Publications by authors named "Harold Nelson"

144 Publications

2020 Updated Asthma Guidelines: Allergen immunotherapy.

Authors:
Harold S Nelson

J Allergy Clin Immunol 2020 Dec;146(6):1286-1287

National Jewish Health, Denver, Colo. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.10.011DOI Listing
December 2020

The evolution of allergy immunotherapy.

Authors:
Harold S Nelson

Ann Allergy Asthma Immunol 2020 Nov 30. Epub 2020 Nov 30.

Division of Allergy and Clinical Immunology, Department of Medicine, National Jewish Health, Denver, Colorado. Electronic address:

Objective: The objective of this review is to trace the evolution of the art and science of allergy immunotherapy (AIT).

Data Sources: Original reports relating to the evolution of the concept of respiratory allergy and its specific treatment were identified by following references in journal articles, review articles, and allergy textbooks from the mid-20th century to the present.

Study Selections: Studies highlighting substantial milestones in the evolution of the practice of allergy immunotherapy were included.

Results: The story of AIT begins with the recognition of hay fever as a distinct entity and subsequent studies that established grass pollen as one of the causes. This knowledge led several investigators, most notable Leonard Noon and John Freeman who worked at St. Mary's Hospital in London, to attempt to induce tolerance giving grass pollen extract by injection to their patients. After the publication of the work of Noon and Freeman in 1911, the practice of AIT spread rapidly and was applied to many other pollen allergens besides grass and for perennial rhinitis and asthma. The early studies were largely anecdotal, but over the past 60 to 70 years, studies of AIT have been conducted with increasingly sophisticated scientific methods. Nowadays, not only is the practice of AIT based on carefully conducted studies, but the underlying immunologic basis of allergy and the response to AIT have also been and still are being firmly established.

Conclusion: Both the art and the science behind the practice of AIT have been established by a solid base of clinical and immunologic studies.
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http://dx.doi.org/10.1016/j.anai.2020.11.011DOI Listing
November 2020

Allergy immunotherapy: Future directions for the 2020s.

Authors:
Harold S Nelson

Allergy Asthma Proc 2020 09;41(5):314-325

Allergy immunotherapy (AIT), whether administered as subcutaneous immunotherapy or as sublingual immunotherapy (SLIT), is an effective treatment for sensitization to inhalant allergens. There remain, however, some important unresolved issues, such as the need for compelling evidence for or against the efficacy of treatment with multiple unrelated allergen extracts and optimal dosing with SLIT-liquid preparations. Both methods of AIT involve prolonged periods of treatment to achieve persisting benefit. This can be inconvenient and expensive, and failure to complete the period of prescribed treatment is common with both methods. New approaches are being developed and studied to make AIT more effective, safer, or more convenient. Among these approaches are using alternative routes of administration; using adjuvants, including vitamin D, Toll-like receptor ligand agonists, biologics, or probiotics; introducing additional SLIT tablets; defining the patterns of major and minor allergen sensitivity of patients and the content of allergen extracts to better match sensitization with treatment; and treating cats to reduce their allergen release. The allergen molecules themselves are being altered to make them less reactive with specific immunoglobulin E, both by creating allergoids and by using recombinant technology to produce modified allergen molecules. Which, if any, of these new approaches will become part of AIT practice in the next decade depends in part on their efficacy and in part on the availability of the resources to adequately study them.
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http://dx.doi.org/10.2500/aap.2020.41.200041DOI Listing
September 2020

Clinical Practice of Allergen Immunotherapy for Allergic Rhinoconjunctivitis and Asthma: An Expert Panel Report.

J Allergy Clin Immunol Pract 2020 Oct 16;8(9):2920-2936.e1. Epub 2020 May 16.

ALK, Bedminster, NJ.

Allergen immunotherapy (AIT) reduces symptoms and medication use associated with allergic rhinitis with or without conjunctivitis and allergic asthma. Although several AIT guidelines exist, there remain unanswered questions about AIT that are relevant to everyday practice. Our objective was to prepare an evidence-based overview addressing the practical aspects of AIT in clinical practice based on published evidence and the experience of international experts in the field. Topics covered include interpretation and translation of clinical trial data into everyday clinical practice (eg, allergen doses and treatment duration), assessment of risk and treatment of local and systemic allergic reactions, recommendations for improvement of AIT guidelines, and identification of appropriate data for seeking regulatory approval, to name a few. Many informational gaps in AIT practice need further evaluation as products and practices evolve.
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http://dx.doi.org/10.1016/j.jaip.2020.04.071DOI Listing
October 2020

Efficacy and Safety of Ragweed SLIT-Tablet in Children with Allergic Rhinoconjunctivitis in a Randomized, Placebo-Controlled Trial.

J Allergy Clin Immunol Pract 2020 Jul - Aug;8(7):2322-2331.e5. Epub 2020 Apr 15.

Merck & Co., Inc., Kenilworth, NJ.

Background: Ragweed sublingual immunotherapy (SLIT) tablet reduces symptoms and symptom-relieving medication use in adults with allergic rhinitis with or without conjunctivitis (AR/C) but has not been evaluated in children.

Objective: This international, multicenter, double-blind, placebo-controlled trial evaluated the efficacy and safety of ragweed SLIT-tablet in children with AR/C.

Methods: Children (N = 1025; 77.7% polysensitized) aged 5 to 17 years with ragweed pollen-induced AR/C with or without asthma (FEV ≥80% predicted) were randomized 1:1 to daily ragweed SLIT-tablet (12 Amb a 1-Unit) or placebo for up to 28 weeks (NCT02478398). The primary end point was the average total combined score (TCS; sum of rhinoconjunctivitis daily symptom score [DSS] and daily medication score [DMS]) during peak ragweed pollen season (RPS). Key secondary end points were TCS during the entire RPS, and DSS and DMS during the peak RPS.

Results: Relative TCS (95% CI) improvements with ragweed SLIT-tablet versus placebo were -38.3% (-46.0% to -29.7%; least square [LS] mean difference, -2.73; P < .001) during peak RPS and -32.4% (-40.7% to -23.3%; LS mean difference, -1.86; P < .001) during the entire RPS. DSS and DMS during peak RPS improved with SLIT-tablet versus placebo by -35.4% (-43.2% to -26.1%; LS mean difference, -1.40; P < .001) and -47.7% (-59.8% to -32.5%; LS mean difference, -1.84; P < .001), respectively. Asthma DSS, short-acting β-agonist use, and nocturnal awakenings during peak RPS improved with SLIT-tablet versus placebo by -30.7%, -68.1%, and -75.1%, respectively (all nominal P ≤ .02). No events of anaphylaxis, airway compromise, or severe treatment-related systemic allergic reactions were reported.

Conclusions: Ragweed SLIT-tablet significantly improved symptoms and decreased symptom-relieving medication use in children with ragweed pollen-induced AR/C and was well tolerated.
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http://dx.doi.org/10.1016/j.jaip.2020.03.041DOI Listing
April 2020

Allergy immunotherapy for inhalant allergens: Strategies to minimize adverse reactions.

Authors:
Harold S Nelson

Allergy Asthma Proc 2020 01;41(1):38-44

Allergy immunotherapy (AIT), both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), is an effective and safe treatment for allergic rhinitis and allergic asthma due to inhalant allergens. However, there are many variables in how it is administered. To review the evidence that suggests the optimal practice(s) to minimize adverse reactions to AIT. Articles that reported the results of various approaches to the practice of AIT and evidence-based guidelines were consulted for guidance about approaches that would minimize adverse reactions to AIT. Evidence is presented that supports care in the preparation of allergy extracts for treatment; use of modified extracts; location for administration of SCIT and SLIT; risk factors for systemic reactions; AIT in patients on adrenergic blocking agents and angiotensin-converting enzyme inhibitors; use of premedication; the need for prescription of epinephrine autoinjectors; adjustments in dose for pollen seasons, interruptions in treatment, and for local and systemic reactions; and the safety in patients with autoimmune diseases and during pregnancy. Although some of these variables have not been adequately studied, there are many studies that indicate practices that minimize the risk of adverse reactions for both SCIT and SLIT.
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http://dx.doi.org/10.2500/aap.2020.41.190014DOI Listing
January 2020

Allergy immunotherapy for inhalant allergens: Strategies to improve efficacy.

Authors:
Harold S Nelson

Allergy Asthma Proc 2020 01;41(1):26-37

Allergy immunotherapy (AIT), both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), is an effective and safe treatment for allergic rhinitis and allergic asthma due to inhalant allergens. However, there are many variables in how it is administered. To review the evidence that suggests the optimum practices to enhance the efficacy of AIT. Articles that reported the results of various approaches to the practice of AIT and evidence-based guidelines were consulted for guidance on what approaches would enhance the efficacy of AIT. Evidence is presented that supports optimum dosing for SCIT, a discussion of dosing with liquid SLIT, the management of the patient who is polyallergic, considerations in mixing allergen extracts, advantages and disadvantages of different up-dosing regimens with SCIT, the optimum duration of AIT, the comparative efficacy of SCIT and SLIT, and improving adherence to AIT. Also reviewed were two approaches, the use of adjuvants and of alternative routes of administration of currently available extracts, which may be useful in the future after further studies have defined their effectiveness. Although there is still controversy about some aspects of AIT, there is literature to support approaches that enhance the efficacy of both SCIT and SLIT.
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http://dx.doi.org/10.2500/aap.2020.41.190013DOI Listing
January 2020

Mind the gaps: Clinical trial concepts to address unanswered questions in aeroallergen immunotherapy-An NIAID/AHRQ Workshop.

J Allergy Clin Immunol 2019 05 5;143(5):1711-1726. Epub 2019 Feb 5.

Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Md.

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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http://dx.doi.org/10.1016/j.jaci.2019.01.032DOI Listing
May 2019

Ragweed allergy immunotherapy tablet MK-3641 (Ragwitek®) for the treatment of allergic rhinitis.

Authors:
Harold S Nelson

Expert Rev Clin Immunol 2018 12 8;14(12):1003-1011. Epub 2018 Nov 8.

a Department of Medicine, Division of Allergy/Immunology , National Jewish Health , Denver , Colorado USA.

Introduction: Allergic rhinitis (AR) is among the most common chronic conditions affecting both children and adults. It is the cause of significant morbidity from the symptoms and interference with sleep. It results in major impairment of performance both at school and at work. In the U.S. and certain parts of Europe, ragweed pollen is a major cause of seasonal AR. In 2014, the U.S. Food and Drug Administration (FDA) approved a sublingual ragweed tablet (MK-3641) for use in adults with ragweed-induced AR. Areas covered: This paper will review the impact of ragweed-induced AR and available treatments including subcutaneous immunotherapy and studies with MK-3641. The principal search method was PubMed. Expert commentary: One dosing finding, two 28-day safety and two 52-week safety and efficacy studies have been conducted with MK-3641. The 12-U (12μg Amb a 1) tablet was the most effective. Local application site reactions were common but usually not serious. Only one, non-serious systemic reaction was reported in four safety studies. MK-3641 is a safe and effective treatment for ragweed-pollen-induced AR when treatment is initiated ≥ 12 weeks prior to the onset of the ragweed pollen season.
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http://dx.doi.org/10.1080/1744666X.2018.1538788DOI Listing
December 2018

Recent advances in allergic rhinitis.

F1000Res 2018 23;7. Epub 2018 Aug 23.

Department of Medicine, Division of Allergy/Immunology, National Jewish Health, Denver, CO, 80206, USA.

Allergic rhinitis affects 20 to 30% of adults in both the United States and Europe and perhaps a somewhat higher percentage of children. In addition to nasal and ocular symptoms directly related to the allergic process, interference of these symptoms with sleep leads to daytime sleepiness and impaired quality of life. Patients miss work because of symptoms but an even greater problem is interference with work productivity, or presenteeism, which has been reported to be the biggest contributor to the total economic cost of allergic rhinitis. There has been increasing awareness that many patients with either seasonal or perennial symptoms but negative skin and tests for allergen sensitivity have local nasal allergy, diagnosable by the presence of allergen-specific IgE in their nasal secretions or a positive nasal allergen challenge or both. The pharmaceutical management of allergic rhinitis rests on symptomatic treatment with antihistamines that perhaps are more effectively administered intranasally than orally and intranasal corticosteroids. Allergen immunotherapy is very effective, even for local allergic rhinitis, and the shortcomings of subcutaneous immunotherapy of inconvenience and safety are reduced by the introduction of sublingual immunotherapy (SLIT). Use of the latter is currently somewhat limited by the lack of appropriate dosing information for SLIT liquids and the limited number of allergens for which SLIT tablets are available.
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http://dx.doi.org/10.12688/f1000research.15367.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107993PMC
July 2019

Immunotherapy for house-dust mite allergy.

Authors:
Harold S Nelson

Allergy Asthma Proc 2018 Jul;39(4):264-272

Background: Since the discovery of house-dust mites (HDM) in the 1960's, allergy immunotherapy trials that used extracts of these mites have been conducted, first by subcutaneous (SCIT) and later by the sublingual (SLIT) route. When reviewed in 2013, published studies of HDM immunotherapy were found to often be characterized by small sample size, widely varying doses, and poorly defined disease severity and outcomes. These trials were thought to to support the efficacy of HDM subcutaneous allergy immunotherapy but the evidence for efficacy of sublingual immunotherapy was less firm.

Methods: This report will review a large number of well-designed studies reported since 2013, mostly of SLIT, and in particular, of two newly developed HDM sublingual tablets. In addition, other aspects of HDM immunotherapy will be addressed, including use in atopic dermatitis, optimum duration of treatment, evidence for disease modification and use with adjuvants.

Results: Seventeen reports on 15 randomized, double-blind, placebo-controlled trials were identified as having been published since the cut-off date of the 2013 systematic review. Twelve of these reported results with the 2 HDM SLIT-tablets. These studies clearly established the appropriate doses and the efficacy and safety of these tablets in treating allergic rhinitis and asthma. Other reports offered support for use of HDM immunotherapy in selected patients with atopic dermatitis, for administration of HDM immunotherapy for 3 to 5 years, for anticipating disease modification after 3-5 years of treatment, and for the use of vitamin D and selected probiotics to enhance its efficacy.

Conclusion: HDM SCIT and SLIT-tablet therapy have demonstrated effectiveness in allergic rhinitis and asthma. Appropriate dosing with HDM SLIT-liquid has not been established although a limited number of studies suggest it can be effective as well. HDM SCIT and HDM SLIT share efficacy in allergic rhinitis and asthma, disease modification and the duration of treatment required to produce persisting benefit.
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http://dx.doi.org/10.2500/aap.2018.39.4145DOI Listing
July 2018

SQ house dust mite sublingual immunotherapy tablet subgroup efficacy and local application site reaction duration.

Ann Allergy Asthma Immunol 2018 07 12;121(1):105-110. Epub 2018 Apr 12.

ALK-Abelló A/S, Hørsholm, Denmark. Electronic address:

Background: Allergic rhinitis with or without conjunctivitis (AR/C) is common, necessitating evaluation of SQ house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet efficacy in various subgroups.

Objective: To evaluate 12 SQ-HDM efficacy and safety across subgroups, and the onset, duration, and recurrence of local application site reactions.

Methods: Subgroup (age, sex, race, asthma status, and allergen sensitization) efficacy was assessed using pooled data from 2 previously described trials of daily 12 SQ-HDM vs placebo for AR/C (n = 2,138). Efficacy was measured by average total combined rhinitis score (TCRS; rhinitis daily symptom plus medication score) during the last 8 weeks of treatment. Safety in subgroups and local application site reaction onset, duration, and recurrence were evaluated using pooled data from 5 previously described trials of SQ HDM SLIT-tablet (n = 2,923).

Results: Significant (based on 95% confidence intervals [CIs]) reduction in TCRS was seen with 12 SQ-HDM relative to placebo across all subgroups, with TCRS improvements ranging from 15% to 25%. The AE profile was generally similar within subgroups. Approximately 95% of local application site reactions were mild to moderate in severity. Median duration on day 1 of treatment for the most common local application site reactions (throat irritation, oral pruritus, ear pruritus, and lip swelling) ranged from 30 to 60 minutes; median first day of onset ranged from days 1 to 4 of treatment; median days that reactions recurred ranged from 3 to 12 days.

Conclusion: Treatment with 12 SQ-HDM consistently improved symptoms and was well tolerated in relevant subgroups of subjects with HDM AR/C. Local application site reactions to 12 SQ-HDM were typically mild to moderate and transient.
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http://dx.doi.org/10.1016/j.anai.2018.04.007DOI Listing
July 2018

International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis.

Int Forum Allergy Rhinol 2018 02;8(2):108-352

Otolaryngology, University of Michigan, USA.

Background: Critical examination of the quality and validity of available allergic rhinitis (AR) literature is necessary to improve understanding and to appropriately translate this knowledge to clinical care of the AR patient. To evaluate the existing AR literature, international multidisciplinary experts with an interest in AR have produced the International Consensus statement on Allergy and Rhinology: Allergic Rhinitis (ICAR:AR).

Methods: Using previously described methodology, specific topics were developed relating to AR. Each topic was assigned a literature review, evidence-based review (EBR), or evidence-based review with recommendations (EBRR) format as dictated by available evidence and purpose within the ICAR:AR document. Following iterative reviews of each topic, the ICAR:AR document was synthesized and reviewed by all authors for consensus.

Results: The ICAR:AR document addresses over 100 individual topics related to AR, including diagnosis, pathophysiology, epidemiology, disease burden, risk factors for the development of AR, allergy testing modalities, treatment, and other conditions/comorbidities associated with AR.

Conclusion: This critical review of the AR literature has identified several strengths; providers can be confident that treatment decisions are supported by rigorous studies. However, there are also substantial gaps in the AR literature. These knowledge gaps should be viewed as opportunities for improvement, as often the things that we teach and the medicine that we practice are not based on the best quality evidence. This document aims to highlight the strengths and weaknesses of the AR literature to identify areas for future AR research and improved understanding.
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http://dx.doi.org/10.1002/alr.22073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286723PMC
February 2018

Impact of Adverse Event Solicitation on the Safety Profile of SQ House Dust Mite Sublingual Immunotherapy Tablet.

J Allergy Clin Immunol Pract 2018 Nov - Dec;6(6):2081-2086.e1. Epub 2018 Feb 10.

Division of Allergy and Clinical Immunology, Department of Medicine, National Jewish Health, Denver, Colo.

Background: It has been recommended that sublingual immunotherapy (SLIT) safety be assessed using solicited adverse event (AE) collection methods.

Objectives: The objectives of this study were to describe the impact on the safety profile of SQ house dust mite (HDM) SLIT-tablet (12 SQ-HDM dose) when prespecified local application site reactions were solicited versus unsolicited, and discuss ramifications of AE solicitation.

Methods: Subjects were randomized to daily 12 SQ-HDM or placebo for up to 52 weeks in 4 double-blinded, multicenter trials. In one trial (NCT01700192; N = 1272), subjects documented daily the presence or absence of 15 World Allergy Organization-defined local application site reactions using a structured questionnaire of closed-ended questions (solicited AEs). Subjects in the other trials were not asked about specific AEs (unsolicited AEs), and AE data were pooled (N = 1287). Analysis was limited to adults aged 18 to 65 years.

Results: Whether AEs were solicited or unsolicited, the most common AEs leading to study discontinuation with 12 SQ-HDM were throat irritation and oral pruritus. Approximately 95% of treatment-related AEs were mild to moderate. Placebo-subtracted frequencies of local application site reactions associated with 12 SQ-HDM were higher when solicited versus unsolicited (ie, throat irritation, 46% vs 13%, respectively; oral pruritus, 47% vs 17%; ear pruritus, 40% vs 4%; mouth swelling, 8% vs 2%; tongue ulceration, 10% vs 0%; mouth ulceration, 7% vs <1%).

Conclusions: Qualitatively, the safety profile of 12 SQ-HDM was similar when AEs were solicited versus unsolicited; hence, solicitation did not alter the safety profile. Higher observed frequencies of local application site reactions with AE solicitation may be partly due to suggestive reporting bias, as observed in placebo-treated subjects.
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http://dx.doi.org/10.1016/j.jaip.2018.01.037DOI Listing
November 2019

Current and future challenges of subcutaneous and sublingual allergy immunotherapy for allergists in the United States.

Authors:
Harold S Nelson

Ann Allergy Asthma Immunol 2018 09 12;121(3):278-280. Epub 2018 Jun 12.

National Jewish Health, University of Colorado Denver School of Medicine, Denver, Colorado. Electronic address:

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http://dx.doi.org/10.1016/j.anai.2017.12.013DOI Listing
September 2018

Heart Rate Variability Biofeedback Does Not Substitute for Asthma Steroid Controller Medication.

Appl Psychophysiol Biofeedback 2018 03;43(1):57-73

University of Colorado School of Medicine, Aurora, CO, USA.

Despite previous findings of therapeutic effects for heart rate variability biofeedback (HRVB) on asthma, it is not known whether HRVB can substitute either for controller or rescue medication, or whether it affects airway inflammation. Sixty-eight paid volunteer steroid naïve study participants with mild or moderate asthma were given 3 months of HRVB or a comparison condition consisting of EEG alpha biofeedback with relaxing music and relaxed paced breathing (EEG+), in a two-center trial. All participants received a month of intensive asthma education prior to randomization. Both treatment conditions produced similar significant improvements on the methacholine challenge test (MCT), asthma symptoms, and asthma quality of life (AQOL). MCT effects were of similar size to those of enhanced placebo procedures reported elsewhere, and were 65% of those of a course of a high-potency inhaled steroid budesonide given to a sub-group of participants following biofeedback training. Exhaled nitric oxide decreased significantly only in the HRVB group, 81% of the budesonide effect, but with no significant differences between groups. Participants reported becoming more relaxed during practice of both techniques. Administration of albuterol after biofeedback sessions produced a large improvement in pulmonary function test results, indicating that neither treatment normalized pulmonary function as a potent controller medication would have done. Impulse oscillometry showed increased upper airway (vocal cord) resistance during biofeedback periods in both groups. These data suggest that HRVB should not be considered an alternative to asthma controller medications (e.g., inhaled steroids), although both biofeedback conditions produced some beneficial effects, warranting further research, and suggesting potential complementary effects. Various hypotheses are presented to explain why HRVB effects on asthma appeared smaller in this study than in earlier studies. Clinical Trial Registration NCT02766374.
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http://dx.doi.org/10.1007/s10484-017-9382-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871536PMC
March 2018

Pooled efficacy and safety data for house dust mite sublingual immunotherapy tablets in adolescents.

Pediatr Allergy Immunol 2017 Nov 31;28(7):661-667. Epub 2017 Aug 31.

Division of Allergy/Immunology, Department of Medicine National Jewish Health, Denver, CO, USA.

Background: House dust mite (HDM) respiratory allergy is a common and burdensome disease in children and adolescents. There are few HDM allergy immunotherapy trials in children with perennial allergic rhinitis. This post hoc analysis used pooled data to evaluate efficacy and safety of the SQ HDM sublingual immunotherapy (SLIT) tablet in adolescents (12-17 years).

Methods: In two double-blind, placebo-controlled trials conducted in North America and Japan, respectively, subjects aged 12+ years with HDM allergic rhinitis were randomized to up to 1 year of treatment. The primary end-point in both trials was the average total combined rhinitis score (TCRS) during the last 8 weeks of treatment in the active group compared with placebo. Data from subjects aged 12-17 years were pooled (N=395).

Results: In the pooled adolescent subpopulation, average TCRS improved 22% with 12 SQ HDM vs placebo (absolute treatment difference of 1.04; P<.01). Rhinitis daily symptom score (DSS), conjunctivitis DSS and rhinitis daily medication score (DMS) were also significantly improved vs placebo in the pooled adolescent subpopulation (all P<.05). There were no new safety signals for adolescents. The frequency of adverse events was similar in adolescents and adults with the majority being mild application site-related events.

Conclusions: Treatment with 12 SQ HDM appears to be effective and well tolerated in adolescents with HDM allergic rhinitis.
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http://dx.doi.org/10.1111/pai.12747DOI Listing
November 2017

Immunotherapy coming of age: notable advances during the first hundred years.

Authors:
Harold S Nelson

Expert Rev Clin Immunol 2017 05 15;13(5):389-392. Epub 2017 Feb 15.

a Department of Medicine, Division of Allergy/Immunology , National Jewish Health , Denver , CO , USA.

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http://dx.doi.org/10.1080/1744666X.2017.1292136DOI Listing
May 2017

Sublingual immunotherapy tablets as a disease-modifying add-on treatment option to pharmacotherapy for allergic rhinitis and asthma.

Postgrad Med 2017 Aug 27;129(6):581-589. Epub 2017 Mar 27.

e Merck & Co., Inc. , Kenilworth , NJ , USA.

Allergic rhinitis (AR) with or without conjunctivitis (AR/C) is associated with a significant health and economic burden, and is often accompanied by asthma. Pharmacotherapies are the mainstay treatment options for AR and asthma, but guidelines also recommend allergy immunotherapy (AIT). Unlike pharmacotherapies, AIT has the ability to modify the underlying immunologic mechanisms of AR and asthma with the potential for long-term benefits after treatment is discontinued. Immunotherapy may also prevent progression of AR/C to asthma. Sublingual immunotherapy (SLIT)-tablets are a self-administered alternative to subcutaneous immunotherapy that provide the benefits of AIT without the cost and inconvenience of frequent office visits or the discomfort of injections. SLIT-tablets are also an option that can be utilized by primary care clinicians. Pharmacotherapies are generally effective in mild disease although a number of patients remain uncontrolled. SLIT-tablets have proven efficacy for AR in adults, children, and poly-sensitized allergic patients. Indirect comparisons indicate that SLIT-tablets have superior or comparable efficacy compared with traditional pharmacotherapies for seasonal AR, and superior efficacy for perennial AR. House dust mite (HDM) SLIT-tablets have also demonstrated clinically relevant benefits for asthma, with significant observed reductions in daily inhaled corticosteroid use, risk of asthma exacerbations, and asthma symptoms. SLIT-tablets are well tolerated, with minimal risk of systemic allergic reactions. The most common treatment-related adverse events are oral site reactions such as oral pruritus and throat irritation. Based on the favorable efficacy and safety profile, as well as the convenience of at-home oral administration and disease-modifying effects, SLIT-tablets should be considered as an alternative or add-on treatment to pharmacotherapy for AR/C, and as an add-on treatment for HDM allergic asthma.
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http://dx.doi.org/10.1080/00325481.2017.1308208DOI Listing
August 2017

Allergen Immunotherapy Clinical Trial Outcomes and Design: Working Toward Harmonization of Methods and Principles.

Curr Allergy Asthma Rep 2017 Mar;17(3):18

ALK, Horsholm, Denmark.

Progress has been made in the harmonization of efficacy and safety outcome measures for allergen immunotherapy (AIT) trials, but unresolved issues still remain. Furthermore, there are discrepancies in recommendations from professional medical societies and regulatory agencies regarding requirements for AIT trials. In this article, we reviewed published recommendations and current data from recent clinical trials, as well as the criteria applied by regulatory authorities for approval of AIT products, to provide updated considerations for conducting phase 3 AIT trials. Topics discussed include analysis of outcomes and trial designs for pediatric and asthma indications, as well as trial designs for perennial allergic rhinoconjunctivitis. In addition, the need for harmonization of safety reporting is emphasized. Considerations presented in this article may further effort to find common ground among professional medical societies and government agencies in developing future recommendations for AIT trial design.
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http://dx.doi.org/10.1007/s11882-017-0687-0DOI Listing
March 2017

Allergen Immunotherapy for a Teenager with Seasonal Allergic Rhinitis Due to Grass Pollen: Subcutaneous or Sublingual Route?

J Allergy Clin Immunol Pract 2017 Jan - Feb;5(1):52-57

Allergy and Clinical Immunology, Division of Respiratory Science, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

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http://dx.doi.org/10.1016/j.jaip.2016.10.012DOI Listing
December 2018

Long-term effects of a house dust mite sublingual immunotherapy tablet in an environmental exposure chamber trial.

Ann Allergy Asthma Immunol 2016 12;117(6):690-696.e1

Vienna Challenge Chamber, Vienna, Austria.

Background: Treatment with SQ house dust mite (HDM) sublingual immunotherapy (SLIT) tablet is effective for HDM respiratory allergic disease, but data on long-term effects are lacking.

Objective: Post hoc analyses were conducted to determine the long-term effect of SQ HDM SLIT-tablet on nasal, ocular, and cough symptoms 1 year after discontinuation of treatment.

Methods: Study participants underwent environmental exposure chamber (EEC) challenges at baseline and week 24 in a randomized, placebo-controlled, double-blind trial (NCT01644617) during which participants received daily 12 SQ-HDM, 6 SQ-HDM, or placebo for 24 weeks. Asthma had to be stable, well controlled, and nonsevere. The mean total asthma symptom score (TASS; sum of 3 symptoms: cough, wheeze, and dyspnea) during baseline and week 24 EEC challenge was analyzed in all participants who completed the trial (n = 106). Approximately 1 year after trial completion, another EEC challenge was conducted in a subset of participants (n = 51). Total nasal symptom score (sum of 4 symptoms), total ocular symptom score (sum of 2 symptoms), and cough were assessed.

Results: Compared with baseline and end-of-treatment values, sustained improvement of all symptoms assessed at the 1-year follow-up EEC challenge was evident in participants treated with 12 SQ-HDM. Results with 6 SQ-HDM were less notable. After 24 weeks of 12 SQ-HDM, TASS during EEC challenge was improved 65% vs baseline; at 1-year follow-up, cough was improved 57% vs baseline.

Conclusion: Persistent improvement of nasal and ocular symptoms was observed up to 1 year after completing 24 weeks of 12 SQ-HDM treatment. Beneficial effects on cough were also observed.

Trial Registration: clinicaltrials.gov Identifier NCT01644617.
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http://dx.doi.org/10.1016/j.anai.2016.10.015DOI Listing
December 2016

Inhalation devices, delivery systems, and patient technique.

Authors:
Harold S Nelson

Ann Allergy Asthma Immunol 2016 12;117(6):606-612

National Jewish Health and University of Colorado Denver School of Medicine, Denver, Colorado. Electronic address:

Background: In real-life clinical settings, physicians often consider the properties of various inhaled corticosteroids (ICSs), but typically little consideration is given to the properties of different inhalers and formulations.

Objective: To discuss the effects of inhalation devices and user technique on efficacy, safety, and adherence with the aim of improving asthma management.

Methods: Relevant publications were selected to augment discussion.

Results: There are many types of devices available, each with advantages, disadvantages, ease of use, and rate of misuse. Aerosol particle size influences the deposition pattern of a drug in the lungs, and the optimal particle size range is 1 to 5 μm. Retrospective reviews suggest that smaller particles (1-2 μm) could provide improved asthma control, but randomized, prospective studies are needed. Multiple studies have demonstrated high misuse rates in patients for pressurized metered-dose inhalers and dry powder inhalers. Because of this, repeated education should include physical demonstrations of using the device, checking the patient's technique, correcting the technique, and rechecking the technique. This also means that dedicated, trained staff and placebo devices should be available for instructing patients. Furthermore, the device should be selected to be cost effective and to fit the patient's preference and ability to use it correctly to enhance compliance. Asthma management guidelines and algorithms are available to guide the clinician.

Conclusion: The choice of inhaler device should depend on cost effectiveness and the patient's preference and ability to use it correctly. Patient inhaler technique should be checked and, if necessary, corrected and rechecked, with retraining if needed, at every opportunity.
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http://dx.doi.org/10.1016/j.anai.2016.05.006DOI Listing
December 2016

Epinephrine Use in Clinical Trials of Sublingual Immunotherapy Tablets.

J Allergy Clin Immunol Pract 2017 Jan - Feb;5(1):84-89.e3. Epub 2016 Nov 9.

Department of Medicine, National Jewish Health, Denver, Colo.

Background: Allergy immunotherapy can result in systemic allergic reactions and even life-threatening anaphylaxis requiring epinephrine administration.

Objective: The objective of this study was to describe epinephrine use in the clinical trial development programs of 3 rapidly dissolving sublingual immunotherapy tablets (SLIT-tablets; Merck & Co., Inc., Kenilworth, NJ/ALK, Hørsholm, Denmark/Torii Pharmaceutical Co., Ltd., Tokyo, Japan).

Methods: Data on epinephrine use were collected from 13 timothy grass SLIT-tablet trials (MK-7243; ≤2800 bioequivalent allergen units/75,000 SQ-T dose, n = 2497; placebo, n = 2139), 5 short ragweed SLIT-tablet trials (MK-3641; ≤12 Amb a 1-U, n = 1725; placebo, n = 770), and 11 house dust mite (HDM) SLIT-tablet trials (MK-8237; ≤12 SQ-HDM; n = 3930; placebo, n = 2246).

Results: In grass SLIT-tablet trials, epinephrine was used 13 times (grass SLIT-tablet, n = 10; placebo, n = 3). Eight administrations were for grass SLIT-tablet-related adverse events (AEs): 4 for systemic allergic reactions and 4 for local mouth and/or throat swelling. In ragweed SLIT-tablet trials, epinephrine was used 9 times in 8 subjects (ragweed SLIT-tablet, n = 7; placebo, n = 1 [2 administrations for protracted anaphylaxis]). Four administrations were for ragweed SLIT-tablet-related AEs: 1 for systemic allergic reaction and 3 for local mouth and/or pharynx/throat swelling. In HDM SLIT-tablet trials, epinephrine was administered 13 times (HDM SLIT-tablet, n = 8; placebo, n = 5). Four administrations were for HDM SLIT-tablet-related AEs: 1 for systemic allergic reaction and 3 for local events. Of the 16 epinephrine administrations for events related to SLIT-tablet treatment, 11 occurred within the first week of treatment (7 administrations on day 1) and 5 were subject self-administered.

Conclusions: Epinephrine administrations in response to SLIT-tablet-related reactions in clinical trials are uncommon, typically occur within the first week of treatment, and are rarely self-administered. All SLIT-tablet-related events treated with epinephrine were nonserious.
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http://dx.doi.org/10.1016/j.jaip.2016.08.017DOI Listing
November 2017

Allergen immunotherapy (AIT) for the multiple-pollen sensitive patient.

Authors:
Harold S Nelson

Expert Rev Clin Pharmacol 2016 Nov 6;9(11):1443-1451. Epub 2016 Oct 6.

a Department of Medicine , National Jewish Health , Denver , CO , USA.

Introduction: The majority of allergic subjects are polysensitized. In Europe, allergy immunotherapy (AIT) in these patients is usually limited to their single clinically most troublesome allergy while in the U.S. the immunotherapy prescription usually includes all allergen extracts to which the patient has evidence of clinical sensitivity. Areas covered: This article will review the evidence supporting the U.S. practice. It will also review the major new development in the management of polysensitized patients, the introduction of component-resolved diagnosis (CRD). Expert commentary: This allows, in many cases, distinguishing in polysensitized patients between sensitization to the major allergens of several unrelated allergen extracts and to panallergens that cause broad patterns of cross-reactivity.
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http://dx.doi.org/10.1080/17512433.2016.1237874DOI Listing
November 2016

Treatment effect of sublingual immunotherapy tablets and pharmacotherapies for seasonal and perennial allergic rhinitis: Pooled analyses.

J Allergy Clin Immunol 2016 10 15;138(4):1081-1088.e4. Epub 2016 Jul 15.

Merck & Co, Kenilworth, NJ. Electronic address:

Background: Data comparing the treatment effect of allergy immunotherapy and pharmacotherapy are lacking.

Objective: We sought to indirectly compare the treatment effect of sublingual immunotherapy (SLIT)-tablets with pharmacotherapy for seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR).

Methods: Pooled data from randomized, double-blind, placebo-controlled trials for the clinical development programs of selected allergic rhinitis treatments were evaluated. Total nasal symptom scores (TNSSs) relative to placebo were compared. Subjects scored symptoms daily during entire pollen seasons in 6 timothy grass SLIT-tablet trials (n = 3094) and 2 ragweed SLIT-tablet trials (n = 658) and during the last 8 weeks of treatment in 2 house dust mite (HDM) SLIT-tablet trials (n = 1768). Subjects scored symptoms daily in 7 montelukast (10 mg, n = 6799), 9 desloratadine (5 mg, n = 4455), and 8 mometasone furoate nasal spray (MFNS; 200 μg daily, n = 2140) SAR or PAR trials. SLIT-tablet trials allowed rescue medication use, whereas most pharmacotherapy trials did not. A fixed-effect meta-analysis method estimated differences in on-treatment average TNSSs.

Results: In grass and ragweed SLIT-tablet trials, overall improvement in TNSSs relative to placebo was 16.3% and 17.1%, respectively. In HDM SLIT-tablet trials, TNSS overall improvement relative to placebo was 16.1%. In the montelukast, desloratadine, and MFNS trials, TNSS overall improvement relative to placebo was 5.4%, 8.5%, and 22.2%, respectively, for SAR trials, and 3.7%, 4.8%, and 11.2%, respectively, for PAR trials.

Conclusions: Although comparisons were limited by study design heterogeneity and use of rescue medications in SLIT-tablet trials, effects on nasal symptoms with timothy grass and ragweed SLIT-tablets were nearly as great as with MFNS and numerically greater than with montelukast and desloratadine for SAR. HDM SLIT-tablet effects were numerically greater than all pharmacotherapies for PAR. SLIT-tablets offer the additional benefit of long-term efficacy.
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http://dx.doi.org/10.1016/j.jaci.2016.04.061DOI Listing
October 2016

Efficacy of house dust mite sublingual immunotherapy tablet in North American adolescents and adults in a randomized, placebo-controlled trial.

J Allergy Clin Immunol 2016 12 10;138(6):1631-1638. Epub 2016 Aug 10.

Merck & Co, Kenilworth, NJ.

Background: The house dust mite (HDM) sublingual immunotherapy (SLIT) tablet (MK-8237; Merck & Co, Kenilworth, NJ/ALK-Abelló, Hørsholm, Denmark) has demonstrated beneficial effects on allergic rhinoconjunctivitis and asthma outcomes in European trials.

Objective: This is the first trial to assess the efficacy/safety of HDM SLIT-tablets in North American subjects with HDM-induced allergic rhinitis with or without conjunctivitis (AR/C).

Methods: In this double-blind, multicenter trial (NCT01700192) 1482 subjects (aged ≥12 years) with HDM-induced AR/C with or without asthma were randomized to a daily SQ HDM SLIT-tablet (12 SQ-HDM dose) or placebo for up to approximately 52 weeks. A rhinitis daily symptom score (DSS; 4 nasal symptoms, maximum score = 12) of 6 or greater, or 5 or greater with 1 symptom being severe, on 5 of 7 consecutive days before randomization was required. The primary end point was the average total combined rhinitis score, which was defined as the rhinitis DSS plus rhinitis daily medication score (DMS), during the last 8 treatment weeks.

Results: Treatment with 12 SQ-HDM improved the total combined rhinitis score by 17% (95% CI, 10% to 25%) versus placebo. Improvements versus placebo in the secondary end points of average rhinitis DSS, rhinitis DMS, total combined rhinoconjunctivitis score, and visual analog scale-assessed AR/C symptoms were 16%, 18%, 17%, and 16%, respectively. All nominal P values were less than .001 versus placebo, except rhinitis DMS (P = 0.15). No treatment-related adverse events meeting the International Council on Harmonization definition of a serious adverse event were reported; 1 nonserious treatment-related systemic allergic reaction occurred (assessed as moderate intensity) at first administration under medical supervision and was treated with epinephrine.

Conclusions: In the first North American trial of use of a SLIT-tablet for HDM allergy, 12 SQ-HDM was well tolerated and improved HDM-induced rhinitis symptoms in adults and adolescents.
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http://dx.doi.org/10.1016/j.jaci.2016.06.044DOI Listing
December 2016

Allergen immunotherapy now and in the future.

Authors:
Harold S Nelson

Allergy Asthma Proc 2016 Jul;37(4):268-72

Department of Medicine, Allergy/Immunology Division, National Jewish Health, Denver, Colorado.

Background: Subcutaneous (SCIT) and sublingual (SLIT) immunotherapy provide effective treatment for allergic rhinitis and allergic asthma with clinical improvement following an adequate course of therapy persisting in most patients for years after treatment is discontinued. However, both require prolonged courses of therapy and many or most patients either do not begin or stop long before they have completed the prescribed course of treatment.

Methods: Based on review of the recent medical literature, the current status of SCIT and SLIT was reviewed as well as new approaches to allergy immunotherapy (AIT) that have promise to overcome the safety and inconvenience concerns of both the current approaches.

Results: New approaches to AIT include application of extracts to the skin with patches, injection into inguinal lymph nodes, alterations in the allergen molecules by chemical treatment or recombinant technology to make them less reactive with specific IgE, shifting the immune response by stimulation of toll-like receptors or suppression of Th2 responses, and finally by adjuvants such as probiotics and vitamin D.

Conclusions: Current forms of immunotherapy require years of treatment. New approaches, although differing markedly in their approach to AIT, all offer marked reduction in the required period of treatment. Hopefully, some of these new approaches will prove safe and effective and obtain approval for general use. If approved, they should make AIT more widely utilized to the benefit of the allergic population.
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http://dx.doi.org/10.2500/aap.2016.37.3966DOI Listing
July 2016

SQ grass sublingual allergy immunotherapy tablet for disease-modifying treatment of grass pollen allergic rhinoconjunctivitis.

Allergy Asthma Proc 2016 Mar-Apr;37(2):92-104. Epub 2016 Jan 21.

Allergy Centre, Odense University Hospital, Odense, Denmark.

Background: Allergy immunotherapy is a treatment option for allergic rhinoconjunctivitis (ARC). It is unique compared with pharmacotherapy in that it modifies the immunologic pathways that elicit an allergic response. The SQ Timothy grass sublingual immunotherapy (SLIT) tablet is approved in North America and throughout Europe for the treatment of adults and children (≥5 years old) with grass pollen-induced ARC.

Objective: The clinical evidence for the use of SQ grass SLIT-tablet as a disease-modifying treatment for grass pollen ARC is discussed in this review.

Methods: The review included the suitability of SQ grass SLIT-tablet for patients with clinically relevant symptoms to multiple Pooideae grass species, single-season efficacy, safety, adherence, coseasonal initiation, and cost-effectiveness. The data from the long-term SQ grass SLIT-tablet clinical trial that evaluated a clinical effect 2 years after a continuous 3-year treatment period were presented in the context of regulatory criteria that define a clinically meaningful effect.

Results: This trial demonstrated that the clinical effect of the SQ grass SLIT-tablet is maintained, which is also supported by the immunologic findings.

Conclusion: Therefore, the SQ grass SLIT-tablet has an indication as a disease-modifying therapy in Europe, and a sustained effect is recognized in the United States.
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http://dx.doi.org/10.2500/aap.2016.37.3937DOI Listing
December 2016

Sequential Treatment Initiation with Timothy Grass and Ragweed Sublingual Immunotherapy Tablets Followed by Simultaneous Treatment Is Well Tolerated.

J Allergy Clin Immunol Pract 2016 Mar-Apr;4(2):301-9.e2. Epub 2016 Jan 2.

Merck & Co., Inc, Kenilworth, NJ. Electronic address:

Background: Dual treatment with grass and ragweed sublingual immunotherapy (SLIT) tablets has not been studied.

Objective: To characterize the safety and tolerability of dual grass and ragweed SLIT-tablet administration.

Methods: This open-label, multicenter trial (NCT02256553) enrolled North American adults (N = 102) allergic to grass and ragweed. The trial had 3 periods, each of 2 weeks duration. In period 1, subjects received once-daily timothy grass SLIT tablet (2800 bioequivalent allergen unit; Merck, Inc, Kenilworth, NJ/ALK, Hørsholm, Denmark). In period 2, subjects received a short ragweed SLIT tablet (12 Ambrosia artemisiifolia 1-U; Merck/ALK) every morning and a grass SLIT tablet every evening. In period 3, subjects received once-daily grass and ragweed SLIT tablets within 5 minutes (simultaneous intake). The primary end point was the proportion of subjects with 1 or more local swelling events in each period. Secondary end points were the proportion of subjects with 1 or more local adverse events (AEs), that discontinued the treatment because of AEs, and subjects with 1 or more local AEs requiring treatment.

Results: No severe swellings, systemic allergic reactions, asthma attacks, or reactions requiring epinephrine were reported. Most (99%) AEs were graded mild to moderate. The proportions of subjects with 1 or more local swelling events were 14%, 22%, and 15% for periods 1, 2, and 3, respectively. For periods 1, 2, and 3, the proportions of subjects with 1 or more local AEs were 71%, 69%, and 56%, respectively; the proportions discontinuing the treatment because of treatment-related AEs were 5%, 1%, and 2%, and the proportions with 1 or more local AEs requiring treatment were 4%, 4%, and 1%.

Conclusions: In this trial, a 4-week sequential SLIT-tablet dosing schedule followed by simultaneous intake of timothy grass and ragweed tablets was well tolerated.
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http://dx.doi.org/10.1016/j.jaip.2015.11.004DOI Listing
December 2016