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Immunological Responses and Biomarkers for Allergen-Specific Immunotherapy Against Inhaled Allergens

By | Artículos seleccionados, New, Selected articles

Mohamed H. Shamji, Janice A. Layhadi, Hanisah Sharif, Martin Penagos, Stephen R. Durham

J Allergy Clin Immunol Pract. 2021 Mar 27:S2213-2198(21)00363-9. doi: 10.1016/j.jaip.2021.03.029.

Patients with IgE-mediated rhinoconjunctivitis and/or bronchial asthma who do not respond to symptomatic treatment or have severe side effects are often recommended allergen immunotherapy. Prolonged treatment has shown long-term benefits in patients with moderate to severe allergic rhinitis. The long-term efficacy from allergen immunotherapy represents a decrease in IgE activation of mast cells and tissue eosinophilia, which is accompanied by early induction of regulatory T cells, immune deviation in favor of TH1 responses, and induction of local and systemic IgG and IgA antibodies. These antibodies, whose primary function is to be protective, can prevent the formation of allergen-IgE complex and subsequent activation of the mast cells and TH2 facilitated by IgE.

Some studies demonstrate the importance of innate responses mediated by type 2 dendritic cells and innate lymphoid cells in allergic inflammation. Type 2 dendritic cells and lymphoid cells are regulated by cytokines derived from the respiratory epithelium. New subsets of regulatory cells induced by immunotherapy include:

  • IL-35-producing regulatory T cells,
  • Regulatory B cells,
  • A subset of T follicular regulatory cells, and
  • IL-10-producing group 2 innate lymphoid cells.

These regulatory cells may represent biomarkers that will predict the clinical response to immunotherapy and evaluate the efficacy, safety, and long-term tolerance.

More studies are required to identify candidate biomarkers as a routine immune-monitoring tool for assessing allergen immunotherapy response.

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B cells and upper airway disease: allergic rhinitis and chronic rhinosinusitis with nasal polyps evaluated

By | New, Selected articles

Harsha H Kariyawasam & Louisa K James

Expert Rev Clin Immunol. 2021 Apr 1:1-15. doi: 10.1080/1744666X.2021.1905527. Epub ahead of print.

Allergic rhinitis and chronic rhinosinusitis with nasal polips (CRSwP) are upper airway immunological conditions with complex mechanisms of action. Airway local mucosal B cells are drivers for the conditions, with B cells migrating into the airway mucosa when there is an airway injury.

B-cells are very important in the defense, tissue surveillance, and immune modulation of the upper airways. Allergic rhinitis and CRSwP are two of the upper airway conditions that can be identified as expressing B-cells or dysregulating their function within T2-high mucosal inflammatory states. B cells can drive T2 inflammatory states via functional antibody production and also through interactions with commensal microbes and other recruited inflammatory cells such as Th2 cells and eosinophils, leading to immune amplification and dysregulation.

This review aimed to report the existing knowledge of the key role of B cells in allergic inflammatory upper airway disease and highlight the need for more focus on human B-cell-directed disease-context-specific upper airway studies.

The authors concluded that there is a lack of studies concerning the role of B-cell overexpression and dysfunction, especially those which relate sinonasal infection and mucosal inflammation. It is important to understand how respiratory inflammation, together with augmented or impaired B-cell function, increases and dysregulates immune signaling pathways in allergic rhinitis and CRSwP to develop novel B-cell disease-specific therapeutic interventions with molecular manipulation.

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Chronic Spontaneous Urticaria

The Pathogenesis of Chronic Spontaneous Urticaria: The Role of Infiltrating Cells

By | Artículos seleccionados, New, Selected articles

Ana M. Giménez-Arnau, Laurence DeMontojoye, Riccardo Asero, Massimo Cugno, Kanokvalai Kulthanan, Yuhki Yanase, Michihiro Hide, Allen P. Kaplan

J Allergy Clin Immunol Pract. 2021 Apr 3:S2213-2198(21)00374-3. doi: 10.1016/j.jaip.2021.03.033. Epub ahead of print.

In chronic spontaneous urticaria, cutaneous mast cells are activated to initiate the process. There are different triggers, including the hypothesis that it is an autoimmune disease not driven by exposure to an exogenous agent.

It is characterized by a perivascular non-necrotizing cellular infiltrate around small venules of the skin. These infiltrates include CD4+ lymphocytes, Th2 and Th1 subtypes, Th17 cell-derived cytokines, neutrophils, eosinophils, basophils and monocytes, which contribute to the pathogenesis and responsiveness to steroid

This review focuses on each cell’s contribution to the inflammatory response and a view toward developing therapeutic options.

Immunohistochemistry can help reveal the function of each cell within the perivenular infiltrate. Rituximab efficacy is probably due to the prevention of autoantibody synthesis. Corticosteroids inhibit the function of T lymphocytes and eosinophils and prevent egress of most cell types from the bloodstream into tissues.

In the future, there may be studies that include drugs with increasing specificity in the course of urticaria, such as secukinumab (targets IL-17), dupilumab (targets TH-2 dependent cytokines, IL-4 and IL-3), mepolizumab, reslizumab and benralizumab (target TH2 and eosinophil-dependent cytokines), avdoralimab (complement C5a receptor) and lirentelimab (targets Siglec-8 on the surface of mast cells and eosinophils).

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Use of H-1 Antihistamine in Dermatology: More than Itch and Urticaria Control: A Systematic Review

By | Artículos seleccionados, New, Selected articles

Chang-Yu Hsieh, Tsen-Fang Tsai

Dermatol Ther (Heidelb). 2021 Apr 12. doi: 10.1007/s13555-021-00524-w. Epub ahead of print.

H1-antihistamines are known for their effects in suppression of pruritus, especially in urticaria. However, there are many other dermatological uses of H1-antihistamines, such as scarring and nonscarring alopecia, acne, Darier disease, eosinophilic dermatoses, paraneoplastic dermatoses, psoriasis, lichen nitidus, radiation dermatitis, skin dysesthesia, and cutaneous malignancies.

This review includes a literature search on articles that report the use of H1-antihistamines.

It is the modulation of the immune system, inflammatory cytokines, and mast cells that explain why H1-antihistamines are effective in some autoimmune conditions, such as Kaposi sarcoma, melanoma, and alopecia areata. Some eosinophilic dermatosis may be relieved with the use of cetirizine and bilastine due to their effects on the chemotaxis of eosinophils. Hydroxyzine, together with GABA receptor agonists, may have an effect on cutaneous dysesthesia. A combination of antihistamines with isotretinoin helps control acne better, probably due to the inhibition of the production of sebum. The reversing vascular effect of histamine seems to be of interest for erythema, edema, and pain control in radiation dermatitis and erythromelalgia.

New properties of antihistamines have also been studied in vitro: antibacterial activity, antiangiogenesis, and antifibrosis.

H1-antihistamines may improve symptoms of some conditions when used alone or in combination with other treatments; however, this evidence is still limited. More studies are needed to assess the efficacy and dosage of H1-antihistamines in other dermatological conditions.

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Systematic review of measures of disease severity in rhinitis

By | New, Selected articles

Andraia R. Li, Kathy Zhang, Priyanka D. Reddy, Shaun A. Nguyen, Amar Miglani, Jacob Fried, Mariam I. Nguyen, Rodney J. Schlosser

Int Forum Allergy Rhinol. 2021 Mar 27. doi: 10.1002/alr.22794. Epub ahead of print.

Rhinitis is an inflammation of the nasal mucosa with itching, sneezing, rhinorrhea, and congestion. It may be classified into allergic rhinitis and nonallergic rhinitis. The ARIA (allergic rhinitis and its impact on asthma) guidelines categorize allergic rhinitis upon intermittent or persistent timing of symptoms and mild, moderate or severe. The objective of this review was to assess if patient-reported outcome measures (PROMs) and clinical physiological measures vary, and which factors impact rhinitis.

A systematic search identified allergic rhinitis and nonallergic rhinitis that reported Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), total nasal symptom score (TNSS), or visual analog scale (VAS) scores, and physiologic measures (peak nasal inspiratory flow and nasal airflow). The relationship between PROMs, physiologic measures, and associated factors was statistically evaluated.

The review included 171 studies, which reflected 33843 patients. Patients with allergic rhinitis had more severe symptoms than nonallergic rhinitis ones. There was no significant correlation between PROMs and demographic factors, comorbidities, or physiologic measures. Statistical analysis identified a correlation between the worse quality of life and shorter disease duration.

In conclusion, patients with rhinitis have a more severe impact in their quality of life in the presence of allergy with variable impact upon specific symptom subdomains. PROMs did not show a correlation with demographic factors, comorbidities, or physiologic measures of nasal airflow.

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

By | Artículos seleccionados, 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

By | Artículos seleccionados, Selected articles

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, 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 | Artículos seleccionados, 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 | Artículos seleccionados, 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 | Artículos seleccionados, 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, 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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