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Artículos seleccionados

New transcriptome and clinical findings of platelet-activating factor in chronic spontaneous urticaria: Pathogenic and treatment relevance

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Andrades E, Clarós M, Torres JV

Biofactors . 2022 Aug 4. doi: 10.1002/biof.1880. Online ahead of print.

Urticaria is characterized by transient wheal-and-flare skin reaction with pruritus. More than 5 million people suffer from persisting urticaria symptoms in Europe, causing a huge burden on patients and healthcare systems. The aim of this study was to evaluate the relevance of Platelet Activating factor (PAF) in chronic spontaneous urticaria (CSU).

Skin samples of 45 patients with moderate/severe CSU and 17 healthy controls were analyzed for the expression and cellular location of PAF receptor (PAFR) and serum levels of PAF and PAF acetylhydrolase (PAF-AH). Serum PAF and PAF-AH levels were assessed by ELISA and compared between patient and healthy controls and also between those refractory and non-refractory to 2nd-generation H1-antihistamines. PAFR mRNA expression was significantly higher in LS-CSU versus HCs (p = 0.014). PAFR positive staining in immunohistochemistry was mainly found in the epidermal basal layer in HCs, while it was largely present along the epidermis in LS-CSU samples. Endothelial cells showed PAFR expression exclusively in LS-CSU and NLS-CSU samples. PAFR expression was observed in the nerves of HC, LS-CSU, and NLS-CSU samples. Double PAFR/CD43 expression demonstrated that T-lymphocytes were the main cell type from the wheal inflammatory infiltrate expressing PAFR. A significantly lower PAF-AH/PAF ratio was observed in 2nd-generation H1-antihistamines non-responders versus responders (6.1 vs. 12.6; p = 0.049).

In conclusion, this study corroborates that PAF is a mediator of wheal pathogenesis in CSU and suggests that PAF could be a potential biomarker of 2nd-generation H1-antihistamines refractoriness due to the significantly lower PAF-AH/PAF ratio in 2nd-generation H1-antihistamines non-responders vs responders.

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Acute Urticaria and Anaphylaxis: Differences and Similarities in Clinical Management

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Ensina LF, Min TK, Félix MMR, et al.

Front Allergy. 2022 Apr 15;3:840999. doi: 10.3389/falgy.2022.840999. eCollection 2022.

Acute urticaria is common and presents with wheals and/or angioedema. These symptoms are also frequent in anaphylaxis, a life-threatening reaction that must be immediately treated. In both conditions, mast cells have a central role in their mechanism of action. Although these similarities, the diagnostic approach is usually different, as it depends on the suspicious triggers, age of the patient and region where they’re based.

Anaphylaxis must be treated with adrenaline as first-line while urticaria flares can be treated with H1-antihistamines are the first choice.

The best approach to prevent anaphylaxis or acute urticaria episodes is to avoid the trigger that is responsible for the reaction, having in consideration that a solution may be desensitization to drugs and foods in selected patients to improve their quality of life.

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Academic productivity of young people with allergic rhinitis: A MASK-air® study

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Viera RJ, Pham-Thi N, Anto JM

J Allergy Clin Immunol Pract. 2022 Aug 20;S2213-2198(22)00820-0. doi: 10.1016/j.jaip.2022.08.015. Versión digital previa a la impresión.

Allergic rhinitis has a high prevalence, with more than 400 million affected globally. The aim of this study was to use real-world data to assess the impact of allergic rhinitis on academic performance (measured through a visual analog scale – VAS education – and the WPAI+CIQ:AS questionnaire), and to identify factors associated with the impact of allergic rhinitis on academic performance.

Data from 1970 users of the MASK-air® mHealth app between 13 and 29 years old was used. Researchers assessed the correlation between variables calculating the impact of allergies on academic performance (VAS education, WPAI+CIQ:AS impact of allergy symptoms on academic performance, and WPAI+CIQ:AS percentage of education hours lost due to allergies), and other variables. Furthermore, they have identified factors linked to the impact of allergic symptoms on academic productivity through statistical models.

VAS education was strongly correlated with the WPAI+CIQ:AS impact of allergy symptoms on academic productivity, VAS global allergy symptoms, and VAS nose. In multivariable regression models, immunotherapy showed a strong negative association with VAS education. Poor rhinitis control, measured by the combined symptom-medication score, was associated with worse VAS education, higher impact on academic productivity, and higher percentage of missed education hours due to allergy.

In conclusion, allergy symptoms and worse rhinitis control are correlated with worse academic productivity, while immunotherapy is linked to higher productivity.

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Current treatment strategies for seasonal allergic rhinitis: where are we heading?

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Ridolo E, Incorvaia C, Pucciarini F, et al.

Clin Mol Allergy. 2022 Aug 10;20(1):9. doi: 10.1186/s12948-022-00176-x.

Allergic rhinitis is caused by pollens and its symptoms include sneezing, nasal congestion, rhinorrhea, nasal itching and airflow obstruction. Allergic rhinitis diagnosis is usually made based on clinical history, skin prick tests and biomarkers measurement of specific IgE, but there is space for precision medicine to provide more accurate diagnostic tools.

The aim of this review was to describe the advances in the treatment of seasonal allergic rhinitis and evaluate the drugs to be used according to the grade of disease and the characteristics of the patients, and the role of allergen immunotherapy.

The experts concluded that treatment of allergic rhinitis includes various agents, depending on the severity of the disease. Allergen immunotherapy has high evidence of demonstrated efficacy demonstrated, and precision medicine is improving a lot the diagnosis of allergic rhinitis. Nevertheless, there is a long-term low adherence to allergen immunotherapy that needs to be resolved in the future.

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The ARIA approach of Value-Added Medicines: as-needed treatment in allergic rhinitis

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Bousquet J, Toumi M, Sousa-Pinto B, et al.

J Allergy Clin Immunol Pract . 2022 Aug 4;S2213-2198(22)00749-8. doi: 10.1016/j.jaip.2022.07.020. Online ahead of print.

Allergic rhinitis has a lifetime prevalence of up to 50% in some countries. This constitutes a high burden in social, school and work life. The aim of this report is to demonstrate that Value-Added Medicines such as the use of on-demand (PRN) nasal sprays may be enough to manage allergic rhinitis.

Value-Added Medicines consists of the research of existing medicines for new therapeutic purposes.

Current treatment for allergic rhinitis consists in continuous long-term treatments after clinical trials carried for at least 14 days with over 70% adherence. A new format to treat allergic rhinitis could be using on demand treatments according to symptoms, instead of the continuous treatment.

Real-world data found that 90% of the patients increase their medications to control symptoms during the pollen season, including oral H1-antihistamines, which is not in line with the recommendations.

As most patients who request for a primary care appointment have uncontrolled symptoms, they don’t follow the long-term prescription and self-medicate.

In conclusion, real-life data indicates that patients prefer on-demand treatment instead of continuous and this should be reflected in the upcoming orientations: individualized treatment according to symptom profile, severity, and duration, along with the patient’s preference for oral or intranasal administration.

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Mechanism of Lower Airway Hyperresponsiveness Induced by Allergic Rhinitis Yiting Liu

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Liu Y, Sha J, Meng C, Zhu D

J Immunol Res. 2022 Jul 12;2022:4351345. doi: 10.1155/2022/4351345. eCollection 2022.

Allergic rhinitis affects up to 40% of adults and 25% of children globally, however its mechanisms are not yet well elucidated. The majority of people with allergic rhinitis also have lower airway hyperresponsiveness, and an allergic rhinitis occurrence can increase this hyperresponsiveness.

The aim of this review was to understand the mechanism of the effect of allergic rhinitis on the lower airways. The effects of allergic rhinitis on the lower airways were studied in terms of epidemiology, anatomy, pathophysiology, nasal function loss, inflammation drainage, nasobronchial reflex, and whole-body circulatory flow to elucidate the mechanisms involved and provide patterns for future diagnosis, treatment, and experiments.

Researchers concluded that these mechanisms cannot be explained by a single mechanism, but by an interaction of several ones. The hyperresponsiveness of the lower airway may be caused by the rhinopulmonary reflex, lower airway drainage of allergens and nasal obstruction. However, it may also be caused by circulating factors such as IL-5 that stimulate bone marrow cells to differentiate into eosinophils and for IL-4 and IL-13 to upregulate adhesion- and chemotaxis-related proteins. More studies are needed to design future diagnosis and treatment approaches.

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Urticaria in Pregnancy and Lactation

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Kocatürk E, Podder I, Zenclussen AC, Kasperska Zajac A, Elieh-Ali-Komi D, Church MK, Maurer M

Front Allergy. 2022 Jul 7;3:892673. doi: 10.3389/falgy.2022.892673. eCollection 2022.

More women than men suffer from chronic urticaria, and they are mostly affected in their reproductive age, including pregnancy. Sex hormones affect mast cell biology and the hormonal changes that occur in pregnancy modulate inflammatory conditions such as chronic urticaria.

Pregnancy-related changes in the immune system, involving local adaptation of innate and adaptive immune responses and skewing of adaptive immunity toward a Th2/Treg profile were found to be related to changes in inflammatory diseases. The PREG-CU study provided the first insights on the effect of pregnancy on chronic urticaria, the outcomes of pregnancy in pregnant women with chronic urticaria and safety of urticaria medications and revealed that chronic urticaria improves during pregnancy in half of pregnant women, whereas it worsens in one-third. Also, two of five pregnant women with chronic urticaria experience flare-ups during pregnancy.

The international EAACI/GALEN/EuroGuiDerm/APAAACI guideline for urticaria recommends the same management strategy in pregnant and lactating women with chronic urticaria: start with standard doses of second-generation (non-sedative) H1 antihistamines and increase the dose up to 4-folds in case of no response. Antihistamine-refractory patients should be given omalizumab.

The PREG-CU study assessed treatments and their outcomes during pregnancy: H1 antihistamines, montelukast, omalizumab, cyclosporine-A and systemic steroids, however there isn’t still enough information on the management of chronic urticaria during pregnancy.

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Usage patterns of oral H1-antihistamines in 10 European countries: A study using MASK-air® and Google Trends real-world data

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Vieira RJ, Sousa-Pinto B, Anto JM, Sheikh A, Klimek L, Zuberbier T, Fonseca JA, Bousquet J

World Allergy Organ J. 2022 Jun 24;15(7):100660. doi: 10.1016/j.waojou.2022.100660. eCollection 2022 Jul.

Real-world data may help provide important data on different conditions, namely allergic rhinitis. However, evaluating this information can represent a challenge, as results from internet users may be influenced by different factors, from the real epidemiology of the conditions being evaluated, but also by the attention they get in the media.

This study compared real-world data from MASK-air®, a mobile app for allergic rhinitis on the usage of oral H1-antihistamines from 2016 to 2020 in 10 European countries with Google Trends data on the relative volume of search for these antihistamines.

5 different oral H1-antihistamines were selected for each country and the investigators perceived a perfect agreement on the order of antihistamine use in MASK-air® and Google Trends in France, Germany, Sweden, and the United Kingdom. Different levels of agreement were observed in the remaining countries (Italy, Poland, Portugal, Spain, Switzerland, Netherlands). Sales data-wise, there was a consistency in data from Google Trends and MASK-air® in France, Germany and the United Kingdom.

In conclusion, these results suggest that the mobile app MASK-air® data may have a common trend in relation to other real-world data, however, more studies are needed.

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Urticaria (angioedema) and COVID- 19 infection

Chronic Urticaria: The Need for Improved Definition

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Gómez RM, Bernstein JA, Ansotegui I, Maurer M

Front Allergy. 2022 Jun 9;3:905677. doi: 10.3389/falgy.2022.905677. PMID: 35769560; PMCID: PMC9234868.

Chronic urticaria is usually diagnosed after daily or almost daily presence of symptoms for more than 6 weeks. Urticaria symptoms include pruritic wheals or hives, accompanied by angioedema in 40% of cases. Up to 20% of patients have isolated angioedema. Chronic urticaria represents a significant burden which has been extensively reported with numerous validated patient-reported outcome measures that represent a significant impact on several aspects of life ranging from physical discomfort to personal mood changes (anxiety and depression) which frequently interferes with interpersonal relationships, daily activities including work and school. It is not a surprise that management of chronic urticaria is related to substantial

costs to health care systems due to recurrent medical visits and treatments. Consequently, it is crucial to generate awareness among healthcare payors and other stakeholders on the prevalence of chronic urticaria and its impact on quality of life and on the economic burden it has on society. There is no consensus on diagnostic and management criteria for CU, which makes this task more challenging.

In conclusion, the health and economic burden of chronic urticaria is significant and should not be underestimated. The significant impact of this condition requires that physicians and other health care providers understand how to properly identify and manage this condition.

An expert consensus on diagnostic and management criteria for chronic urticaria is needed.

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Compositional alteration of the nasal microbiome and Staphylococcus aureus-characterized dysbiosis in the nasal mucosa of patients with allergic rhinitis

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Kim HJ, Kim JH, Han S, Kim W

Clin Exp Otorhinolaryngol. 2022 Jun 8. doi: 10.21053/ceo.2021.01928. Epub ahead of print. PMID: 35680131.

Allergic rhinitis (AR) is an IgE and Th2-mediated inflammatory nasal disease. It originates from a sensitized immune response to inhaled allergens, which is thought to result from an imbalance in the Th1-Th2 immune regulation, resulting in increased levels of Th2 cytokines. Nasal ephitelial cells exposed to allergens induce Th2 inflammatory responses that spread to the upper airway mucosa. A commensalism host-microbial can be the basis of the innate immune responses in the nasal mucosa, and the microbial characteristics of the nasal mucus can impact the mechanisms of the initial allergic response. The aim of this study was to evaluate changes in the microbial composition in the nasal mucus of patients with AR and to understand the relationship between dysbiosis of the nasal microbiome and allergic inflammation.

The investigators analyzed the microbiota of 104 samples (n=42 participants with AR vs. n=30 healthy participants), in a total of 364,923 high-quality bacterial 16S ribosomal RNA-encoding gene sequence reads. The nasal mucus of healthy participants had mainly Proteobacteria (Ralstonia genus) and Actinobacteria (Propionibacterium genus) phyla, whereas the Firmicutes (Staphylococcus genus) phylum was significantly abundant in the nasal mucus of participants with AR. More sequencing data from 32 participants (healthy participants: n=15, AR patients: n=17) shown a greater abundance of Staphylococcus epidermidis, Corynebacterium

accolens, and Nocardia coeliaca, in 41.55% of mapped sequences in the nasal mucus of healthy participants. Patients with AR had a more pronounced dysbiosis of nasal microbiome and Staphylococcus aureus exhibited the greatest abundance (37.69%).

In conclusion, this study demonstrated that the nasal mucus of patients with AR have S. aureus–dominant dysbiosis, which suggests a role of host–microbial commensalism in allergic inflammation.

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Autoimmune chronic spontaneous urticaria

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Kolkhir P, Muñoz M, Asero R, Ferrer M, Kocatürk E, Metz M, Xiang YK, Maurer M

J Allergy Clin Immunol. 2022 Jun;149(6):1819-1831. doi: 10.1016/j.jaci.2022.04.010. PMID: 35667749.

Chronic spontaneous urticaria (CSU) symptoms include the recurrent spontaneous appearance of wheals and intense itch that may last from hours to days and occur for several years. Some patients develop localized and self-limiting angioedema. These manifestations result from a temporary increase in vascular permeability. Almost 13% of patients with CSU experience angioedema and do not develop wheals.

There are 2 main autoimmune mechanisms for CSU: type I autoimmune (autoallergic) CSU, which is associated with with IgE antibodies against autoantigens; and type IIb autoimmune CSU, which is mediated by autoantibodies that activate mast cells via IgE and FceRI. Type IIb autoimmune CSU is present in almost 10% of patients and is characterized by higher disease severity, concomitant autoimmune diseases, low levels of total IgE, elevated levels of IgG-anti–thyroid peroxidase, basopenia, eosinopenia, poor response to antihistamines and to omalizumab, and a good response to cyclosporine. Some new targeted therapies are under development, such as the anti-IgE, ligelizumab, and the Bruton’s tyrosine kinase inhibitors, fenebrutinib and remibrutinib, and an anti-IL-4Ra, dupilumab.

There are missing some studies on the overlap between autoallergic and type IIb autoimmune CSU and on the optimal management of both types of autoimmune CSU, with easy-to-perform, noninvasive and inexpensive markers to assess the treatment response.

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Comorbid allergic rhinitis and asthma: important clinical considerations

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Nappi E, Paoletti G, Malvezzi L, Ferri S, Racca F, Messina MR, Puggioni F, Heffler E, Canonica GW

Expert Rev Clin Immunol. 2022 Jun 19:1-12. doi: 10.1080/1744666X.2022.2089654. Epub ahead of print. PMID: 35695326.

There are several links between asthma and allergic rhinitis in the same patient, although these conditions are frequently underdiagnosed with suboptimal clinical outcomes. The two conditions coexist and share clinical, pathogenic, and pathophysiological mechanisms.

The aim of this article was to review the major links between the mechanisms of allergic rhinitis and asthma, as well as their treatment according to existing guidelines, focusing on treatment of allergic rhinitis in patients with comorbid asthma.

The authors concluded there are some unmet needs for patients with asthma and allergic rhinitis. Not all allergic rhinitis patients are screened for asthma. This screening should be conducted with a multidisciplinary approach to characterize the journey of patients with respiratory allergies to subsequently refer adequately to Allergy/Asthma centers. There may be advantages in treatment with allergen immunotherapy and/or biosimilars, which might represent encouraging advances in the management of both conditions.

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Intralymphatic immunotherapy with one or two allergens renders similar clinical response in patients with allergic rhinitis due to birch and grass pollen

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Ahlbeck L, Ahlberg E, Björkander J, Aldén C, Papapavlou G, Palmberg L, Nyström U, Retsas P, Nordenfelt P, Togö T, Johansen P, Rolander B, Duchén K, Jenmalm MC

Clin Exp Allergy. 2022 Jun;52(6):747-759. doi: 10.1111/cea.14138. Epub 2022 Apr 1. PMID: 35332591

Nearly 1/3 of the adult population of Sweden report allergic rhinitis. Although the prevalence of allergic sensitization is up to nearly half of the patients, there is a gap for a fast, efficient, and safe way to stimulate tolerance in patients with severe allergic rhinitis.

The aim of this study was to assess the safety and efficacy after intralymphatic immunotherapy with one or two allergens: birch- or grass pollen or both and to determine its immune modulatory effects including changes in spontaneous and allergen-induced cytokine and chemokine production, and proportions of T helper cell subsets in circulation.

People with severe birch and timothy allergy were randomized and received three doses of 0.1 ml of birch and 5-grass allergen extracts (10,000 SQ units/ml), or birch and placebo or 5-grass and placebo by ultrasound-guided injections into inguinal lymph nodes at monthly intervals. Characteristics reported before treatment and after each birch and grass pollen season included: rhinoconjunctivitis total symptom score, medication score and rhinoconjunctivitis quality of life questionnaire and circulating proportions of T helper subsets and allergen-induced cytokine and chemokine production (analysed by flow cytometry and Luminex).

After treatment with one or two allergens, the three groups related less symptoms, littler use of medication and better quality of life during the birch and grass pollen seasons, at an approximate rate. The most common adverse event reported was mild local pain. IgE levels to birch decreased, whereas birch-induced IL-10 secretion increased in all three groups. IgG4 levels to birch and timothy and skin prick test reactivity persisted mainly unaffected. Conjunctival challenge tests with timothy extract indicated a superior threshold for allergen. In all three groups, regulatory T cell frequencies were augmented 3 years after treatment.

In conclusion, intralymphatic immunotherapy with one or two allergens in people with grass and birch pollen allergy was effective and safe and may be associated with other immune modulatory responses.

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Clinical and histological characteristics during chronic urticaria with dermal neutrophilic infiltrate: Proposal of a diagnostic score

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A Brehon, P Moguelet, V Seta, E Amsler, A Fajac, A Barbaud, A Soria, JB Monfort

J Eur Acad Dermatol Venereol . 2021 Nov 6. doi: 10.1111/jdv.17788. Online ahead of print.

There are some arguments on whether neutrophilic urticaria (NU) is distinct from chronic spontaneous urticaria (CSU), although with no consensus. This study aimed to compare clinical, biological, and histological characteristics and therapeutic responses between NU and CSU.

This was an observational, retrospective study that included adults with chronic urticarial rash who had undergone a skin biopsy. One dermatologist and one cytopathologist blindly and independently reviewed the biopsies [cytology counting technique for a precise proportion of neutrophilic/eosinophilic polynuclear cells (PNN/PNEo)]. NU was defined by an inflammatory dermal infiltrate composed of at least 60% PNN, without leukocytoclasia/vasculitis.

Forty-four patients were included, and their biopsies were classified into two groups: NU (n=28) and CSU (n=16). From the bibliography, there are no characteristics related to PNN at histology, but an increase in erythrocyte sedimentation rate in the NU group (p=0.03). Colchicine also showed to be more effective in cases of significant neutrophilic infiltrate: 42.85% effectiveness in NU group versus 6.25% in CSU group.

Two other findings were a statistically associated relation with neutrophilic venulitis (p=0.04) (corresponding to an intraparietal aggregation of PNN without vasculitis) and a basophilic interstitial flame figure corresponding to degranulation of the PNN cytoplasm and exclusively associated with NU (p=0.04).

A diagnostic score was established using strict quantitative histological criteria (intensity of neutrophilic infiltrate, the existence of neutrophilic venulitis, basophilic flame figures, and intense leukocytoclasia), which allows the classification of urticarial eruptions into NU or UCS.

This score will allow diagnosis and homogenization of NU patients (it correctly classified 40 of the 44 patients from the study).

In conclusion, NU is an independent entity as some histological images were significantly (neutrophilic venulitis) or exclusively (basophilic flame figure) associated with an intense neutrophilic infiltrate. A prospective study is needed to validate this new score.

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Impact of Allergic Rhinitis and Asthma on COVID-19 Infection, Hospitalization and Mortality

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Jianjun Ren, et al.

J Allergy Clin Immunol Pract . 2021 Oct 30;S2213-2198(21)01202-2. doi: 10.1016/j.jaip.2021.10.049. Online ahead of print.

The COVID-19 pandemic has impacted worldwide health. Underlying diseases have been shown to affect the prevalence and outcomes of COVID-19. Allergic rhinitis and asthma can increase the susceptibility and severity of COVID-19, but it is not known to which extension. This study aimed to study the role of allergic rhinitis and/or asthma in COVID-19 infection, severity, and mortality and evaluate whether its long-term medication can affect COVID-19 outcomes.

A total of 70,557 persons who had a SARS-CoV-2 test between March 16 and December 31, 2020, in the UK Biobank were analyzed. The rate of COVID-19 infection, hospitalization, and mortality concerning existing allergic rhinitis and/or asthma were statistically analyzed, together with the impact of long-term medications and the risk of hospitalization and death due to COVID-19 infection.

People with allergic rhinitis had lower positive rates of SARS-CoV-2 tests (RR:0.75; 95%CI, 0.69-0.81, p<0.001), with men having a lower susceptibility (RR:0.74; 95%CI, 0.65-0.85, p<0.001) than women (RR:0.8; 95%CI, 0.72-0.9, p<0.001). People with asthma had comparable results if they were <65 years-old (RR:0.93; 95%CI, 0.86-1, p=0.044). People with asthma who tested positive for SARS-CoV-2 had a higher risk of hospitalization (RR:1.42; 95%CI, 1.32-1.54, p<0.001). COVID-19 mortality was not impacted by allergic rhinitis or asthma. There was no relation between COVID-19 infection and severity and conventional medications for allergic rhinitis and/or asthma.

In conclusion, allergic rhinitis and asthma (<65 years old) may be a protective factor against COVID-19 infection, with asthma increasing the risk of hospitalization.

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