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Selected articles

Manifesto on united airways diseases (UAD): an Interasma (global asthma association – GAA) document

By | Artículos seleccionados, New, Selected articles

Angelica Titiu, et al.

Received 21 Oct 2020, Accepted 17 Jan 2021, Accepted author version posted online: 25 Jan 2021, Published online: 05 Mar 2021

The large amount of evidence and the renewed interest in upper and lower airways involvement in infectious and inflammatory diseases has led Interasma (Global Asthma Association) to take a position on United Airways Diseases (UAD). Starting from an extensive literature review, Interasma executive committee discussed and approved this Manifesto developed by Interasma scientific network (INES) members.

The manifesto describes the evidence gathered to date and defines, states, advocates, and proposes issues on UAD (rhinitis, rhinosinusitis and nasal polyposis), and concomitant/comorbid lower airways disorders (asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, obstructive sleep apnoea) with the aim of challenging assumptions, fostering commitment, and bringing about change. UAD refers to clinical pictures characterized by the coexistence of upper and lower airways involvement, driven by a common pathophysiological mechanism, leading to a greater burden on patient’s health status and requiring an integrated diagnostic and therapeutic plan. The high prevalence of UAD must be taken into account. Upper and lower airways diseases influence disease control and patient’s quality of life.

The Manifesto concludes that patients with UAD need to have a timely and adequate diagnosis, treatment, and, when recommended, referral for management in a specialized center. Diagnostic testing including skin prick or serum specific IgE, lung function, fractional exhaled nitric oxide (FeNO), polysomnography, allergen-specific immunotherapies, biological therapies and home based continuous positive airway pressure (CPAP) whenever these are recommended, should be part of the management plan for UAD. Education of medical students, physicians, health professionals, patients and caregivers on the UAD is needed.

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Biologics for the Use in Chronic Spontaneous Urticaria: When and Which

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Marcus Maurer, David A. Khan, Daniel Elieh Ali Komi, Allen P. Kaplan

J Allergy Clin Immunol Pract . 2021 Mar;9(3):1067-1078. doi: 10.1016/j.jaip.2020.11.043.

Urticaria treatment has evolved a lot during the past decade. Current guidelines for the treatment of chronic spontaneous urticaria recommend the use of omalizumab, an IgE-targeted biologic. IgE has high-affinity to the receptor FcεRI, and degranulate skin mast cells, which are responsible for the development of signs and symptoms of urticaria, itchy wheals and angioedema. This study aims to review the existing understanding of the pathogenesis of chronic urticaria and its autoimmune endotypes.

Omalizumab is the only licensed biologic for use in chronic urticaria from 12 years old age. It is recommended as the third step of the therapy in patients who have failed standard or high-dose second-generation antihistamines and is generally well tolerated. Omalizumab has multiple potential mechanisms of action in chronic urticaria, with effects on mast cells and basophils, reducing mediators’ release and decreasing FcεRI expression. It has been approved for chronic urticaria at doses of 150 or 300 mg every 4 weeks. Poor responders may benefit from shortening the dosing interval to every 2 or 3 weeks or by adjunctive therapy with cyclosporine 3 mg/kg/day for 4 months each.

Some other biologic drugs used as off-label in chronic urticaria include dupilumab, benralizumab, mepolizumab, reslizumab, and secukinumab. New biologics under development aim to reduce mast cell activation by blocking activating pathways or engaging inhibitory receptors or mast cell numbers. These include ligelizumab and GI-301, avdoralimab, tezepelumab, lirentelimab, LY3454738, and CDX-0159 at different stages of development.

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Health Disparities in Allergic and Immunologic Conditions in Racial and Ethnic Underserved Populations

By | Artículos seleccionados, New, Selected articles

Carla M. Davis, et al.

J Allergy Clin Immunol . 2021 Mar 10;S0091-6749(21)00365-1. doi: 10.1016/j.jaci.2021.02.034. Online ahead of print.

Health disparities negatively impact groups with greater social or economic obstacles in health based on race, ethnicity, religion, socioeconomic status, gender, age, disability, sexual orientation, and/or geographic location. The American Academy of Allergy, Asthma, and Immunology participated in a Commission to End Health Disparities 10 years ago. This study describes health disparities in allergy/immunology in racial and ethnic underserved populations and how they address people with allergic rhinitis and other allergic conditions.

Certain racial and ethnic populations are frequently not included in guidelines of care for patients with allergic rhinitis. Racial minorities show less allergic rhinitis prevalence, probable due to variability in self-reporting the disease: a 2017 report revealed that 5% of black children and 5% of Hispanic children had allergic rhinitis, compared to 9% of white children.

It is known that allergic rhinitis significantly impacts the quality of life and morbidity in underserved populations, and allergic rhinitis control was associated with fewer school absences.

Studies have shown that low-income and minority groups are less likely to receive allergen immunotherapy and have highlighted that additional burdens faced by these minorities can contribute to fewer resources needed to adhere to AIT schedules.

In conclusion, adherence could be improved when medical resources are provided to increase specialty care access in underserved communities. Observational and interventional studies are important for allergic rhinitis diagnosis, management, and outcomes for these underserved populations. A multi-level approach should also be addressed, involving patients, health providers, local agencies, professional societies, and national governmental agencies.

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Differences in gut microbiota between allergic rhinitis, atopic dermatitis, and skin urticaria: A pilot study

By | New, Selected articles

Yu-Jih Su, Sheng-Dean Luo, Chung-Yuan, Ho-Chang Kuo

Medicine (Baltimore) . 2021 Mar 5;100(9):e25091. doi: 10.1097/MD.0000000000025091.

Allergic rhinitis and urticaria prevalence are increasing. The intestinal flora or microbiota may influence their pathogeneses. This study aimed to compare differences between the gut microbiota of people with atopic dermatitis, allergic rhinitis, and chronic urticaria.

The study included 19 participants with eczema, nine with urticaria, and 11 with allergic rhinitis. The microbiota was compared by examining participants’ fecal samples using 16S ribosomal ribonucleic acid amplicon sequencing and bioinformatics and statistical analysis.

All three groups of patients had similar clinical data. The microbiota was substantially different between participants with atopic dermatitis, allergic rhinitis, and chronic urticaria, demonstrating gut-skin and gut-nose axes. Bacteroidales species were found in skin allergies more than in allergic rhinitis. This may represent a link between gut flora and skin allergy because gut flora colonies differ significantly between them.

In conclusion, different conditions have heterogeneous microbiota. Bacteroidales species could represent a link between gut flora and skin allergy, with Bacteroids Plebeius DSM 17135 being significantly associated with urticaria. Ruminococcaceae is also associated with allergic diseases.

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The role of mobile health technologies in stratifying patients for AIT and its cessation. The ARIA-EAACI perspective

By | New, Selected articles

Jean Bousquet, et al.

J Allergy Clin Immunol Pract . 2021 Mar 1;S2213-2198(21)00240-3. doi: 10.1016/j.jaip.2021.02.035. Online ahead of print.

Allergic rhinitis treatment options include allergen immunotherapy (AIT). There are different guidelines and national practice parameters or care pathways for AIT. However, the decision to prescribe AIT should be personalized and based on the importance of the allergens and the persistence of the symptoms, even when using appropriate medications.

The practice of medicine has been revolutionized by digital transformation, including mHealth and artificial intelligence, where the patient is placed at the health system’s center. There are different biomarkers associated with mHealth and clinical decision support systems. However, there are two conditions that should be considered before any mHealth tool is used: comply with privacy regulations and validation. Of the few tools available for allergic rhinitis, evidence-based development was found for four Apps: MASK-air, AllergyMonitor, Polle, and Air Rater.

This review focuses on patient stratification for AIT, symptom medication scores for follow-up, clinical trials, and the European Academy of Allergy and Clinical Immunology (EAACI).

Patient stratification is required to:

–           Identify the best candidates for intervention through complex care management

–           Reduce the time and resources needed to match a patient to a care management programme

–           Optimize costs.

Symptom medication scores are needed to assess the efficacy of AIT, especially in clinical trials and observational studies.

The EAACI task force was created to evaluate the state of the art and the future potential of technology in the field of allergic rhinitis. This task force evaluated the design, user engagement, content, potential of inducing behavioural change, credibility, and privacy policies of mHealth products.

In conclusion, mHealth technology is a potential tool to aid AIT’s decision-making, increase adherence, monitor efficacy and safety, and identify responders to the treatment. However, these tools may also have their inconveniences, namely if they are improperly used or are not validated.

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Association of Serum Vitamin D and Immunoglobulin E Levels with Severity of Allergic Rhinitis

By | New, Selected articles

Nukhbat U. Awan, Shahzada K. Sohail, Fatima Naumeri, Shahida Niazi, Khalid Cheema, Samina Qamar, Syeda Fatima Rizvi

Cureus. 2021 Jan 25;13(1): e12911. doi: 10.7759/cureus. 12911..

Allergic rhinitis symptoms include inflammation of the nasal mucosa and affect up to 30-40% of the population with an increasing prevalence. This study’s objective was to assess the relationship between the severity of allergic rhinitis and serum vitamin D and immunoglobulin E (IgE) levels.

This was a case-control study conducted between June and September 2020, which included a total of 224 participants divided into two groups. Group A included 112 participants with moderate to severe asthma symptoms, and group B (control) included 112 participants with mild asthma symptoms after treatment of allergic rhinitis. Both groups were compared by assessing the mean difference between serum IgE and serum vitamin D levels. The relationship was evaluated by logistic regression and odds ratio.

There were 106 female participants (47,3%), with a mean age of 26.78±8.92 years old in group A and 25.72±8.12 years in group B. Mean serum IgE levels were 383.69±154.86 IU/mL for group A and 373.03±106.83 IU/mL for group B (p=0.0001). Mean serum vitamin D levels were 16.24±6.7 ng/mL for group A and 26.92±35 ng/mL for group B (p=0.0001).

Participants with low vitamin D levels were 24 times more likely to develop moderate to severe allergic rhinitis disease. In conclusion, this study demonstrated that IgE levels are increased in moderate to severe allergic rhinitis compared to mild allergic rhinitis. The deficiency of vitamin D is related to increased severity of allergic rhinitis symptoms.

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Expert consensus on practical aspects in the treatment of chronic urticaria

By | Artículos seleccionados, New, Selected articles

Andrea Bauer, et al.

Allergo J Int . 2021 Feb 24;1-12. doi: 10.1007/s40629-021-00162-w. Online ahead of print.

Chronic urticaria is a frequent disease and represents a large burden for many patients because symptoms are often not adequately controlled. Evidence-based diagnosis and treatment of urticaria are part of the existing guidelines. However, these do not address some questions from everyday clinical practice. This study aimed to summarize the results from a digital meeting held in May 2020, where specialists discussed the practical aspects of chronic urticaria to formulate supporting aids for everyday clinical treatment.

It is known that the diagnosis of chronic urticaria is prompt by a physical examination, anamnesis, and laboratory testing, and treatment should be performed similarly, whether there are wheals, angioedema, or both. A second-generation non-sedating H1 antihistamine is the first treatment of choice. If urticaria doesn’t clear in two to four weeks, a higher dosage is recommended. If there is no improvement after two to four weeks, additional treatment with approved IgE antibodies, such as omalizumab should be administered.

When there is no therapeutic success after six months of treatment with omalizumab, it is recommended an off-label treatment with cyclosporin A in addition to existing therapy with H1 antihistamines. In case of acute exacerbations, oral-systemic glucocorticoids can be given up to 10 days to decrease duration and activity.

In conclusion, these recommendations add on to the existing treatment guidelines and support clinical practice with people with chronic urticaria, with the objective to help them live with no symptoms and a better quality of life, ensuring that the treating physician provides good documentation and education to the patient about off-label use of drugs.

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Exaggerated neurophysiological responses to stressor in patients with chronic spontaneous urticaria

By | Artículos seleccionados, Selected articles

Engel-Yeger B, Maurer M, Hawro T, Zubedat S, Avital A, Kessel A

Clin Exp Allergy. 2021 Feb 22. doi: 10.1111/cea.13854. Versión digital previa a la impresión.

Chronic spontaneous urticaria impacts the quality of life and emotional well-being of people suffering from it. People with chronic spontaneous urticaria have increased emotional distress, anxiety, depression, somatoform disorders, and stress, which correlates with the activity of urticaria.

People with chronic spontaneous urticaria may be more susceptible to stressors and thus have increased stress responses. Stress responses may lead to the secretion of neuropeptides from sensory skin nerves, interacting with mast cells and releasing histamine, causing chronic spontaneous urticaria attacks.

This study compared the stress responses to acoustic startle and stress levels between 47 people with chronic spontaneous urticaria and 56 healthy volunteers. Stress levels were evaluated with the Perceived Stress Scale.

The stressor exposure session was three minutes long. Participants were exposed to 40 randomly spaced auditory startle stimuli. Responses to the stimuli were measured by electromyography assessment of the contraction amplitude of the orbicularis oculi muscle for each startle stimulus and the number of eye blinks.

People with chronic spontaneous urticaria had stronger responses to acoustic startles with high mean electromyography values and a higher number of eye blinks than healthy volunteers. People with urticaria also had longer stress responses and stress levels, as assessed by the Perceived Stress Scale.

In conclusion, people with urticaria have increased stress responses using objective and subjective measures. Underlying neuroimmune mechanisms should be studied further, as it is possible that stress predisposes to chronic spontaneous urticaria and that chronic spontaneous urticaria increases stress, forming a disease amplification loop.

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Antihistamine and cationic amphiphilic drugs, old molecules as new tools against the COVID-19?

By | Artículos seleccionados, Selected articles

Clara Gitahy Falcao Faria, eta al.

Med Hypotheses . 2021 Jan 24;148:110508. doi: 10.1016/j.mehy.2021.110508. Online ahead of print.

Some studies demonstrate that psychoactive drugs may protect from SARS-CoV-2 infection. H1 antihistamines and cationic amphiphilic drugs (CAD) have been identified as potentially effective against coronavirus. CAD lead to intracellular trafficking disturbances, which disrupt viral entry and replication.

Many antihistamines are also CAD, acting on both virus entry and exerting a negative regulation on IL-6 release from human lung macrophages, which are secreted in great amounts during the cytokine-storm of COVID-19.

H1 antihistamines in general and phenothiazines and derivates, in particular, can represent a useful strategy against SARS-CoV-2 at different stages, from the prophylaxis to complications’ prevention. Also, a sample of 219000 health records demonstrated that three antihistamines (azelastine, diphenhydramine, and hydroxyzine) were associated with reduced incidence of SARS-CoV-2 in people older than 61.

Although more recent studies suggest that a psychiatric disorder can increase the risk of COVID-19 or developing a severe form, the authors came to the assumption that mental health patients, once hospitalized due to COVID-19, have their risk increased due to the possible reduction or interruption of medications with a potential effect against SARS-CoV-2.

In conclusion, the best tolerated drugs with few side effects can become prophylactic candidates to reduce the risk of infection by SARS-CoV-2 in the general population. However, the benefit-risk should always be assessed.

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Predictors of treatment response in chronic spontaneous urticaria

By | Artículos seleccionados, Selected articles

Jie Shen Fok, Pavel Kolkhir, Martin K. Church, Marcus Ma

Allergy . 2021 Feb 4. doi: 10.1111/all.14757. Online ahead of print.

Chronic spontaneous urticaria consists of wheals, angioedema, or both for more than six weeks. Patients with chronic urticaria have an impaired quality of life that impacts their relationships, work, and sleep. Existing treatment guidelines recommend a treatment escalation from second-generation H1-antihistamines to omalizumab and cyclosporine until complete response.

This review aimed to evaluate the predictors of response and nonresponse to these treatments in chronic spontaneous urticaria.

A systematic search was executed using the PubMed/MEDLINE database, and 73 studies were included. Different levels of evidence were categorized as strong (robust predictors), weak (emerging predictors), or not associated.

High disease activity, high C-reactive protein levels, and D-dimer are robust predictors of a poor or no response to H1-antihistamines. Low serum levels of total IgE may predict omalizumab response. Cyclosporine response may be predicted by a positive basophil histamine release assay, while low total IgE is an emerging predictor.

In conclusion, there are clinical and biochemical predictors of nonresponse to H1-antihistamines and omalizumab, as well as predictors of response to cyclosporine. These predictors can help specialists counsel patients and prioritize patients at risk of nonresponse to be assessed and switched to more effective treatments.

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Repositioning of histamine H1 receptor antagonist: Doxepin inhibits viropexis of SARS-CoV-2 Spike pseudovirus by blocking ACE2

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Shuai Ge, Xiangjun Wang, Yajing Hou, Yuexin Lv, Cheng Wang, Huaizhen He

Eur J Pharmacol . 2021 Jan 23;896:173897. doi: 10.1016/j.ejphar.2021.173897. Online ahead of print.

The spread of the coronavirus SARS-CoV-2 has continuously threatened our global health since the end of 2019. There is an urgent need for effective drugs and vaccines to fight the COVID-19; however, this may take longer than expected. One of the feasible strategies to combat this situation is to repurpose existing drugs, shorten the development time, and fight this virus outbreak.

It has been shown that histamine H1 receptor antagonists (H1-antihistamines) have broad-spectrum antiviral effects.

This study’s objective was to screen potential drugs among histamine H1 receptors that may have the capacity to inhibit the infection by the SARS-CoV-2 virus.

Five FDA-approved H1-antihistamines were found to have bioaffinity to angiotensin-converting enzyme 2 (ACE2), based on the model of ACE2 overexpressing HEK293T cell membrane chromatography.

Afterward, the interaction between these drugs and ACE2 was determined by frontal analysis and surface plasmon resonance (SPR), which also consistently demonstrated that these hits bind to ACE2 at micromolar levels of affinity.

A pseudovirus assay has helped identify that doxepin could inhibit SARS-CoV-2 spike pseudovirus from entering the ACE2-expressing cell, reducing the infection rate to 25,8%.

Doxepin may be a viable drug candidate for clinical trials to fight COVID-19. It is now recommended to compare these results with in vivo results and provide evidence for clinical trials’ final attempt. (215 words)

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Allergic rhinitis: impact on quality of life of adolescents

Allergic rhinitis: impact on quality of life of adolescents

By | Artículos seleccionados, Selected articles

C S Rosario

Eur Ann Allergy Clin Immunol . 2020 Nov 12. doi: 10.23822/EurAnnACI.1764-1489.176. Online ahead of print.

One of the faster phases of human development is adolescence, with biological maturity anteceding psychosocial maturity. 15% of young people between 13 and 14 years old suffer from allergic rhinitis, double that of those with 6-7 years old. The prevalence of allergic rhinitis is higher in boys up to 10 years old. It reverses to girls having a higher prevalence during adolescence, and by adulthood, there are no differences in prevalence between genders.

Changes that occur in adolescence have health consequences over the life-course and impact the quality of life. Allergic rhinitis has a significant impact on the quality of life of adolescents and their parents: most antihistamines have sedating effects, school absences, and lower performance due to distraction, fatigue, and irritability. It also has a negative impact on the parents, who may become anxious, overprotective, and need to miss work.

Digital technology is the way to help an original approach to characterize allergic rhinitis signs and symptoms, as well as their connection with other allergic conditions. The treatment’s achievement lies in the partnership between teenagers with allergic rhinitis and mobile technology, letting them have more information available on the disease and its treatment.

In conclusion, there is some knowledge on challenges adolescents with asthma face, but some information lacks allergic rhinitis challenges.

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COVID-19 and allergy: How to take care of allergic patients during a pandemic?

COVID-19 and allergy: How to take care of allergic patients during a pandemic?

By | Selected articles

Antonella Cianferoni, Martina Votto

Pediatr Allergy Immunol. 2020 Nov;31 Suppl 26:96-101. doi: 10.1111/pai.13367.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease, also known as COVID-19, constitutes a new threat for everybody due to its high infection rate and morbidity and mortality in vulnerable populations. People with allergic rhinitis need continuity of care by allergists during the pandemic. Allergists face the challenge of protecting themselves from becoming infected and providing care to people with allergic rhinitis. They need to be ready to work safely with adequate changes in their practice until either a universal vaccine or herd immunity is achieved. Some of the diseases under the attention of allergists are not considered risk factors but have symptoms such as cough and sneezing in differential diagnosis with COVID-19.

Below is a summary of how to treat specific conditions in the allergy office:

  • Skin testing can be delayed as often information is not essential for the patient’s immediate treatment.
  • Food challenges may be delayed except for peanut challenge in infants or for introducing a food critical for appropriate nutrition to avoid intervention such as a G tube or NG tube placement.
  • Patients on immunotherapy, the administration can be spaced to up to 6 weeks to reduced visits during the pandemic, with the possibility of dose adjustment until the regular schedule is resumed. However, the initiation of immunotherapy should be avoided.
  • Spirometry may cause aerosolization. Therefore, people with COVID-19 or flu-like symptoms should not be tested. All routine testing should be postponed during the pandemic phase.
  • Asthma is a risk factor for severe disease in the case of coronavirus 2 infections. Nevertheless, current recommendations are to continue to follow guidelines of treatment.
  • Patients with allergic rhinitis should continue their treatment. There is no evidence that these patients are at risk of severe complications during a COVID-19 infection. Allergic rhinitis may be evaluated via remote medicine, or telephone and evaluation of allergy may be postponed.

Any suggestions may change rapidly based on the evolving situation of each territory. Limiting in-person visit may have significant financial consequences, and also, at a certain point, delay of procedure may represent a more substantial risk for the patient than the potential risk of being exposed to COVID-19 and should be take under consideration.

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The usage, quality and relevance of information and communications technologies in patients with chronic urticaria:

The usage, quality and relevance of information and communications technologies in patients with chronic urticaria: A UCARE study

By | Selected articles

Marcus Maurera, et al.

World Allergy Organ J . 2020 Oct 30;13(11):100475. doi:10.1016/j.waojou.2020.100475. eCollection 2020 Nov.

Chronic urticaria is characterized by itchy wheals, angioedema, or both for six weeks or more. It impacts patients’ physical and emotional quality of life. People with chronic urticaria and other chronic conditions are information seekers from information and communications technologies (ICTs). This study aimed to evaluate the frequency of use and preference of ICTs from chronic urticaria patients.

This was a cross-sectional study that included 1800 patients with chronic spontaneous urticaria or chronic inducible urticaria, over 12 years old, recruited from primary healthcare centers, university hospitals, or specialized clinics UCARE (Urticaria Centers of Reference and Excellence) in 16 countries. Patients were requested to complete a 23-item questionnaire with questions about the use of ICT, including the type, frequency, preference, and quality. Answers were registered in a database. ICTs were then categorized into three groups: one-to-one: SMS, WhatsApp, Skype, and email; one-to-many: YouTube, web browsers, blogs or forums; and many-to-many: Instagram, Twitter, Facebook, and LinkedIn.

Globally, most chronic urticaria had access to ICT platforms (99.6%) and internet access (96.7%). One-to-one ICT platforms were used most often (85.4%), followed by one-to-many ICTs (75.5%) and many-to-many ICTs (59.2%). The use of ICT platforms increased with patient education. One-to-many was preferred for general health information and chronic urticaria information. For chronic urticaria specific information, 3 in every 4 patients used a web browser, 20.9% used YouTube, and 13.6% used Facebook. One in five patients didn’t use any form of ICT. The quality of information was rated as very interesting and of good quality for general health information (53.5%) and CU-related information (51.5%) compared to other categories.

In conclusion, the use of information and communications technologies for health and urticaria specific information is very high in all countries, with web browsers being the preferred platform.

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Cold urticaria what we know and what we do not know

Cold urticaria what we know and what we do not know

By | Selected articles

Natalya Maltseva, et al.

Allergy . 2020 Nov 28. doi: 10.1111/all.14674. Online ahead of print.

Cold urticaria is a subtype of chronic inducible urticaria, characterized by wheals and/or angioedema that occur after cold exposure. It constitutes a challenging clinical problem due to the risk of cold-induced anaphylaxis, its long duration, and diagnostic difficulties with atypical cold urticaria. The classification of cold urticaria includes typical and atypical subtypes. Recent studies and guidelines have progressed its understanding and management.

It is thought to involve the formation of autoallergens and IgE to these autoallergens induced by cold, which provoke a release of mediators from skin mast cells.

It is known that cold-induced wheals develop on rewarming and resolve within an hour and that anaphylaxis can occur. Its diagnosis is based on the patient’s history and cold stimulation testing. Other tests include searching for underlying infections, to be done if the patient has a relevant record. The management of cold urticaria includes avoiding cold, using nonsedating antihistamines, and, if needed, omalizumab.

Questions unanswered include cold urticaria epidemiology, underlying pathomechanisms, clinical heterogeneity, and treatment outcomes.

An international multicenter observational prospective study COLD-CE is being conducted to globally improve the understanding of cold urticaria and cold anaphylaxis, with their pathophysiology representing a research priority. Oropharyngeal angioedema and/or cold anaphylaxis in cold urticaria require further studies of innovative agents. The use of genomic, postgenomic, and machine learning approaches is the next frontier in research leading to novel therapeutic targets.

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