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Revista Alergia Mexico (Tecamachalco,... Feb 2024Review the historical records of house dust mites in the countries of the Pacific and continental Caribbean of Latin America.
OBJECTIVE
Review the historical records of house dust mites in the countries of the Pacific and continental Caribbean of Latin America.
METHODS
A systematic review was carried out, adapting the PRISMA method, in digital repositories using a combination of the terms in Spanish: "ácaros domésticos" "alergia" and in English: "dust mites" "allergy" with the names of the countries "Costa Rica". "Panamá" "Venezuela" "Colombia" "Ecuador" "Peru" between 1970-2022. The inclusion criteria were presence of the mite species, city or municipality, country, height above sea level and year. A database was built in Microsoft Excel Office 365. Maps were created using QGIS 3.30 geographic information systems and descriptive statistics were used to analyze the findings.
RESULTS
From the search and identification, 3959 references were obtained, of which 133 were considered potentially eligible, of these 45 met inclusion criteria, and only 32 presented records of domestic mite species. Historically there were 424 records and 27 species (18 genera and 9 families). The countries with the most studies and records were Colombia (14 and 242), Panama (8 and 64) and Peru (5 and 74). 66% (281/424) of the records were of the species (81), followed by (58), (40), (39), . (33) and (30). The species with the greatest altitudinal range were , (2-4800 m.a.s.l) and (2- 3399 m.a.s.l).
CONCLUSIONS
A synthesis was presented on the historical geographical and altitudinal distribution of house dust mites in countries of the Pacific and continental Caribbean of Latin America, which in turn allowed us to determine the species with the greatest records, highlighting those of importance in allergology. These findings are an input for acarological surveillance in public health.
Topics: Animals; History, 20th Century; History, 21st Century; Latin America; Pyroglyphidae; Pacific Ocean; Caribbean Region
PubMed: 38683087
DOI: 10.29262/ram.v71i1.1307 -
Frontiers in Immunology 2023To systematically evaluate the clinical efficacy and safety of sublingual immunotherapy for allergic rhinitis (AR) and provide evidence for clinical treatment. (Meta-Analysis)
Meta-Analysis
BACKGROUND
To systematically evaluate the clinical efficacy and safety of sublingual immunotherapy for allergic rhinitis (AR) and provide evidence for clinical treatment.
METHODS
A literature search was performed on the China National Knowledge Infrastructure (CNKI), Wanfang database, PubMed, Web of Science, Cochrane Library, and Embase database. Data from randomized controlled trials (RCTs) of sublingual immunotherapy for AR were screened and extracted from the establishment of those databases to November 2022. Subsequently, a network meta-analysis was performed using a statistical software R 4.2.
RESULTS
Totally 22 RCTs that met the inclusion and exclusion criteria and screened from 1,164 literature were included. A total of 4,941 AR patients were involved in the 22 trials, as well as five interventions including placebo, pharmacotherapy, subcutaneous immunotherapy_dust mite, sublingual immunotherapy_dust mite, and sublingual immunotherapy_ grass mix plus pollen extract. The results of network meta-analysis showed that, based on symptom scores after different interventions for AR, the most effective treatments for AR were in order as follows: sublingual immunotherapy_dust mite, subcutaneous immunotherapy_dust mite, sublingual immunotherapy_ grass mix plus pollen extract, placebo, and pharmacotherapy. Importantly, sublingual immunotherapy had fewer adverse reactions and higher safety.
CONCLUSION
Sublingual immunotherapy_dust mite for AR has the best efficacy, whereas traditional medicine has the worst. More high-quality studies with a large sample and multiple centers are needed to verify this conclusion in the future, so as to further provide more reliable evidence-based medical evidence for the clinical treatment options of AR patients.
Topics: Animals; Humans; Sublingual Immunotherapy; Network Meta-Analysis; Rhinitis, Allergic; Pyroglyphidae; Plant Extracts
PubMed: 37063866
DOI: 10.3389/fimmu.2023.1144816 -
Asian Pacific Journal of Allergy and... Dec 2022Most patients with allergic rhinitis are polysensitized. The efficacy of house dust mite (HDM) allergen immunotherapy (AIT) compared between monosensitized and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Most patients with allergic rhinitis are polysensitized. The efficacy of house dust mite (HDM) allergen immunotherapy (AIT) compared between monosensitized and polysensitized patients remains limited.
OBJECTIVE
To systematically review the efficacy and safety of HDM AIT compared between monosensitized and polysensitized patients with allergic rhinitis.
METHODS
We searched PubMed/MEDLINE, Scopus, EMBASE, and the Cochrane central register of Controlled Trials (CENTRAL) until June 2022. The primary outcome was the changes from baseline in total nasal symptom score (TNSS). Secondary outcomes were changes from baseline in total medication score (TMS), combined symptom medication score (CSMS), visual analog scale (VAS), Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score, immunological parameters, and adverse events (AEs).
RESULTS
Of 13 eligible studies, 10 prospective cohorts, 2 retrospective cohorts, and 1 matched cohort, we identified 10 studies for quantitative synthesis. There were 1,113 patients with allergic rhinitis, 566 with HDM monosensitization and 547 with polysensitization to HDM and other allergens. There was no significant difference in the pooled mean changes of the 2 groups in TNSS (SMD -0.05, 95%CI: -0.22 to 0.11, p = 0.532) and VAS (SMD -0.20, 95%CI: -0.42 to 0.01, p = 0.060) with moderate certainty of evidence. The changes in TMS, CSMS, and RQLQ were similar between the 2 groups with very low certainty of evidence. The AEs were mild and comparable between the 2 groups. The immunological indices remained inconsistent and were not predictive of clinical responses.
CONCLUSIONS
A single HDM AIT similarly improved clinical outcomes in monosensitized and polysensitized patients with allergic rhinitis.
Topics: Humans; Animals; Retrospective Studies; Prospective Studies; Quality of Life; Sublingual Immunotherapy; Treatment Outcome; Rhinitis, Allergic; Allergens; Antigens, Dermatophagoides; Conjunctivitis; Pyroglyphidae
PubMed: 36278778
DOI: 10.12932/AP-190822-1440 -
The Journal of Allergy and Clinical... Jan 2023Atopic dermatitis (AD, eczema) is driven by a combination of skin barrier defects, immune dysregulation, and extrinsic stimuli such as allergens, irritants, and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Atopic dermatitis (AD, eczema) is driven by a combination of skin barrier defects, immune dysregulation, and extrinsic stimuli such as allergens, irritants, and microbes. The role of environmental allergens (aeroallergens) in triggering AD remains unclear.
OBJECTIVE
We systematically synthesized evidence regarding the benefits and harms of allergen immunotherapy (AIT) for AD.
METHODS
As part of the 2022 American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters AD Guideline update, we searched the MEDLINE, EMBASE, CENTRAL, CINAHL, LILACS, Global Resource for Eczema Trials, and Web of Science databases from inception to December 2021 for randomized controlled trials comparing subcutaneous immunotherapy (SCIT), sublingual immunotherapy (SLIT), and/or no AIT (placebo or standard care) for guideline panel-defined patient-important outcomes: AD severity, itch, AD-related quality of life (QoL), flares, and adverse events. Raters independently screened, extracted data, and assessed risk of bias in duplicate. We synthesized intervention effects using frequentist and Bayesian random-effects models. The GRADE approach determined the quality of evidence.
RESULTS
Twenty-three randomized controlled trials including 1957 adult and pediatric patients sensitized primarily to house dust mite showed that add-on SCIT and SLIT have similar relative and absolute effects and likely result in important improvements in AD severity, defined as a 50% reduction in SCORing Atopic Dermatitis (risk ratio [95% confidence interval] 1.53 [1.31-1.78]; 26% vs 40%, absolute difference 14%) and QoL, defined as an improvement in Dermatology Life Quality Index by 4 points or more (risk ratio [95% confidence interval] 1.44 [1.03-2.01]; 39% vs 56%, absolute difference 17%; both outcomes moderate certainty). Both routes of AIT increased adverse events (risk ratio [95% confidence interval] 1.61 [1.44-1.79]; 66% with SCIT vs 41% with placebo; 13% with SLIT vs 8% with placebo; high certainty). AIT's effect on sleep disturbance and eczema flares was very uncertain. Subgroup and sensitivity analyses were consistent with the main findings.
CONCLUSIONS
SCIT and SLIT to aeroallergens, particularly house dust mite, can similarly and importantly improve AD severity and QoL. SCIT increases adverse effects more than SLIT. These findings support a multidisciplinary and shared decision-making approach to optimally managing AD.
Topics: Adult; Animals; Humans; Child; Dermatitis, Atopic; Quality of Life; Bayes Theorem; Desensitization, Immunologic; Pyroglyphidae; Hypersensitivity; Asthma; Allergens; Sublingual Immunotherapy; Dermatophagoides pteronyssinus; Eczema
PubMed: 36191689
DOI: 10.1016/j.jaci.2022.09.020 -
The Journal of Allergy and Clinical... May 2022House dust mite sublingual immunotherapy (HDM SLIT) effectively treats allergic rhinitis (AR). However, the evidence of HDM SLIT for allergic asthma remained limited.
BACKGROUND
House dust mite sublingual immunotherapy (HDM SLIT) effectively treats allergic rhinitis (AR). However, the evidence of HDM SLIT for allergic asthma remained limited.
OBJECTIVE
To systematically review the efficacy and safety of HDM SLIT tablets in patients with allergic asthma.
METHODS
We performed a systematic search through PubMed, Scopus, EMBASE, Web of Science, the Cochrane Center of Controlled Trials, and Google Scholar for randomized controlled trials (RCTs) that addressed the efficacy and safety of HDM SLIT tablets compared with placebo or no intervention in allergic asthma from their inception date until September 2021. The primary outcome was the reduction in inhaled corticosteroids (ICS) dose. Additional outcomes were asthma control, exacerbation, lung function, quality-of-life, and adverse events.
RESULTS
There were 7 RCTs, 5 studies in allergic asthma (4 in adults and 1 in children), and 2 in AR with or without asthma. The 6 standardized quality (SQ) HDM effectively reduced ICS dose in well- to partly controlled mild-to-moderate asthma in 1 RCT. Two RCTs evaluated the efficacy of 6 SQ and 12 SQ HDM in reducing asthma exacerbation in partly controlled moderate-to-severe asthma, and their results were inconsistent. One study in children with mild-to-moderate asthma found no benefit of HDM SLIT. Two RCTs in AR with or without mild-to-moderate asthma showed improvement of asthma symptoms. Adverse events were primarily local, and anaphylaxis treated with epinephrine was reported in 3 patients.
CONCLUSIONS
The HDM SLIT tablets tend to effectively reduce ICS use in adults and adolescents with well- to partly controlled mild-to-moderate allergic asthma with a favorable safety profile.
Topics: Adolescent; Adult; Animals; Child; Humans; Adrenal Cortex Hormones; Antigens, Dermatophagoides; Asthma; Dermatophagoides pteronyssinus; Pyroglyphidae; Randomized Controlled Trials as Topic; Rhinitis, Allergic; Sublingual Immunotherapy; Tablets; Treatment Outcome
PubMed: 35181547
DOI: 10.1016/j.jaip.2022.01.046 -
Allergologia Et Immunopathologia 2022To determine whether the levels of T-helper (T) 2 cytokines (interleukin (IL)-4 and IL-5) in allergic reactions are allergen dependent and evaluate the impact of various... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
To determine whether the levels of T-helper (T) 2 cytokines (interleukin (IL)-4 and IL-5) in allergic reactions are allergen dependent and evaluate the impact of various treatment strategies on the levels of these cytokines.
METHODS
The PubMed search engine was used from inception until January 2021. The random-effects residual maximum likelihood model was performed, and effect sizes were estimated using the Hedge's statistic. All data analysis was performed using STATA 16.0 (StataCorp LP, TX, USA).
RESULTS
Fourteen studies reporting on 794 participants were included in this study. House dust mite was associated with eliciting a stronger immune response mediated by both IL-4 and IL-5 when compared to pollen. Whereas a mixture of house dust mite and pollen was associated with IL-4-weighted inflammation. Comparisons of IL-4 and IL-5 levels amongst the allergens showed significant differences. The treatment with anti-corticosteroids or allergen-specific immunotherapy was effective in normalising the T2 responses and alleviating allergy symptoms.
CONCLUSION
T2-mediated inflammation in allergic reactions is allergen-dependent. Therefore, the type of allergen should be considered when using cytokine-targeting biologics in allergic reactions.
Topics: Allergens; Animals; Cytokines; Dermatophagoides pteronyssinus; Humans; Hypersensitivity; Inflammation; Interleukin-4; Interleukin-5; Pyroglyphidae; Th2 Cells
PubMed: 34873895
DOI: 10.15586/aei.v50i1.470 -
Rhinology Aug 2021Selecting an appropriate allergen-specific immunotherapy (AIT) regimen for polysensitised allergic rhinitis (AR) patients is challenging for clinicians. Although... (Meta-Analysis)
Meta-Analysis
Selecting an appropriate allergen-specific immunotherapy (AIT) regimen for polysensitised allergic rhinitis (AR) patients is challenging for clinicians. Although previous studies showed comparable effectiveness of single-allergen AIT with house dust mite (HDM) extract between monosensitised and polysensitised AR patients, there is no systematic review and meta-analysis demonstrating the comparable effectiveness of HDM AIT. In this meta-analysis, we analysed nine studies to compare the clinical effectiveness of HDM AIT. The primary outcome was nasal symptom score and secondary outcomes were medication and quality of life scores. The changes in nasal symptom score after HDM AIT did not significantly differ between monosensitised and polysensitised patients. The clinical effectiveness of HDM AIT regarding medication and quality of life score was not significantly different between monosensitised and polysensitised patients). In conclusion, single-allergen AIT with HDM extract showed comparable clinical effectiveness between polysensitised and monosensitised patients with AR.
Topics: Animals; Desensitization, Immunologic; Humans; Pyroglyphidae; Quality of Life; Rhinitis, Allergic; Sublingual Immunotherapy; Treatment Outcome
PubMed: 34180463
DOI: 10.4193/Rhin20.588 -
The Cochrane Database of Systematic... Sep 2020Asthma is a common long-term respiratory disease affecting approximately 300 million people worldwide. Approximately half of people with asthma have an important... (Meta-Analysis)
Meta-Analysis
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.
Topics: Adolescent; Adult; Animals; Asthma; Child; Disease Progression; Hospitalization; Humans; Placebos; Pollen; Pyroglyphidae; Quality of Life; Randomized Controlled Trials as Topic; Rhinitis, Allergic; Sublingual Immunotherapy
PubMed: 32926419
DOI: 10.1002/14651858.CD011293.pub3 -
PloS One 2020Existing evidence on the relationship between childhood lower respiratory tract infections (LRTI) and the subsequent atopy development is controversial. We aimed to... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Existing evidence on the relationship between childhood lower respiratory tract infections (LRTI) and the subsequent atopy development is controversial. We aimed to investigate an association between viral LRTI at <5 years and the development of atopy at > 2 years.
METHODS
We conducted a search at Embase, Pubmed, Web of Science, and Global Index Medicus. We collected data from the included articles. We estimated the odds ratio and the 95% confidence intervals with a random effect model. We determined factors associated with atopy development after childhood LRTI using univariate and multivariate meta-regression analyses. We recorded this systematic review at PROSPERO with the number CRD42018116955.
RESULTS
We included 24 studies. There was no relationship between viral LRTI at <5 years and skin prick test-diagnosed-atopy (OR = 1.2, [95% CI = 0.7-2.0]), unknown diagnosed-atopy (OR = 0.7, [95% CI = 0.4-1.3]), atopic dermatitis (OR = 1.2, [95% CI = 0.9-1.6]), hyperreactivity to pollen (OR = 0.8, [95% CI = 0.3-2.7]), food (OR = 0.8, [95% CI = 0.3-2.5]), or house dust mite (OR = 1.1, [95% CI = 0.6-2.2]). Although not confirmed in all studies with a symmetric distribution of the 23 confounding factors investigated, the overall analyses showed that there was a relationship between childhood viral LRTI at < 5 years and serum test diagnosed-atopy (OR = 2.0, [95% CI = 1.0-4.1]), allergic rhinoconjunctivitis (OR = 1.7, [95% CI = 1.1-2.9]), hyperreactivity diagnosed by serum tests with food (OR = 5.3, [1.7-16.7]) or inhaled allergens (OR = 4.2, [95% CI = 2.1-8.5]), or furred animals (OR = 0.6, [95% CI = 0.5-0.9]).
CONCLUSION
These results suggest that there is no association between viral LRTI at < 5 years and the majority of categories of atopy studied during this work. These results, however, are not confirmed for the remaining categories of atopy and more particularly those diagnosed by serum tests. There is a real need to develop more accurate atopy diagnostic tools.
Topics: Allergens; Animals; Asthma; Child; Conjunctivitis, Allergic; Dermatitis, Atopic; Dermatophagoides pteronyssinus; Humans; Pollen; Respiratory Tract Infections; Rhinitis, Allergic; Skin Tests; Time Factors
PubMed: 32330171
DOI: 10.1371/journal.pone.0231816 -
International Forum of Allergy &... Nov 2020Allergic rhinitis (AR) is a major public health problem and is increasing worldwide. AR affects children's learning efficiency, sleep quality, and other major aspects of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Allergic rhinitis (AR) is a major public health problem and is increasing worldwide. AR affects children's learning efficiency, sleep quality, and other major aspects of life. Sublingual immunotherapy (SLIT) is effective and safe for children with seasonal AR, but for children with perennial allergic rhinitis (PAR) caused by house dust mites (HDM), its effectiveness and safety is less convincing.
METHODS
Medical literature databases up to 2019 were searched for published and unpublished pieces of evidence. Studies were individually screened by 2 reviewers against the eligibility criteria. Primary outcomes were total nasal symptoms scores (TNSS) and total medication scores (TMS). The secondary outcomes were total ocular symptoms scores and adverse events (AEs). Random effect models and fixed-effect models were used to calculate the standard mean difference (SMD) and risk ratio (RR), respectively.
RESULTS
We identified 3772 abstracts, of which only 16 studies met our established criteria. SLIT significantly reduced TNSS (SMD -1.73; 95% CI, -2.62 to -0.84; p = 0.0001) and TMS (SMD -1.21; 95% CI, -1.75 to -0.67; p < 0.00001). Compared with children taking placebo, children taking SLIT were 1.08 (95% CI, 1 to 1.17; p = 0.05), 1.15 (95% CI, 0.87 to 1.51; p = 0.32), and 1.68 (95% CI, 0.68 to 4.11; p = 0.26) times more likely to develop mild, moderate, and severe AEs, respectively.
CONCLUSION
HDM SLIT can effectively alleviate TNSS and TMS in children with PAR, but care should be taken to avoid harm due to possible adverse drug reactions.
Topics: Allergens; Animals; Antigens, Dermatophagoides; Child; Humans; Pyroglyphidae; Rhinitis; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Sublingual Immunotherapy; Treatment Outcome
PubMed: 32329187
DOI: 10.1002/alr.22589