a well-defined immunologic mechanism promoting regulatory T cells and downplaying the immune response induced by allergens. Clinical indications have been well documented for respiratory allergy in the presence of rhinitis and/or allergic asthma, to pollens and dust mites. Patients who have had an anaphylactic reaction to hymenoptera venom are also good candidates for allergen immunotherapy. Administration of allergen is currently mostly either by subcutaneous injections or by sublingual administration. Both methods have been extensively studied and have pros and cons. Specifically in children, the choice of the method of administration according to the patient's profile is important. Although allergen immunotherapy is widely used, there is a need for improvement. More particularly, biomarkers for prediction of the success of the treatments are needed. The strength and efficiency of the immune response may also be boosted by the use of better adjuvants. Finally, novel formulations might be more efficient and might improve the patient's adherence to the treatment. This user's guide reviews current knowledge and aims to provide clinical guidance to healthcare professionals taking care of children undergoing allergen immunotherapy.
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Affiliation(s)
| | - Cezmi A Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.,Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland
| | - Mubeccel Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Cherry Alviani
- The David Hide Asthma and Allergy Research Centre, St Mary's Hospital, Newport, Isle of Wight, UK.,Clinical and Experimental Sciences and Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.,NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Elisabeth Angier
- Primary Care and Population Sciences, University of Southampton, Southampton, UK
| | - Stefania Arasi
- Pediatric Allergology Unit, Department of Pediatric Medicine, Bambino Gesù Children's research Hospital (IRCCS), Rome, Italy
| | - Lisa Arzt-Gradwohl
- Department of Dermatology and Venerology, Medical University of Graz, Graz, Austria
| | - Domingo Barber
- School of Medicine, Institute for Applied Molecular Medicine (IMMA), Universidad CEU San Pablo, Madrid, Spain.,RETIC ARADYAL RD16/0006/0015, Instituto de Salud Carlos III, Madrid, Spain
| | - Raphaëlle Bazire
- Allergy Department, Hospital Infantil Niño Jesús, ARADyAL RD16/0006/0026, Madrid, Spain
| | - Ozlem Cavkaytar
- Department of Paediatric Allergy and Immunology, Faculty of Medicine, Goztepe Training and Research Hospital, Istanbul Medeniyet University, Istanbul, Turkey
| | - Pasquale Comberiati
- Department of Clinical Immunology and Allergology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.,Department of Clinical and Experimental Medicine, Section of Paediatrics, University of Pisa, Pisa, Italy
| | - Stephanie Dramburg
- Department of Pediatric Pneumology, Immunology and Intensive Care Medicine, Charité Medical University, Berlin, Germany
| | - Stephen R Durham
- Immunomodulation and Tolerance Group; Allergy and Clinical Immunology, Section of Inflammation, Repair and Development, National Heart and Lung Institute, Imperial College London, London, UK.,the MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK
| | - Aarif O Eifan
- Allergy and Clinical Immunology, National Heart and Lung Institute, Imperial College London and Royal Brompton Hospitals NHS Foundation Trust, London, UK
| | - Leandra Forchert
- Department of Pediatric Pneumology, Immunology and Intensive Care Medicine, Charité Medical University, Berlin, Germany
| | - Susanne Halken
- Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark
| | - Max Kirtland
- Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Inflammation, Repair and Development, National Heart and Lung Institute, Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, UK
| | - Umut C Kucuksezer
- Aziz Sancar Institute of Experimental Medicine, Department of Immunology, Istanbul University, Istanbul, Turkey
| | - Janice A Layhadi
- Immunomodulation and Tolerance Group; Allergy and Clinical Immunology, Section of Inflammation, Repair and Development, National Heart and Lung Institute, Imperial College London, London, UK.,the MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK.,Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Inflammation, Repair and Development, National Heart and Lung Institute, Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, UK
| | - Paolo Maria Matricardi
- Department of Pediatric Pneumology, Immunology and Intensive Care Medicine, Charité Medical University, Berlin, Germany
| | - Antonella Muraro
- The Referral Centre for Food Allergy Diagnosis and Treatment Veneto Region, Department of Women and Child Health, University of Padua, Padua, Italy
| | - Cevdet Ozdemir
- Institute of Child Health, Department of Pediatric Basic Sciences, Istanbul University, Istanbul, Turkey.,Faculty of Medicine, Department of Pediatrics, Division of Pediatric Allergy and Immunology, Istanbul University, Istanbul, Turkey
| | | | - Oliver Pfaar
- Department of Otorhinolaryngology, Head and Neck Surgery, Section of Rhinology and Allergy, University Hospital Marburg, Philipps-Universität Marburg, Marburg, Germany
| | - Ekaterina Potapova
- Department of Pediatric Pneumology, Immunology and Intensive Care Medicine, Charité Medical University, Berlin, Germany
| | - Carmen Riggioni
- Pediatric Allergy and Clinical Immunology Service, Institut de Reserca Sant Joan de Deú, Barcelona, Spain
| | - Graham Roberts
- The David Hide Asthma and Allergy Research Centre, St Mary's Hospital, Newport, Isle of Wight, UK.,NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK.,Paediatric Allergy and Respiratory Medicine (MP803), Clinical & Experimental Sciences & Human Development in Health Academic Units University of Southampton Faculty of Medicine & University Hospital Southampton, Southampton, UK
| | | | - Mohamed H Shamji
- Immunomodulation and Tolerance Group; Allergy and Clinical Immunology, Section of Inflammation, Repair and Development, National Heart and Lung Institute, Imperial College London, London, UK.,the MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK
| | - Gunter J Sturm
- Department of Dermatology and Venerology, Medical University of Graz, Graz, Austria
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Xian M, Feng M, Dong Y, Wei N, Su Q, Li J. Changes in CD4+CD25+FoxP3+ Regulatory T Cells and Serum Cytokines in Sublingual and Subcutaneous Immunotherapy in Allergic Rhinitis with or without Asthma. Int Arch Allergy Immunol 2019; 181:71-80. [PMID: 31722337 DOI: 10.1159/000503143] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 09/03/2019] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Few studies have directly compared the immunologic responses to specific subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT). OBJECTIVE We aimed to directly compare clinical efficacy and immunological responses between SLIT and SCIT in allergic rhinitis (AR) sensitized to house dust mites. METHODS Sixty-seven patients (age 5-55 years) with moderate-severe Dermatophagoides pteronyssinus (Der-p) and Dermatophagoides farinae AR with or without asthma were randomized (2:2:1) into SLIT (n = 27), SCIT (n = 26) and placebo (n = 14) groups. Symptom and medication scores, visual analogue score, serum Der-p specific immunoglobulin G4 (Der-p-sIgG4), CD4+CD25+FoxP3+ regulatory T cells (Tregs) and serum cytokines were measured. RESULTS After 1-year treatment, a significant improvement of total rhinitis score (TRS), total rhinitis medication score (TRMS) and visual analogue score occurred in both SLIT and SCIT. There were no differences in clinical efficacy except for TRMS (p = 0.026) when SLIT and SCIT were directly compared. CD4+CD25+FoxP3+ Tregs had a trend towards upregulation in the 2 modes and inversely correlated with TRS (p = 0.024) only in SLIT. Der-p-sIgG4 significantly increased in SLIT and SCIT (p < 0.05), and it was 30 times higher in SCIT than SLIT after the treatment (p < 0.05). Serum interferon-γ significantly increased only in SCIT after 1 (p = 0.008), 6 (p = 0.007) and 12 (p = 0.008) months of treatment and inversely correlated with TRS (p = 0.032). CONCLUSION While SCIT and SLIT have similar rates of clinical improvement, the 2 modes reveal heterogeneous changes of CD4+CD25+Foxp3+ Tregs, sIgG4 and cytokines.
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Affiliation(s)
- Mo Xian
- Department of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Mulin Feng
- Department of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yan Dong
- Guangzhou First People's Hospital of Guangdong Province, Guangzhou, China
| | - Nili Wei
- Department of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qiujuan Su
- Department of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jing Li
- Department of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China,
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12
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Wheatley LM, Wood R, Nadeau K, Liu A, Zoratti E, Bacharier L, Brittain E, Calderon M, Casale T, Chipps B, Cox L, Creticos PS, Desai M, Dreborg S, Durham S, Gergen PJ, Gruchalla R, Nelson H, O'Hehir RE, Plaut M, Schwaninger JM, Tilles S, Vickery B, Wittenberg KM, Togias A. Mind the gaps: Clinical trial concepts to address unanswered questions in aeroallergen immunotherapy-An NIAID/AHRQ Workshop. J Allergy Clin Immunol 2019; 143:1711-1726. [PMID: 30731123 DOI: 10.1016/j.jaci.2019.01.032] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 01/08/2019] [Accepted: 01/22/2019] [Indexed: 11/21/2022]
Abstract
The Agency for Healthcare Research and Quality and the National Institute of Allergy and Infectious Diseases organized a workshop to develop trial concepts that could improve the use and effectiveness of aeroallergen immunotherapy (AAIT). Expert groups were formed to accomplish the following tasks: (1) propose a study design to compare the effectiveness and safety of subcutaneous versus sublingual AAIT; (2) propose a study design to compare the effectiveness and safety of AAIT by using 1 or a few allergens versus all or most allergens to which a patient is sensitized; (3) propose a study design to determine whether AAIT can alter the progression of childhood allergic airways disease; and (4) propose a study design to determine the optimal dose and duration of AAIT to achieve maximal effectiveness with acceptable safety. Study designs were presented by the workgroups, extensively discussed at the workshop, and revised for this report. The proposed trials would be of long duration and require large highly characterized patient populations. Scientific caveats and feasibility matters are discussed. These concepts are intended to help the development of clinical trials that can address some of the major questions related to the practice of AAIT for the management and prevention of allergic airways disease.
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Affiliation(s)
- Lisa M Wheatley
- Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Md.
| | | | | | - Andrew Liu
- Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, Colo
| | | | | | - Erica Brittain
- Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Md
| | | | | | - Bradley Chipps
- Capital Allergy and Respiratory Disease Center, Sacramento, Calif
| | - Linda Cox
- Nova Southeastern University, Fort Lauderdale, Fla
| | | | - Manisha Desai
- Quantitative Sciences Unit, Stanford University, Stanford, Calif
| | | | | | - Peter J Gergen
- Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Md
| | | | | | - Robyn E O'Hehir
- Alfred Hospital and Monash University Medical School, Melbourne, Australia
| | - Marshall Plaut
- Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Md
| | - Julie M Schwaninger
- Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Md
| | | | - Brian Vickery
- North Carolina Children's Hospital, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Kim M Wittenberg
- Center for Evidence and Practice Improvement, Agency for Healthcare Research and Quality, Rockville, Md
| | - Alkis Togias
- Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Md
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13
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Kim H, Lee DI, Seo C, Kim D, Jeon H, Lee J. Ionic Liquid‐based
in situ
Film‐forming Sublingual Spray Formulations of Cyanocobalamin. B KOREAN CHEM SOC 2019. [DOI: 10.1002/bkcs.11671] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Hyeongmin Kim
- College of PharmacyChung‐Ang University Seoul 06974 South Korea
| | - Dong Il Lee
- College of PharmacyChung‐Ang University Seoul 06974 South Korea
| | - Chang‐Won Seo
- College of PharmacyChung‐Ang University Seoul 06974 South Korea
| | - Dohyun Kim
- College of PharmacyChung‐Ang University Seoul 06974 South Korea
| | - Hyojin Jeon
- College of PharmacyChung‐Ang University Seoul 06974 South Korea
| | - Jaehwi Lee
- College of PharmacyChung‐Ang University Seoul 06974 South Korea
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Abstract
House dust mite (HDM) is a predominant source of indoor aeroallergen worldwide, which induces allergic diseases including allergic rhinoconjunctivitis, allergic asthma, atopic eczema and other allergic skin diseases. Allergen specific immunotherapy (AIT) is the only potential disease-modifying treatment of HDM allergic subjects. However, AIT remains underused due to no universally accepted allergen standardization and a shortage of rigorous clinical studies to confirm safety and efficacy. With the effort of doctors and researchers in allergy field, efficacy, safety, standardization and strategy of AIT are being continuously developed. This review presents the updated research based on recently published trials and meta-analyses.
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Affiliation(s)
- Lin Yang
- a Department of Allergy , Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology , Wuhan , China
| | - Rongfei Zhu
- a Department of Allergy , Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology , Wuhan , China
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15
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Schwanke T, Carragee E, Bremberg M, Reisacher WR. Quality-of-life outcomes in patients who underwent subcutaneous immunotherapy and sublingual immunotherapy in a real-world clinical setting. Am J Rhinol Allergy 2018; 31:310-316. [PMID: 28859707 DOI: 10.2500/ajra.2017.31.4465] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
OBJECTIVE To compare changes in quality of life (QOL) that resulted from sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) in a real-world clinical setting. BACKGROUND SLIT is established as a viable alternative to SCIT for the treatment of allergic rhinitis. Although comparative trials are increasingly available, few studies have examined QOL outcomes between these two treatments. METHODS One hundred and five participants who underwent immunotherapy for airborne allergies were enrolled in this prospective, single-center study. Forty participants completed the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) at initiation of therapy, after 6 months, and after 1 year of therapy. Only patients with complete time points were included in the ultimate analysis. Twenty-nine of these participants underwent SCIT and 11 underwent SLIT. The effects of age, sex, and asthma history were also examined. RESULTS The participants in both groups demonstrated improvements in QOL regarding allergic rhinoconjunctivitis over the study period. However, the change in the RQLQ score from both baseline to 6 months and baseline to 1 year was only statistically significant in the SCIT group (p = 0.002, 6 months and 1 year). The participants in the SCIT group also demonstrated statistically significant improvement from baseline to 1 year in the specific domains of practical and emotional functioning, nasal symptoms, non-nasal/eye symptoms, and sleep. After 1 year, both SCIT and SLIT demonstrated a minimally important difference from baseline in the overall RQLQ score. Age <35 years in the SCIT group had a significant positive impact on QOL improvement (p = 0.038). CONCLUSION Although improvements in QOL were noted in both groups, changes in overall scores and the majority of domains only achieved statistical significance in the SCIT group. A small study population and difficulties adhering to immunotherapy dosing schedules in the SLIT group may be contributing factors.
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Affiliation(s)
- Theresa Schwanke
- Department of Otolaryngology-Head and Neck Surgery, Weill Cornell Medical College, New York, New York, USA
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16
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Aliu H, Rask C, Brimnes J, Andresen TL. Enhanced efficacy of sublingual immunotherapy by liposome-mediated delivery of allergen. Int J Nanomedicine 2017; 12:8377-8388. [PMID: 29200850 PMCID: PMC5702530 DOI: 10.2147/ijn.s137033] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Immunotherapy by sublingual administration of allergens provides high patient compliance and has emerged as an alternative to subcutaneous immunotherapy for the treatment of IgE-associated allergic diseases. However, sublingual immunotherapy (SLIT) can cause adverse events. Development of allergen delivery systems enabling more efficient delivery and hence lower allergen load might reduce the adverse events. In the present study, we have investigated neutral and cationic liposomes as delivery systems of ovalbumin (OVA), as a model allergen, in an OVA-induced allergic airway inflammation model. We investigated the liposome carriers' ability to improve tolerance induction of antigens compared to the corresponding dose of free OVA. Mice were treated sublingually over 2 weeks with free or liposome encapsulated OVA followed by intraperitoneal injections and intranasal challenge. Mice sublingually treated with OVA-liposomes showed a significant reduction of airway eosinophilia and splenocyte proliferation in comparison to free OVA. A similar nonsignificant pattern was seen for OVA-specific IgE antibodies. In addition, reduced levels of interferon-γ and interleukin-5 were observed in spleen cell culture supernatants from OVA-liposome-treated mice compared to the sham-treated group. In conclusion, in vivo efficacy data showed that prophylactic SLIT with OVA-liposomes is significantly more effective in preventing allergic inflammation than the corresponding dose of free OVA.
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Affiliation(s)
- Have Aliu
- Immunology Department, In vivo Biology Team, ALK Abelló A/S, Hørsholm.,Department of Micro- and Nanotechnology, Technical University of Denmark.,Center for Nanomedicine and Theranostics, Technical University of Denmark, Kgs Lyngby, Denmark
| | - Carola Rask
- Immunology Department, In vivo Biology Team, ALK Abelló A/S, Hørsholm
| | - Jens Brimnes
- Immunology Department, In vivo Biology Team, ALK Abelló A/S, Hørsholm
| | - Thomas Lars Andresen
- Department of Micro- and Nanotechnology, Technical University of Denmark.,Center for Nanomedicine and Theranostics, Technical University of Denmark, Kgs Lyngby, Denmark
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Passalacqua G, Canonica GW, Bagnasco D. Benefit of SLIT and SCIT for Allergic Rhinitis and Asthma. Curr Allergy Asthma Rep 2017; 16:88. [PMID: 27957697 DOI: 10.1007/s11882-016-0666-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Allergen immunotherapy (AIT) has been in use since more than one century, when Leonard Noon experimentally proved its efficacy in hayfever (Noon, in Lancet 1:1572-3, 1911). Since then, AIT was administered only as subcutaneous injections (SCIT) until the sublingual route (SLIT) was proposed in 1986. The use of SLIT was proposed following several surveys from the USA and UK that repeatedly reported fatalities due to SCIT (Lockey et al. in J Allergy Clin Immunol 75(1): 166, 1985; Lockey et al. in J Allergy Clin Immunol 660-77, 1985; Committee on the safety of medicines. CSM update. Desensitizing vaccines. Br Med J, 293: 948, 1986). These reports raised serious concerns about the safety and the risk/benefit ratio of AIT. Many cases of life-threatening events with SCIT were due to avoidable human errors in administration, but a relevant fraction of them remained unexplained and unpredictable (Aaronson and Gandhi in J Allergy Clin Immunol 113: 1117-21, 2014). Subsequently, in a few years, SLIT gained credibility and was included in the official documents and guidelines (Table 1) (Bousquet et al. in J Allergy Clin Immunol 108(5 Supp):S146-S150, 2001; Canonica et al. in Allergy 64 (Supp 91):1-59, 2009) as a viable alternative to traditional SCIT. Of note, the local bronchial (aerosol) and the intranasal route of administration were attempted after the 1970s as alternatives to SCIT: the bronchial route was soon abandoned due to the poor efficacy and/or side effects, and the local nasal route, although effective and safe, was judged substantially impractical (Canonica and Passalacqua in J Allergy Clin Immunol 111: 437-48, 2003). In contrast to SCIT, SLIT was tested in very large clinical trials (need references), including hundreds of patients and with dose-ranging experimental designs, so that some products (tablets) for grass, mite, and ragweed were officially approved as commercial drugs by regulatory agencies such as the Food and Drug Administration and the European Medicines Agency and the optimal content for the maintenance dose was identified for selected allergens. In parallel, the knowledge on the mechanisms of action of AIT was rapidly refined, leading to further improvements, such as the chemically modified extracts and the use of adjuvants to enhance efficacy and safety. In addition, in the last 10 years, there has been an increasing scientific and clinical interest in AIT applied to food allergies, in particular in children, with the use of orally administered extracts (Albin and Nowak-Węgrzyn in Immunol Allergy Clin North Am 35: 77-100, 2015). The results are so far encouraging, at least for cow's milk, egg, and peanut, although the use of treatment is still restricted to clinical trials or within specialized centers. Finally, the introduction of molecular- or component-resolved diagnosis has allowed detailing the prescription of AIT, by better delineating true sensitization versus cross-reactivity (Canonica et al. in World Allergy Organ J 6(1):17, 2013). This latter point is also in strict relation to the use of recombinant, engineered or highly purified molecules, instead of raw extracts, for the desensitization process.
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Affiliation(s)
- Giovanni Passalacqua
- Allergy and Respiratory Diseases, IRCCS San Martino-IST, University of Genoa, Genoa, Italy.
| | | | - Diego Bagnasco
- Allergy and Respiratory Diseases, IRCCS San Martino-IST, University of Genoa, Genoa, Italy
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Mortuaire G, Michel J, Papon JF, Malard O, Ebbo D, Crampette L, Jankowski R, Coste A, Serrano E. Specific immunotherapy in allergic rhinitis. Eur Ann Otorhinolaryngol Head Neck Dis 2017; 134:253-258. [PMID: 28684084 DOI: 10.1016/j.anorl.2017.06.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Allergic rhinitis is a common condition, with significant impact on quality of life depending on severity and quality of control. Allergen-specific immunotherapy (allergen-SIT) is the only known treatment able to alter the natural course of allergic rhinitis. Although well known to allergologists, it has yet to be fully adopted by the ENT community. This review, based on the most recent meta-analyses and clinical studies, shows that SIT significantly reduces symptoms and medication requirements (nasal corticosteroids, H1-antihistamines) in allergic rhinitis. It can reduce the risk of progression to asthma and, if initiated early enough, of developing new sensitizations. Immunobiological analysis shows an altered inflammatory profile following SIT, with immune tolerance involving T-regulatory lymphocyte induction and IgG production. Sublingual SIT with drops is as effective as subcutaneous SIT and is simpler to use, with less anaphylactic risk. Standardization of trial protocols in terms of treatment response assessment and side effect grading is recommended to improve comparative studies. Sublingual SIT with tablets has recently been introduced, providing a good opportunity for ENT practitioners to adopt the SIT approach in rhinitis triggered by allergy to pollens and, in the near future, to house dust mites.
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Affiliation(s)
- G Mortuaire
- Inserm U995, service d'ORL et de chirurgie cervicofaciale, Lille Inflammation Research International Center, université de Lille, hôpital Huriez, CHU de Lille, 59000 Lille, France.
| | - J Michel
- Service d'ORL et de chirurgie cervicofaciale, CHU Hôpital La Conception, AP-HM, 147, boulevard Baille, 13005 Marseille, France
| | - J F Papon
- Service d'ORL et de chirurgie cervicofaciale, Bicêtre, AP-HP, 78, rue du Général-Leclerc, 94270 Le Kremlin-Bicêtre, France
| | - O Malard
- Service d'ORL et de chirurgie cervicofaciale, CHU de Nantes, 44000 Nantes, France
| | - D Ebbo
- Groupe hospitalier Paris-Saint-Joseph, 185, rue Raymond-Losserand, 75014 Paris, France
| | - L Crampette
- Service d'ORL et de chirurgie cervicofaciale, CHU de Montpellier, 34090 Montpellier, France
| | - R Jankowski
- Service d'ORL et de chirurgie cervicofaciale, CHU Nancy, 54500 Vandœuvre-lès-Nancy, France
| | - A Coste
- Service d'ORL et de chirurgie cervicofaciale, CHU de Créteil, 94000 Créteil, France
| | - E Serrano
- Service d'ORL et de chirurgie cervicofaciale, CHU de Toulouse, 31059 Toulouse, France
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Topical ocular treatment with monoclonal antibody Fab fragments targeting Japanese cedar pollen Cry j 1 inhibits Japanese cedar pollen-induced allergic conjunctivitis in mice. Eur J Pharmacol 2017; 798:105-112. [PMID: 28119075 DOI: 10.1016/j.ejphar.2017.01.028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 01/20/2017] [Accepted: 01/20/2017] [Indexed: 12/12/2022]
Abstract
Fab fragments (Fabs) of antibodies having the ability only to bind to specific allergens lack effector functions due to the absence of the Fc portion. In the present study, we examined whether IgG1 monoclonal antibody (mAb) Fabs targeting Japanese cedar pollen (JCP) Cry j 1 were able to regulate JCP-induced allergic conjunctivitis in mice. BALB/c mice actively sensitized with JCP were repeatedly challenged by topical administration of JCP eye drops. Fabs prepared by the digestion of anti-JCP IgG1 mAbs (P1-3 and P1-8) with papain were applied to the eye 15min before the JCP challenges followed by measurement of the clinical conjunctivitis score. In the in vitro experiments, P1-3 and P1-8 showed specific binding to JCP Cry j 1. Furthermore, intact P1-3 binding to Cry j 1 was inhibited by P1-3 Fabs, but not P1-8 Fabs; additionally, P1-8 Fabs, but not P1-3 Fabs, suppressed the intact P1-8 binding, suggesting that the epitopes of Cry j 1 recognized by P1-3 and P1-8 were different. Topical ocular treatment with P1-3 Fabs or P1-8 Fabs was followed by marked suppression of JCP-induced conjunctivitis (P<0.01). In histological evaluation, P1-8 Fabs showed a reduction in eosinophil infiltration in the conjunctiva (P<0.01). These results demonstrated that topical ocular treatment with IgG1 mAb Fabs to Cry j 1 was effective in suppressing JCP-induced allergic conjunctivitis in mice. Furthermore, it suggests the possibility that some epitopes recognized by Fabs could be used as a tool to regulate allergic conjunctivitis.
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Feng B, Xiang H, Jin H, Gao J, Huang S, Shi Y, Chen R, Chen B. Efficacy of Sublingual Immunotherapy for House Dust Mite-Induced Allergic Rhinitis: A Meta-Analysis of Randomized Controlled Trials. ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH 2017; 9:220-228. [PMID: 28293928 PMCID: PMC5352573 DOI: 10.4168/aair.2017.9.3.220] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 10/06/2016] [Accepted: 10/11/2016] [Indexed: 01/04/2023]
Abstract
Purpose Allergic rhinitis (AR) has become a global issue for a large part of the general population. Sublingual immunotherapy (SLIT) has been used extensively to treat persistent allergic rhinitis (PAR). Although systematic reviews have confirmed the effectiveness of SLIT for the treatment of AR, a considerable number of studies using extracts of house dust mites (HDMs) for immunotherapy found no consensus on basic treatment parameters and questioned the efficacy of SLIT. Methods In this study, we evaluated SLIT for PAR by a meta-analysis of randomized controlled trials (RCTs). Medline, Embase, and Cochrane Library database searches were performed for RCTs on the treatment of PAR by SLIT that assessed clinical outcomes related to efficacy through May 2016. Descriptive and quantitative information was abstracted. An analysis was performed with standardized mean differences (SMDs) under a fixed or random effects model. Subgroup analyses were performed. Heterogeneity was assessed using the I2 metric. Results In total, 25 studies were eligible for inclusion in the meta-analysis for symptom scores and 15 studies for medication scores. SLIT was significantly different from the controls for symptom scores (SMD=1.23; 95% confidence interval [CI]=1.74 to 0.73; P<0.001). For medication scores, significant differences for SLIT were also observed versus the controls (SMD=-1.39; 95% CI=-1.90 to -0.88; P<0.001). Conclusions Our meta-analysis indicates that SLIT provided significant symptom relief and reduced the need for medications in PAR. In this study, significant evidence was obtained despite heterogeneity with regard to the use of mite extract. Specifically, the mite extract used was provided by the patients with PAR. Furthermore, to confirm both the objective outcomes and the effective doses of HDM allergen extracts, experimental data should be obtained from large high-quality population-based studies.
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Affiliation(s)
- Bohai Feng
- Department of Otolaryngology, the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Haijie Xiang
- Department of Otolaryngology, the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Haiyong Jin
- Department of Otolaryngology, the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jinjian Gao
- Department of Otolaryngology, the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Saiyu Huang
- Department of Otolaryngology, the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yunbin Shi
- Department of Otolaryngology, the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ruru Chen
- Department of Otolaryngology, the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Bobei Chen
- Department of Otolaryngology, the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
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Aissa S, Ben Jazia R, Ayachi J, Ben Salem C, Hayouni A, Abdelghani A, Ben Saad H, Boussarsar M. Critical appraisal of the clinical utility of sublingual immunotherapy in allergy. Contemp Clin Trials Commun 2016; 4:1-8. [PMID: 29736465 PMCID: PMC5935903 DOI: 10.1016/j.conctc.2016.06.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Revised: 05/25/2016] [Accepted: 06/15/2016] [Indexed: 11/30/2022] Open
Abstract
Since it was introduced by Noon in 1911, allergen-specific immunotherapy or desensitization has been widely prescribed in the management of allergic diseases. Aimed at the etiology, it represents the only effective treatment for allergy. The basic mechanisms of immunotherapy are becoming better understood and allow us to improve this technique in the future. The sublingual immunotherapy as an alternative to subcutaneous route has been widely studied. Several clinical trials confirmed that sublingual immunotherapy is efficient in reducing allergic respiratory symptoms. The sublingual immunotherapy reduces the risk of developing serious side effects due to desensitization. We performed a literature review in order to remind the mechanisms of action and to demonstrate efficacy and tolerability of the sublingual immunotherapy in the treatment of allergic rhinoconjunctivitis and asthma and its impact on the quality of life.
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Affiliation(s)
- S. Aissa
- Pulmonology Department, Farhat Hached University Hospital, Sousse, 4000, Tunisia
| | - R. Ben Jazia
- Pulmonology Department, Farhat Hached University Hospital, Sousse, 4000, Tunisia
| | - J. Ayachi
- Medical Intensive Care Unit, Farhat Hached University Hospital, Sousse, Tunisia
| | - C. Ben Salem
- Department of Clinical Pharmacology, Faculty of Medicine of Sousse, Tunisia
| | - A. Hayouni
- Pulmonology Department, Farhat Hached University Hospital, Sousse, 4000, Tunisia
| | - A. Abdelghani
- Pulmonology Department, Farhat Hached University Hospital, Sousse, 4000, Tunisia
| | - H. Ben Saad
- Laboratory of Physiology, Farhat Hached University Hospital, Sousse, Tunisia
| | - M. Boussarsar
- Medical Intensive Care Unit, Farhat Hached University Hospital, Sousse, Tunisia
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Roger A, Depreux N, Jurgens Y, Serra AT, Heath MD, Garcia G, Skinner MA. A novel microcrystalline tyrosine-adsorbed, mite-allergoid subcutaneous immunotherapy: 1-year follow-up report. Immunotherapy 2016; 8:1169-74. [DOI: 10.2217/imt-2016-0068] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: A 1-year follow-up study comparing the safety and tolerability of the dosing schedules, satisfaction and effectiveness of a novel microcrystalline tyrosine-adsorbed mite (Dermatophagoides pteronyssinus)-allergoid subcutaneous immunotherapy (Acarovac Plus™) in 30 adult patients (18–65 years) with allergic rhinitis and/or asthma. Materials & methods: The effectiveness of the product was assessed by nasal provocation test measuring peak nasal inspiratory flow/symptoms, in vitro immunologic changes (IgE, IgG4 and IL-10) and Treatment Satisfaction Questionnaire for Medication. Results: No adverse events were reported during dosing schedules. Significant decreases in symptom scores and drop of peak nasal inspiratory flow in follow-up visits (4 weeks and 1 year) were recorded. Significant increases in IgG4-specific antibody titers and IL-10 were exhibited. Conclusion: Significant decreases in clinical symptoms and immunological parameters were observed, accompanying a high level of patient satisfaction and tolerance.
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Affiliation(s)
- Albert Roger
- Unitat d'Al.lèrgia. Hospital Universitari Germans Trias Pujol, Badalona, Spain
| | - Nathalie Depreux
- Unitat d'Al.lèrgia. Hospital Universitari Germans Trias Pujol, Badalona, Spain
| | - Yanina Jurgens
- Unitat d'Al.lèrgia. Hospital Universitari Germans Trias Pujol, Badalona, Spain
| | - Aina T Serra
- Unitat d'Al.lèrgia. Hospital Universitari Germans Trias Pujol, Badalona, Spain
| | - Matthew D Heath
- Allergy Therapeutics Plc, Dominion Way, Worthing, BN14 8SA, UK
| | - Gloria Garcia
- Allergy Therapeutics Iberica S.L. Carrer de Joan XXIII, 15, 08950 Esplugues de Llobregat, Barcelona, Spain
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Gostner JM, Becker K, Kofler H, Strasser B, Fuchs D. Tryptophan Metabolism in Allergic Disorders. Int Arch Allergy Immunol 2016; 169:203-15. [PMID: 27161289 PMCID: PMC5433561 DOI: 10.1159/000445500] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Allergic diseases such as asthma and rhinitis, as well the early phase of atopic dermatitis, are characterized by a Th2-skewed immune environment. Th2-type cytokines are upregulated in allergic inflammation, whereas there is downregulation of the Th1-type immune response and related cytokines, such as interferon-x03B3; (IFN-x03B3;). The latter is a strong inducer of indoleamine 2,3-dioxygenase-1 (IDO-1), which degrades the essential amino acid tryptophan, as part of an antiproliferative strategy of immunocompetent cells to halt the growth of infected and malignant cells, and also of T cells - an immunoregulatory intervention to avoid overactivation of the immune system. Raised serum tryptophan concentrations have been reported in patients with pollen allergy compared to healthy blood donors. Moreover, higher baseline tryptophan concentrations have been associated with a poor response to specific immunotherapy. It has been shown that the increase in tryptophan concentrations in patients with pollen allergy only exists outside the pollen season, and not during the season. Interestingly, there is only a minor alteration of the kynurenine to tryptophan ratio (Kyn/Trp, an index of tryptophan breakdown). The reason for the higher tryptophan concentrations in patients with pollen allergy outside the season remains a matter of discussion. To this regard, the specific interaction of nitric oxide (NO∙) with the tryptophan-degrading enzyme IDO-1 could be important, because an enhanced formation of NO∙ has been reported in patients with asthma and allergic rhinitis. Importantly, NO∙ suppresses the activity of the heme enzyme IDO-1, which could explain the higher tryptophan levels. Thus, inhibitors of inducible NO∙ synthase should be reconsidered as candidates for antiallergic therapy out of season that may abrogate the arrest of IDO-1 by decreasing the production of NO∙. Considering its association with the pathophysiology of atopic disease, tryptophan metabolism may play a relevant role in the pathophysiology of allergic disorders.
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Affiliation(s)
- Johanna M. Gostner
- Division of Medical Biochemistry, Biocenter, Innsbruck Medical
University, Innsbruck
| | - Katrin Becker
- Division of Biological Chemistry, Biocenter, Innsbruck Medical
University, Innsbruck
| | | | - Barbara Strasser
- Division of Medical Biochemistry, Biocenter, Innsbruck Medical
University, Innsbruck
| | - Dietmar Fuchs
- Division of Biological Chemistry, Biocenter, Innsbruck Medical
University, Innsbruck
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Klimek L, Mosbech H, Zieglmayer P, Rehm D, Stage BS, Demoly P. SQ house dust mite (HDM) SLIT-tablet provides clinical improvement in HDM-induced allergic rhinitis. Expert Rev Clin Immunol 2016; 12:369-77. [DOI: 10.1586/1744666x.2016.1144473] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Sublingual grass and ragweed immunotherapy: Clinical considerations—a PRACTALL consensus report. J Allergy Clin Immunol 2016; 137:369-76. [DOI: 10.1016/j.jaci.2015.06.046] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 06/25/2015] [Accepted: 06/30/2015] [Indexed: 01/31/2023]
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Durham SR, Penagos M. Sublingual or subcutaneous immunotherapy for allergic rhinitis? J Allergy Clin Immunol 2016; 137:339-349.e10. [DOI: 10.1016/j.jaci.2015.12.1298] [Citation(s) in RCA: 132] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 12/17/2015] [Accepted: 12/17/2015] [Indexed: 02/01/2023]
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Abstract
BACKGROUND Asthma is a common long-term respiratory disease affecting approximately 300 million people worldwide. Approximately half of people with asthma have an important allergic component to their disease, which may provide an opportunity for targeted treatment. Sublingual immunotherapy (SLIT) aims to reduce asthma symptoms by delivering increasing doses of an allergen (e.g. house dust mite, pollen extract) under the tongue to induce immune tolerance. However, it is not clear whether the sublingual delivery route is safe and effective in asthma. OBJECTIVES To assess the efficacy and safety of sublingual immunotherapy compared with placebo or standard care for adults and children with asthma. SEARCH METHODS We identified trials from the Cochrane Airways Group Specialised Register (CAGR), ClinicalTrials.gov (www.ClinicalTrials.gov), the World Health Organization (WHO) trials portal (www.who.int/ictrp/en/) and reference lists of all primary studies and review articles. The search is up to date as of 25 March 2015. SELECTION CRITERIA We included parallel randomised controlled trials (RCTs), irrespective of blinding or duration, that evaluated sublingual immunotherapy versus placebo or as an add-on to standard asthma management. We included both adults and children with asthma of any severity and with any allergen-sensitisation pattern. We included studies that recruited participants with asthma, rhinitis, or both, providing at least 80% of trial participants had a diagnosis of asthma. DATA COLLECTION AND ANALYSIS Two review authors independently screened the search results for included trials, extracted numerical data and assessed risk of bias, all of which were cross-checked for accuracy. We resolved disagreements by discussion.We analysed dichotomous data as odds ratios (ORs) or risk differences (RDs) using study participants as the unit of analysis; we analysed continuous data as mean differences (MDs) or standardised mean differences (SMDs) using random-effects models. We rated all outcomes using GRADE (Grades of Recommendation, Assessment, Development and Evaluation) and presented results in the 'Summary of findings' table. MAIN RESULTS Fifty-two studies met our inclusion criteria, randomly assigning 5077 participants to comparisons of interest. Most studies were double-blind and placebo-controlled, but studies varied in duration from one day to three years. Most participants had mild or intermittent asthma, often with co-morbid allergic rhinitis. Eighteen studies recruited only adults, 25 recruited only children and several recruited both or did not specify (n = 9).With the exception of adverse events, reporting of outcomes of interest to this review was infrequent, and selective reporting may have had a serious effect on the completeness of the evidence. Allocation procedures generally were not well described, about a quarter of the studies were at high risk of bias for performance or detection bias or both and participant attrition was high or unknown in around half of the studies.One short study reported exacerbations requiring a hospital visit and observed no adverse events. Five studies reported quality of life, but the data were not suitable for meta-analysis. Serious adverse events were infrequent, and analysis using risk differences suggests that no more than 1 in 100 are likely to suffer a serious adverse event as a result of treatment with SLIT (RD 0.0012, 95% confidence interval (CI) -0.0077 to 0.0102; participants = 2560; studies = 22; moderate-quality evidence).Within secondary outcomes, wide but varied reporting of largely unvalidated asthma symptom and medication scores precluded meaningful meta-analysis; a general trend suggested SLIT benefit over placebo, but variation in scales meant that results were difficult to interpret.Changes in inhaled corticosteroid use in micrograms per day (MD 35.10 mcg/d, 95% CI -50.21 to 120.42; low-quality evidence), exacerbations requiring oral steroids (studies = 2; no events) and bronchial provocation (SMD 0.69, 95% CI -0.04 to 1.43; very low-quality evidence) were not often reported. This led to many imprecise estimates with wide confidence intervals that included the possibility of both benefit and harm from SLIT.More people taking SLIT had adverse events of any kind compared with control (OR 1.70, 95% CI 1.21 to 2.38; low-quality evidence; participants = 1755; studies = 19), but events were usually reported to be transient and mild.Lack of data prevented most of the planned subgroup and sensitivity analyses. AUTHORS' CONCLUSIONS Lack of data for important outcomes such as exacerbations and quality of life and use of different unvalidated symptom and medication scores have limited our ability to draw a clinically useful conclusion. Further research using validated scales and important outcomes for patients and decision makers is needed so that SLIT can be properly assessed as clinical treatment for asthma. Very few serious adverse events have been reported, but most studies have included patients with intermittent or mild asthma, so we cannot comment on the safety of SLIT for those with moderate or severe asthma. SLIT is associated with increased risk of all adverse events.
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Affiliation(s)
- Rebecca Normansell
- St George's, University of LondonPopulation Health Research InstituteLondonUKSW17 0RE
| | - Kayleigh M Kew
- St George's, University of LondonPopulation Health Research InstituteLondonUKSW17 0RE
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Keating GM. Allergen extract suspension for subcutaneous injection (Alustal®; Phostal®): a guide to its use for allergen-specific immunotherapy. DRUGS & THERAPY PERSPECTIVES 2015. [DOI: 10.1007/s40267-015-0213-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Bauer CS, Rank MA. Comparative efficacy and safety of subcutaneous versus sublingual immunotherapy. J Allergy Clin Immunol 2015; 134:765-765.e2. [PMID: 25171871 DOI: 10.1016/j.jaci.2014.07.024] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2014] [Revised: 07/08/2014] [Accepted: 07/16/2014] [Indexed: 10/24/2022]
Affiliation(s)
- Cindy S Bauer
- Division of Allergy and Immunology, Phoenix Children's Hospital, Phoenix, Ariz.
| | - Matthew A Rank
- Division of Allergy, Asthma, and Clinical Immunology, Mayo Clinic, Scottsdale, Ariz
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Pfaar O, Gerth van Wijk R. Mite-Allergic Rhinitis: How to Evaluate Clinical Efficacy in Allergen-Specific Immunotherapy Trials? CURRENT TREATMENT OPTIONS IN ALLERGY 2015; 2:1-9. [PMID: 25798370 PMCID: PMC4361724 DOI: 10.1007/s40521-014-0040-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
House dust mite (HDM) allergen exposure is the most important cause of perennial allergic rhinitis and/or asthma. Although allergen-specific immunotherapy (AIT) with HDM is well established, published studies have been characterized by substantial heterogeneity in clinical endpoints. Standardization in measuring clinical efficacy is required. Moreover, when designing an AIT trial with HDM allergens, several considerations have to be taken into account. The history of HDM allergy is less clear cut than the typical history of pollen allergy. In addition, clinical features of HDM allergy may differ from those of pollen allergy. Moreover, although not easily measurable, fluctuation in allergen exposure may cause variation in symptom severity and determine the timing of assessment of clinical effects of HDM AIT. Key points 1. A combined symptom and medication score (CSMS) is recommended as standard for the primary endpoint in future house dust mite (HDM) allergen-specific immunotherapy trials. 2. The diagnosis of HDM allergy is based on a carefully taken history in combination with sensitization to HDM allergens. 3. Eye symptoms are less prominent in patients with HDM-induced allergic rhinitis. Nasal symptoms, but not eye symptoms, should be included in the CSMS and in symptom scores as well. 4. As methods to determine allergen exposure vary and the efficacy of environmental control is a matter of debate, a practical approach consists of restraining patients from implementing HDM-reducing measures, such as removing carpets and introducing anti-mite covers, after the start of the study. 5. Efficacy evaluation in the period with the highest exposure to mites is recommended.
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Affiliation(s)
- Oliver Pfaar
- Center for Rhinology and Allergology Wiesbaden, Germany, An den Quellen 10, 65189 Wiesbaden, Germany ; Department of Otorhinolaryngology, Head and Neck Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Roy Gerth van Wijk
- Section of Allergology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
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Lee E, Kim MJ, Yang SI, Yu J, Hong SJ. Comparison of short-term effects between subcutaneous and sublingual immunotherapies in children with house dust mite-sensitized allergic rhinitis and asthma. ALLERGY ASTHMA & RESPIRATORY DISEASE 2015. [DOI: 10.4168/aard.2015.3.3.180] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Affiliation(s)
- Eun Lee
- Department of Pediatrics, Childhood Asthma Atopy Center, Asan Medical Center, Unversity of Ulsan College of Medicine, Seoul, Korea
- Research Center for Standardization of Allergic Diseases, Asan Medical Center, Unversity of Ulsan College of Medicine, Seoul, Korea
| | - Min-Ju Kim
- Department of Pediatrics, Childhood Asthma Atopy Center, Asan Medical Center, Unversity of Ulsan College of Medicine, Seoul, Korea
| | - Song-I Yang
- Department of Pediatrics, Childhood Asthma Atopy Center, Asan Medical Center, Unversity of Ulsan College of Medicine, Seoul, Korea
- Research Center for Standardization of Allergic Diseases, Asan Medical Center, Unversity of Ulsan College of Medicine, Seoul, Korea
| | - Jinho Yu
- Department of Pediatrics, Childhood Asthma Atopy Center, Asan Medical Center, Unversity of Ulsan College of Medicine, Seoul, Korea
| | - Soo-Jong Hong
- Department of Pediatrics, Childhood Asthma Atopy Center, Asan Medical Center, Unversity of Ulsan College of Medicine, Seoul, Korea
- Research Center for Standardization of Allergic Diseases, Asan Medical Center, Unversity of Ulsan College of Medicine, Seoul, Korea
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Yukselen A, Kendirli SG. Role of immunotherapy in the treatment of allergic asthma. World J Clin Cases 2014; 2:859-865. [PMID: 25516861 PMCID: PMC4266834 DOI: 10.12998/wjcc.v2.i12.859] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2014] [Revised: 08/27/2014] [Accepted: 10/16/2014] [Indexed: 02/05/2023] Open
Abstract
Allergen-specific immunotherapy (SIT) induces clinical and immunological tolerance as defined by persistence of clinical benefit and associated long-term immunological parameters after cessation of treatment. Although the efficacy of SIT has been shown in terms of reducing symptoms, medication consumption and ameliorating quality of life in both allergic rhinitis and asthma, there has long been some controversies about effectiveness of SIT in the treatment of allergic asthma. The type of allergen, the dose and protocol of immunotherapy, patient selection criteria, the severity and control of asthma, all are significant contributors to the power of efficacy in allergic asthma. The initiation of SIT in allergic asthma should be considered in case of coexisting of other allergic diseases such as allergic rhinitis, unacceptable adverse effects of medications, patient’s preference to avoid long-term pharmacotherapy. Steroid sparing effect of SIT in allergic asthma is also an important benefit particularly in patients who have to use these drugs in high doses for a long-time. Symptomatic asthma is a risk factor for systemic reactions and asthma should be controlled at the time of administration of SIT. Both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) have been found to be effective in patients with allergic asthma. Although the safety profile of SLIT seems to be better than SCIT, the results of some studies and meta-analyses suggest that the efficacy of SCIT may appear better and earlier than SLIT in children with allergic asthma.
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Yukselen A, Kendirli SG. Subcutaneous and sublingual immunotherapy: Where do we stand? World J Immunol 2014; 4:130-140. [DOI: 10.5411/wji.v4.i3.130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2014] [Revised: 05/01/2014] [Accepted: 07/14/2014] [Indexed: 02/05/2023] Open
Abstract
Though symptoms of allergic diseases can be reduced by the use of drugs such as corticosteroids, antihistamines or leukotrien antagonists, the only treatment directed to change the natural course of allergic disease is allergen-specific immunotherapy (SIT). Its efficacy can last years after the cessassion of the treatment. SIT brings on regulatory T cells with the capacity to generate interleukin-10 and transforming growth factor-b, restricts activation of mast cells and basophils, and shifts antibody isotype from IgE to the noninflammatory type immunoglobulin G4. Subcutaneous (SCIT) and sublingual (SLIT) immunotherapy are the two most used ways at the present for applying SIT. These two treatments were demonstrated to be effective on reducing symptoms and medication use, in prevention of new sensitizations and in protecting from progression of rhinitis to asthma. The safety of SLIT appears to be better than SCIT although there have been a few head to head comparisons. In order to overcome compliance problems or possible systemic side effects which may be faced during this long-term treatment, recent investigations have been focused on the implementation of allergens in quite efficacious and safer ways.
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Bahceciler NN, Babayigit Hocaoglu A, Galip N. A milestone in house dust-mite-allergen immunotherapy: the new sublingual tablet S-524101 (actair). Expert Rev Vaccines 2014; 13:1427-38. [PMID: 25345538 DOI: 10.1586/14760584.2014.972949] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Subcutaneous allergen-specific immunotherapy has long been used in the treatment of allergic rhinitis and/or asthma and its efficacy has been confirmed. However, due to the discomfort of injections and the risk of severe adverse reactions, alternative routes of allergen administration have emerged. Delivery of allergens through the mucosal route had been proposed and investigated thoroughly, confirming the sublingual route to be the most efficacious. Later, the efficacy and safety of this route have been documented by numerous controlled trials both for house dust mite (HDM) and pollens. Recently, sublingual orodispersable grass pollen allergen tablets were in use followed by the newly developed HDM allergen tablets with satisfactory clinical results: Moreover, very recently 1 year of HDM tablet treatment was demonstrated to exert its clinical efficacy 1 year after discontinuation of tablet IT. The persistence of efficacy after only 1 year of treatment is a new and promising era. Currently, Sublingual Immunotherapy is the most easily administered and safe treatment option until more immunogenic, less allergenic and more efficient allergen extracts are developed.
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Affiliation(s)
- Nerin N Bahceciler
- Department of Pediatrics, Division of Allergy and Clinical Immunology, Nicosia, North Cyprus, Turkey
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Lin SY. Sublingual immunotherapy: current concepts for the U.S. practitioner. Int Forum Allergy Rhinol 2014; 4 Suppl 2:S55-9. [DOI: 10.1002/alr.21388] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Revised: 07/02/2014] [Accepted: 07/02/2014] [Indexed: 11/06/2022]
Affiliation(s)
- Sandra Y. Lin
- Department of Otolaryngology-Head and Neck Surgery; The Johns Hopkins School of Medicine; Baltimore MD
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Baiula M, Spampinato S. Phase II drugs under investigation for allergic conjunctivitis. Expert Opin Investig Drugs 2014; 23:1671-86. [DOI: 10.1517/13543784.2014.944640] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Kennedy JL, Borish L, Christophel J, Payne SC. To the Editor. Am J Rhinol Allergy 2014; 28:353-4. [DOI: 10.2500/ajra.2014.28.0715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Affiliation(s)
- Joshua L. Kennedy
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Larry Borish
- Asthma and Allergic Disease Center, Carter Immunology Center, University of Virginia Health System, Charlottesville, VA Jared
| | - Jared Christophel
- Departments of Otolaryngology–Head and Neck Surgery and Public Health Sciences, University of Virginia Health System, Charlottesville, VA
| | - Spencer C. Payne
- Asthma and Allergic Disease Center, Carter Immunology Center, Department of Otolaryngology–Head and Neck Surgery, University of Virginia Health System, Charlottesville, VA
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Matsuoka D, Mizutani N, Sae-Wong C, Yoshino S. Allergen-specific regulation of allergic rhinitis in mice by intranasal exposure to IgG1 monoclonal antibody Fab fragments against pathogenic allergen. Immunol Lett 2014; 161:149-56. [PMID: 24954639 DOI: 10.1016/j.imlet.2014.06.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Revised: 05/23/2014] [Accepted: 06/12/2014] [Indexed: 12/27/2022]
Abstract
Fab fragments (Fabs) have the ability to bind to specific antigens but lack the Fc portion for binding to receptors on immune and inflammatory cells that play a critical role in allergic diseases. In the present study, we investigated whether Fabs of an allergen-specific IgG1 monoclonal antibody (mAb) inhibited allergic rhinitis in mice. BALB/c mice sensitized by intraperitoneal injections of ovalbumin (OVA) plus alum on days 0 and 14 were intranasally challenged with OVA on days 28-30, and 35. Fabs prepared by the digestion of an anti-OVA IgG1 mAb (O1-10) with papain were also intranasally administered 15min before each OVA challenge. The results showed that treatment with O1-10 Fabs significantly suppressed the sneezing frequency, associated with decrease of OVA-specific IgE in the serum and infiltration by mast cells in the nasal mucosa seen following the fourth antigenic challenge; additionally, the level of mouse mast cell protease-1, a marker of mast cell activation, in serum was decreased. Furthermore, infiltration of eosinophils and goblet cell hyperplasia in the nasal mucosa at the fourth challenge were inhibited by treatment with O1-10 Fabs. In conclusion, these results suggest that intranasal exposure to Fabs of a pathogenic antigen-specific IgG1 mAb may be effective in regulating allergic rhinitis through allergen capture by Fabs in the nasal mucosa before the interaction of the intact antibody and allergen.
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Affiliation(s)
- Daiko Matsuoka
- Department of Pharmacology, Kobe Pharmaceutical University, 4-19-1 Motoyamakita, Higashinada, Kobe 658-8558, Japan
| | - Nobuaki Mizutani
- Department of Pharmacology, Kobe Pharmaceutical University, 4-19-1 Motoyamakita, Higashinada, Kobe 658-8558, Japan.
| | - Chutha Sae-Wong
- Department of Pharmacology, Kobe Pharmaceutical University, 4-19-1 Motoyamakita, Higashinada, Kobe 658-8558, Japan
| | - Shin Yoshino
- Department of Pharmacology, Kobe Pharmaceutical University, 4-19-1 Motoyamakita, Higashinada, Kobe 658-8558, Japan
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Nelson HS. Subcutaneous immunotherapy versus sublingual immunotherapy: which is more effective? THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2014; 2:144-9; quiz 150-1. [PMID: 24607040 DOI: 10.1016/j.jaip.2013.11.018] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Revised: 11/21/2013] [Accepted: 11/23/2013] [Indexed: 01/22/2023]
Abstract
Subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are both effective treatments for allergic rhinitis and allergic asthma, both show clinical evidence of disease modification by decreasing new sensitizations in individuals who were monosensitized, by reducing the development of asthma in patients with allergic rhinitis, and by inducing clinical improvement that persists for years after discontinuation of a successful course of treatment. Initiation of SLIT is accompanied by a high incidence of local symptoms, but these are generally mild and do not usually persist beyond the first few weeks. Systemic reactions do occasionally occur with SLIT but much less frequently than with SCIT, and, to date, no fatal or near fatal reactions have been reported. Effective doses have been defined for many allergens for SCIT and are now being defined for SLIT. There remains the unanswered question of the effectiveness of SLIT with multiple allergen extracts. The relative clinical efficacy of SCIT and SLIT remains to be defined. When each is compared with placebo, results of meta-analyses suggest greater efficacy of SCIT. In the limited number of randomized, head-to-head studies, SCIT has more often provided greater clinical and immunologic responses. However, head-to-head studies with well-defined effective doses by the 2 routes are urgently needed.
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Affiliation(s)
- Harold S Nelson
- Department of Medicine, National Jewish Health and University of Colorado Denver School of Medicine, National Jewish Health, Denver, Colo.
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Yoshino S, Mizutani N, Matsuoka D, Sae-Wong C. Intratracheal exposure to Fab fragments of an allergen-specific monoclonal antibody regulates asthmatic responses in mice. Immunology 2014; 141:617-27. [PMID: 24303921 DOI: 10.1111/imm.12225] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2013] [Revised: 11/08/2013] [Accepted: 11/24/2013] [Indexed: 12/20/2022] Open
Abstract
Fab fragments (Fabs) maintain the ability to bind to specific antigens but lack effector functions due to the absence of the Fc portion. In the present study, we tested whether Fabs of an allergen-specific monoclonal antibody (mAb) were able to regulate asthmatic responses in mice. Asthmatic responses were induced in BALB/c mice by passive sensitization with anti-ovalbumin (OVA) polyclonal antibodies (pAbs) (day 0) and by active sensitization with OVA (days 0 and 14), followed by intratracheal (i.t.) challenge with OVA on day 1 and days 28, 29, 30 and 35. Fabs prepared by the digestion of an anti-OVA IgG1 (O1-10) mAb with papain were i.t. administered only once 30 min before antigenic challenge on day 1 or day 35. The results showed that i.t. administration of O1-10 Fabs with OVA markedly suppressed the early and/or late phases of asthmatic responses caused by passive and active sensitization. Similar results were obtained when Fabs of anti-OVA IgG2b mAb (O2B-3) were i.t. administered. In contrast, neither i.t. injection of intact 01-10/O2B-3 nor systemic injection of O1-10 Fabs suppressed the asthmatic responses. In vitro studies revealed that the capture of OVA by O1-10 Fabs prevented the subsequent binding of intact anti-OVA pAbs to the captured OVA. These results suggest that asthmatic responses may be down-regulated by the i.t. exposure to Fabs of an allergen-specific mAb via a mechanism involving the capture of allergen by Fabs in the respiratory tract before the interaction of intact antibody and allergen essential for the induction of asthmatic responses.
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Affiliation(s)
- Shin Yoshino
- Department of Pharmacology, Kobe Pharmaceutical University, Kobe, Japan
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Makatsori M, Scadding GW, Lombardo C, Bisoffi G, Ridolo E, Durham SR, Senna G. Dropouts in sublingual allergen immunotherapy trials - a systematic review. Allergy 2014; 69:571-80. [PMID: 24673502 DOI: 10.1111/all.12385] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/02/2014] [Indexed: 11/27/2022]
Abstract
Participant dropouts can reduce the power of allergen immunotherapy clinical trials. Evaluation of the dropout rate and reasons for dropout are important not only in the planning of clinical studies but are also relevant for adherence to immunotherapy in daily clinical practice. A systematic review was carried out in order to establish the overall dropout rate among published double-blind, placebo-controlled randomized clinical trials of sublingual immunotherapy for respiratory allergic diseases. Dropouts were analysed in regards to allergen, formulation, treatment schedule, participant age, study size, number of centres and type of allergic disease. Relative dropout rates in placebo and active groups as well as reasons for dropout were also assessed. A total of 81 studies, comprising 9998 patients, were included. Dropout rates in sublingual immunotherapy controlled studies do not appear to be a major problem with a composite dropout percentage of 14% (95% CI:11.9-16). Furthermore, they are not different for active compared to placebo-treated participants. This lends support to the positive clinical outcomes seen in meta-analyses of these trials.
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Affiliation(s)
- M. Makatsori
- Allergy Department; Royal Brompton & Harefield NHS Foundation Trust; London UK
- National Heart & Lung Institute; Allergy & Clinical Immunology; Imperial College London; London UK
| | - G. W. Scadding
- Allergy Department; Royal Brompton & Harefield NHS Foundation Trust; London UK
- National Heart & Lung Institute; Allergy & Clinical Immunology; Imperial College London; London UK
| | - C. Lombardo
- Verona University Hospital; Allergy Unit; Verona Italy
| | - G. Bisoffi
- Verona University Hospital; Research Support Unit and Biostatistics; Verona
| | - E. Ridolo
- Department of Clinical and Experimental Medicine; University of Parma; Parma Italy
| | - S. R. Durham
- Allergy Department; Royal Brompton & Harefield NHS Foundation Trust; London UK
- National Heart & Lung Institute; Allergy & Clinical Immunology; Imperial College London; London UK
| | - G. Senna
- Verona University Hospital; Allergy Unit; Verona Italy
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An evidence-based analysis of house dust mite allergen immunotherapy: a call for more rigorous clinical studies. J Allergy Clin Immunol 2013; 132:1322-36. [PMID: 24139829 DOI: 10.1016/j.jaci.2013.09.004] [Citation(s) in RCA: 104] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2013] [Revised: 09/05/2013] [Accepted: 09/09/2013] [Indexed: 11/23/2022]
Abstract
BACKGROUND According to meta-analyses and reviews, subcutaneous allergen immunotherapy (SCIT) and sublingual allergen immunotherapy (SLIT) are beneficial in patients with allergic rhinitis (AR) and allergic asthma (AA) induced by house dust mites (HDMs). However, the reported effect sizes have varied greatly from one study to another. OBJECTIVE We sought to perform an evidence-based medicine assessment of commercially available SCIT and SLIT formulations in patients with HDM-induced AA and HDM-induced AR. METHODS We searched for double-blind, placebo-controlled randomized clinical trials and analyzed study designs, doses, regimens, patient-reported outcomes, safety reporting, and compliance. RESULTS Forty-four studies met our inclusion criteria. Some studies tested both SLIT and SCIT or scored both AA and AR outcomes; therefore we reviewed 35 treatment arms in patients with AA (20 for SCIT and 15 for SLIT) and 23 treatment arms in patients with AR (7 for SCIT and 16 for SLIT). The treatment duration ranged from 6 weeks to 3 years. For SCIT, the dose of Der p 1 major allergen (when reported) ranged from 7 to 30 μg for maintenance doses and 60 to 420 μg for cumulative doses. For SLIT, the doses of Der p 1 (when reported) were 0.8 to 70 μg for maintenance doses and 60 to 23,695 μg for cumulative doses. Safety data were often absent or poorly reported. A statistically significant active versus placebo symptom score was observed more frequently for SCIT than for SLIT. CONCLUSION There is no consensus on basic treatment parameters (eg, dose and duration) in HDM SCIT and SLIT. There is an urgent need for rigorous, long-term, double-blind, placebo-controlled randomized clinical trials with an efficacy criterion that reflects the particular features of HDM-induced allergic disease.
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Eifan AO, Calderon MA, Durham SR. Allergen immunotherapy for house dust mite: clinical efficacy and immunological mechanisms in allergic rhinitis and asthma. Expert Opin Biol Ther 2013; 13:1543-56. [PMID: 24099116 DOI: 10.1517/14712598.2013.844226] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
INTRODUCTION There is an increasing prevalence of atopic diseases such as allergic rhinitis and asthma with house dust mite (HDM) being the common allergen that is highly associated with allergic rhinitis and asthma. Allergen avoidance and pharmacotherapy are part of treatment but it has proved difficult to change the course of HDM-related allergic diseases. Allergen immunotherapy (AIT) has been in use for the past century and has been shown to be effective in the treatment of allergic respiratory disease. AREAS COVERED This review exclusively focuses on HDM-AIT and discusses the differences in clinical efficacy and safety, long-term effect after discontinuation and immunological changes observed in both HDM-subcutaneous immunotherapy (SCIT) and HDM-sublingual immunotherapy (SLIT) in the treatment of allergic rhinitis and asthma in both pediatric and adult populations. EXPERT OPINION The majority of studies involved small numbers of patients, variable doses of major allergens and are of variable quality. There is good evidence for HDM-SCIT efficacy and its long-term effect in adults and children, whereas at the present time, evidence for HDM-SLIT is unconvincing, particularly in children. In carefully selected patients, HDM-SCIT is effective and safe. More definitive trials are needed before HDM-SLIT can be recommended in routine practice for rhinitis and/or asthma.
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Affiliation(s)
- Aarif O Eifan
- Imperial College London, Allergy and Clinical Immunology , NHLI, London, SW7 2AZ , UK
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Chelladurai Y, Suarez-Cuervo C, Erekosima N, Kim JM, Ramanathan M, Segal JB, Lin SY. Effectiveness of subcutaneous versus sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: a systematic review. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2013; 1:361-9. [PMID: 24565541 DOI: 10.1016/j.jaip.2013.04.005] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2012] [Revised: 04/09/2013] [Accepted: 04/12/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND Allergen-specific immunotherapy is widely used in the management of patients with allergic rhinoconjunctivitis and asthma, but the best route of delivery is unclear. OBJECTIVE We performed a systematic review of studies with head-to-head comparison of effectiveness and safety of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) in the treatment of allergic rhinoconjunctivitis and asthma. METHODS MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials databases were searched through December 21, 2012. We included English language randomized controlled trials that enrolled patients with allergic rhinoconjunctivitis and/or asthma with head-to-head comparisons of SCIT with SLIT. Paired reviewers extracted detailed information from included articles on standardized forms and assessed the risk of bias in each article. RESULTS Eight trials compared the effectiveness and safety of SCIT and SLIT. The effectiveness of the 2 forms of immunotherapy in managing allergic asthma and rhinoconjunctivitis were reported in 4 and 6 clinical trials, respectively. Low-grade evidence supports greater effectiveness of SCIT than SLIT for asthma symptom reduction and also at reducing a combined measure of rhinitis symptoms and medication use. Moderate-grade evidence supports greater effectiveness of SCIT than SLIT for nasal and/or eye symptom reduction. All 8 trials reported on adverse events with an episode of anaphylaxis reported in a child treated with SCIT. CONCLUSION Our review provides low-grade evidence to support that SCIT is superior to SLIT for reduction in asthma symptoms and moderate-grade evidence for reduction of allergic rhinoconjunctivitis. Additional studies are required to strengthen this evidence base for clinical decision making.
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Affiliation(s)
| | | | - Nkiruka Erekosima
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Julia M Kim
- Department of Pediatrics, Division of General Pediatrics and Adolescent Medicine, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Murugappan Ramanathan
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Jodi B Segal
- Department of Pediatrics, Division of General Pediatrics and Adolescent Medicine, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Sandra Y Lin
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Md.
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Abstract
PURPOSE OF REVIEW Although allergen-specific sublingual (SLIT) and subcutaneous immunotherapy (SCIT) have been demonstrated to be clinically effective with similar immunological responses, head-to-head studies comparing those two modes of allergen administration in terms of onset of clinical improvement along with simultaneous immunological responses and underlying mechanisms of preventive effect are scarce. The present review will update current data on this issue. RECENT FINDINGS Compared with SLIT, SCIT provides a rapid onset of clinical improvement by eliciting a simultaneous surge in production of T helper 1 (Th1) and T regulatory cell (Treg) cytokines and blocking antibodies. Similar immunological and clinical responses are evoked quite later, with no effect on Immunoglobulin G (IgG)4 levels during SLIT. Increases in TGFβ secretion due to nonrelevant allergens during SLIT may explain the preventive effect on new sensitizations. SUMMARY SLIT and SCIT are both clinically effective in the treatment of respiratory allergic diseases with slight differences in the early phase in terms of onset of clinical efficacy and simultaneous immunological responses. Both SLIT and SCIT induce similar T-cell responses in time, but specific IgG4-blocking antibody responses are more prevalent following SCIT. Further head-to-head studies addressing the preventive effect of monotherapy and the efficacy and immunological responses of nonrelated multiallergen immunotherapy in polysensitized patients are warranted.
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Lin SY. Current Concepts and Update for Sublingual Immunotherapy. CURRENT OTORHINOLARYNGOLOGY REPORTS 2013. [DOI: 10.1007/s40136-013-0010-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Mailhol C, Didier A. [Allergen-specific immunotherapy in the treatment of pollen allergy]. Rev Mal Respir 2012; 30:142-51. [PMID: 23419445 DOI: 10.1016/j.rmr.2012.07.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2011] [Accepted: 07/25/2012] [Indexed: 10/27/2022]
Abstract
Since its description by Noon in 1911, desensitization or allergen-specific immunotherapy (SIT) has been largely given by sub cutaneous injection in the treatment of allergic diseases. It remains the only treatment for allergic diseases aimed at the etiology. The development of sublingual route as an alternative to sub cutaneous injection, and of new forms of medication, has led to large-scale clinical trials, many of them performed with allergen tablets, particularly in the field of pollen allergy. These studies have confirmed that SIT is efficient in reducing allergic respiratory symptoms. Data on long term benefits and sustained efficacy after stopping treatment have also been published. These show an impact on the natural history of allergic disease and, in particular, a reduction in the risk of asthma in desensitized rhinitic subjects and in the acquisition of new sensitivities. The basic mechanisms of immunotherapy are becoming better understood and allow us to envisage improvements in this technique in the future. The sublingual route improves the risk/benefit ratio of desensitization and reduces the risk of serious side effects. These data suggest that the indications for SIT may be extended in a large number of patients with allergic respiratory diseases.
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Affiliation(s)
- C Mailhol
- Service de pneumologie-allergologie, hôpital Larrey, 24, chemin de Pouvourville TSA 30030, 31059 Toulouse cedex 9, France
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Mailhol C, Didier A. Specific immunotherapy in grass pollen allergy. Hum Vaccin Immunother 2012; 8:1544-7. [PMID: 23095875 PMCID: PMC3660776 DOI: 10.4161/hv.22357] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2012] [Accepted: 09/25/2012] [Indexed: 01/01/2023] Open
Abstract
Since its description by noon in 1911, desensitization, or allergen specific immunotherapy (SIT), has been largely used in respiratory allergic diseases treatment. It remains the only etiologic treatment for allergic diseases. The development of the sublingual route and new forms of medication, as an alternative to subcutaneous injection, has led to large scale clinical trials. Many of them had been performed with allergen tablets, particularly in the field of pollen allergy. These studies have confirmed that SIT is efficient in reducing all respiratory allergic symptoms. Data on long-term benefits and sustained efficacy after stopping treatment have also been published. These show an impact on natural history of allergic disease, in particular, a reduction in the risk of asthma in desensitized rhinitic subjects and in the acquisition of new sensitivities. The basic mechanisms of immunotherapy are becoming better understood and allow us to envisage improvements in this therapeutic method in the future. The sublingual route appears to be safer with a better safety profile. This may lead to an extension of allergen specific immunotherapy indications in patients with respiratory allergic diseases.
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Affiliation(s)
- Claire Mailhol
- Pulmonology and Allergology Department; Toulouse University Hospital; Toulouse, France
| | - Alain Didier
- Pulmonology and Allergology Department; Toulouse University Hospital; Toulouse, France
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Viswanathan RK, Busse WW. Allergen immunotherapy in allergic respiratory diseases: from mechanisms to meta-analyses. Chest 2012; 141:1303-1314. [PMID: 22553263 DOI: 10.1378/chest.11-2800] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Allergen-specific immunotherapy (SIT) involves the repeated administration of allergenic extracts to atopic individuals over a period of 3 to 5 years either subcutaneously (SCIT) or sublingually (SLIT) for the treatment of allergic respiratory diseases, including asthma and allergic rhinitis (AR). In studies, SCIT and SLIT have been shown to improve existing symptoms of asthma and AR and to also have the capability to cause disease-modifying changes of the underlying atopic condition so as to prevent new allergic sensitization as well as arrest progression of AR to asthma. Recent evidence suggests that immunotherapy brings about these effects through actions that use T-regulatory cells and blocking antibodies such as IgG(4) and IgA(2,) which can then result in an "immune deviation" from a T-helper (Th) 2 cell pattern to a Th1 cell pattern. Numerous meta-analyses and studies have been performed to evaluate the existing data among these studies, with the consensus recommendation favoring the use of immunotherapy because of its potential to modify existing diseases. Significant adverse reactions can occur with immunotherapy, including anaphylaxis and, very rarely, death. A primary factor in considering SIT is its potential to provide long-lasting effects that are able to be sustained well after its discontinuation. Given the significant burden these allergic diseases impose on the health-care system, SIT appears to be a cost-effective adjunctive treatment in modifying the existing disease state.
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Affiliation(s)
- Ravi K Viswanathan
- Division of Allergy, Pulmonary, and Critical Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - William W Busse
- Division of Allergy, Pulmonary, and Critical Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI.
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Calderón MA, Simons FER, Malling HJ, Lockey RF, Moingeon P, Demoly P. Sublingual allergen immunotherapy: mode of action and its relationship with the safety profile. Allergy 2012; 67:302-11. [PMID: 22150126 DOI: 10.1111/j.1398-9995.2011.02761.x] [Citation(s) in RCA: 197] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Allergen immunotherapy reorients inappropriate immune responses in allergic patients. Sublingual allergen immunotherapy (SLIT) has been approved, notably in the European Union, as an effective alternative to subcutaneous allergen immunotherapy (SCIT) for allergic rhinitis patients. Compared with SCIT, SLIT has a better safety profile. This is possibly because oral antigen-presenting cells (mostly Langerhans and myeloid dendritic cells) exhibit a tolerogenic phenotype, despite constant exposure to danger signals from food and microbes. This reduces the induction of pro-inflammatory immune responses leading to systemic allergic reactions. Oral tissues contain relatively few mast cells and eosinophils (mostly located in submucosal areas) and, in comparison with subcutaneous tissue, are less likely to give rise to anaphylactic reactions. SLIT-associated immune responses include the induction of circulating, allergen-specific Th1 and regulatory CD4+ T cells, leading to clinical tolerance. Although 40-75% of patients receiving SLIT experience mild, transient local reactions in the oral mucosa, these primary reactions rarely necessitate dose reduction or treatment interruption. We discuss 11 published case reports of anaphylaxis (all nonfatal) diagnosed according to the World Allergy Organization criteria and relate this figure to the approximately 1 billion SLIT doses administered worldwide since 2000. Anaphylaxis risk factors associated with SCIT and/or SLIT should be characterized further.
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Affiliation(s)
- M A Calderón
- Section of Allergy and Clinical Immunology, Imperial College-NHLI, Royal Brompton Hospital, London, UK.
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