Molecular Allergy Diagnosis in Clinical Practice: Frequently Asked Questions.

Considerable progress has been made in the field of molecular biology in recent years, enabling the study of sensitization to the individual components of an allergenic source, a practice that has been termed molecular allergy diagnosis (MD) or component-resolved diagnosis (CRD). The present review provides the clinician with a practical approach to the use of MD by answering questions frequently asked by physicians on how MD can help improve the diagnosis of allergy in daily clinical practice. The article is divided into 3 sections. First, we provide a brief review of the importance for the clinician of knowing the main allergens in the different allergenic sources, their structure, and their in vitro cross-reactivity before approaching MD (section A). Second, we review the usefulness of MD in clinical practice (section B) and answer frequently asked questions on the subject. Finally, section C addresses the interpretation of MD and its integration with other tools available for the diagnosis of allergy.

Consensus on the Definition of Control and Remission in Chronic Urticaria.

The terms control and remission and other key terms used in chronic urticaria (CU) such as flare-up, relapse, exacerbation, and recurrence have not been fully defined in the literature. Disease monitoring and treatment goals in clinical practice are not well established. After a qualitative appraisal of available evidence, we aimed to find a consensus definition of control and remission, clarify key terminology, provide guidance on how to monitor the disease, and establish treatment goals in clinical practice. A modified Delphi consensus approach was used. Based on a literature review, a scientific committee provided 137 statements addressing controversial definitions and terms, available patient-reported outcomes (PROs), and recommendations on how to measure therapeutic objectives in CU. The questionnaire was evaluated by 138 expert allergists and dermatologists. A consensus was reached on 105 out of the 137 proposed items (76.6%). The experts agreed that complete control and remission of CU could be defined as the absence of signs or symptoms while on treatment and in the absence of treatment, respectively. Consensus was not reached on the definition of other key terms such as flare-up, exacerbation, and recurrence. The panel agreed that the objective of therapy in CU should be to achieve complete control. PROs that define the degree of control (complete, good, partial, or absence) were established. An algorithm for disease assessment is provided. In conclusion, this work offers consensus definitions and tools that may be useful in the management of patients with CU.

Onset of Nut Allergy in a Pediatric Cohort: Clinical and Molecular Patterns in the AFRUSEN Study.

BACKGROUND AND OBJECTIVE: Nut allergy is a growing problem, yet little is known about its onset in children. Objective: To characterize the onset of nut allergy in children in southern Europe. METHODS: The study population comprised consecutive patients up to 14 years of age who visited allergy departments with an initial allergic reaction to peanut, tree nut, or seed. The allergy work-up included a clinical history, food challenge, skin prick testing, determination of whole-extract sIgE, and ImmunoCAP ISAC-112 assay. RESULTS: Of the 271 children included, 260 were first diagnosed with nut allergy at a mean age of 6.5 years and at a mean (SD) of 11.8 (21.2) months after the index reaction. The most common culprit nuts at onset were walnut (36.5%), peanut (28.5%), cashew (10.4%), hazelnut (8.5%), pistachio (5.4%), and almond (5%). Onset of peanut allergy was more frequent in children ≤6 years and walnut in those aged >6 years (P=.032). In 65% of cases, the allergic reaction occurred the first time the patient consumed the nut, and 35% of reactions were anaphylactic. Overall, polysensitization to nuts was detected by skin prick testing in 64.9% of patients, although this rate was lower among walnut-allergic children (54.7%) and peanut-allergic children (54.1%) (P<.0001). Sensitization to 2S albumins was predominant (75%), especially Jug r 1 (52.8%), whereas sensitization to lipid transfer proteins was less relevant (37%). CONCLUSION: In the population we assessed, the onset of nut allergy occurred around 6 years of age, slightly later than that reported in English-speaking countries. Walnut was the main trigger, followed by peanut. 2S albumin storage proteins, especially Jug r 1, were the most relevant allergens. This study will help guide management and may contribute to preventive strategies in pediatric nut allergy.

Daily Clinical Practice in the Management of Chronic Urticaria in Spain: Results of the UCREX Study.

BACKGROUND: Chronic Urticaria (CU) is a debilitating disease whose treatment is mainly symptomatic. UCREX study aimed to identify CU patients' profile, disease management and quality-of-life (QoL) in daily clinical practice in Spain. METHODS: Observational, 12-months prospective, multicenter study, included de novo or established CU patients attending to dermatology/allergy consultations in 39 Spanish hospitals. MAIN VARIABLES: Urticaria Activity Score (UAS), UAS over 7 days (UAS7). Secondary variables: CU-QoL Questionnaire (CU-Q2oL), EuroQol-5 dimensions (EQ-5D), Medical Outcomes Study Sleep (MOS-Sleep) scale, Hospital Anxiety and Depression Scale (HADS). RESULTS: 361 patients included. Of them, 176 (48.8%) considered for the main objective analysis. Mean age (SD) of 46.6 (14.2) years and 71.8% women. The year prior to inclusion, most patients (57.1%) were treated with non-sedating H1-antihistamines (NS-H1AH). At baseline, mean (SD) 3.6 (6.8) visits were registered to primary care. Mean (SD) UAS7 at baseline was 14.3 (11.0) and CU-Q2oL 24.1 (17.0) which tended to improve by 8.6 (9.7) and 13.9 (15.0), respectively, at 12-months. MOS-Sleep and EQ-5D remained steady during the study, except pain/discomfort and anxiety/depression which went from 58.7% and 49.6% to 29.6% and 26.9%, respectively. At baseline, HADS showed a mean (SD) anxiety of 8.7 (4.5) and depression 5.1 (4.4), decreasing to 7.0 (4.3) and 4.7 (4.3), respectively, at 12-months. CONCLUSIONS: Although most CU patients are treated with NS-H1AH, disease activity is still important, negatively affecting patients' QoL, work activity and healthcare resources use. An appropriate disease management could be the basis for symptoms control, QoL improvement and resources optimization.

Daily Clinical Practice in the Management of Chronic Urticaria in Spain: Results of the UCREX Study. / [Artículo traducido] Práctica clínica diaria en el manejo de la urticaria crónica en España: resultados del estudio UCREX.

BACKGROUND: Chronic Urticaria (CU) is a debilitating disease whose treatment is mainly symptomatic. UCREX study aimed to identify CU patients' profile, disease management and quality-of-life (QoL) in daily clinical practice in Spain. METHODS: Observational, 12-months prospective, multicenter study, included de novo or established CU patients attending to dermatology/allergy consultations in 39 Spanish hospitals. MAIN VARIABLES: Urticaria Activity Score (UAS), UAS over 7 days (UAS7). Secondary variables: CU-QoL Questionnaire (CU-Q2oL), EuroQol-5 dimensions (EQ-5D), Medical Outcomes Study Sleep (MOS-Sleep) scale, Hospital Anxiety and Depression Scale (HADS). RESULTS: 361 patients included. Of them, 176 (48.8%) considered for the main objective analysis. Mean age (SD) of 46.6 (14.2) years and 71.8% women. The year prior to inclusion, most patients (57.1%) were treated with non-sedating H1-antihistamines (NS-H1AH). At baseline, mean (SD) 3.6 (6.8) visits were registered to primary care. Mean (SD) UAS7 at baseline was 14.3 (11.0) and CU-Q2oL 24.1 (17.0) which tended to improve by 8.6 (9.7) and 13.9 (15.0), respectively, at 12-months. MOS-Sleep and EQ-5D remained steady during the study, except pain/discomfort and anxiety/depression which went from 58.7% and 49.6% to 29.6% and 26.9%, respectively. At baseline, HADS showed a mean (SD) anxiety of 8.7 (4.5) and depression 5.1 (4.4), decreasing to 7.0 (4.3) and 4.7 (4.3), respectively, at 12-months. CONCLUSIONS: Although most CU patients are treated with NS-H1AH, disease activity is still important, negatively affecting patients' QoL, work activity and healthcare resources use. An appropriate disease management could be the basis for symptoms control, QoL improvement and resources optimization.

Clinical Approach to Mast Cell Activation Syndrome: A Practical Overview.

The diagnosis of mast cell activation syndrome (MCAS) is defined by 3 criteria: (1) typical clinical signs and symptoms of acute, recurrent (episodic), and systemic mast cell activation (MCA); (2) increase in tryptase level to >20% + 2 ng/mL within 1-4 hours after onset of the acute crisis; and (3) response of MCA symptoms to antimediator therapy. Classification of MCAS requires highly sensitive and specific methodological approaches for the assessment of clonal bone marrow mast cells at low frequencies. The Spanish Network on Mastocytosis score has been used successfully as a predictive model for selecting MCAS candidates for bone marrow studies based on a high probability of an underlying clonal mast cell disorder. In this article, we propose a diagnostic algorithm and focus on the practical evaluation and management of patients with suspected MCAS.

Therapeutic Strategy According to Differences in Response to Omalizumab in Patients With Chronic Spontaneous Urticaria.

Chronic spontaneous urticaria (CSU) is a heterogeneous condition that can severely impact quality of life. Consequently, rapid disease control is essential. First-line treatment of the symptoms of CSU is the licensed dose of second-generation H1 antihistamines. For second-line treatment, this dose may be increased by up to 4 times. In patients who fail to respond to higher doses of H1 antihistamines, omalizumab for up to 24 weeks is recommended to achieve disease control. After this 24-week period, the patient's response to omalizumab should be assessed in order to identify refractory patients. Optimal management of refractory patients has not been established. Therefore, the aim of the present consensus document, which was drafted by allergists and dermatologists with specific expertise in treating urticaria, was to define specific patient profiles based on differences in their response to omalizumab. We also developed a treatment algorithm based on the specific response profile. After a comprehensive literature review, a group meeting was held to discuss issues related to the therapeutic management of patients with CSU that had not been addressed in previous studies. The experts considered both the available evidence and their own clinical experience with omalizumab. We believe that implementation of the proposed algorithm will optimize management of CSU patients who are refractory to antihistamines, reduce disease-related costs, and improve quality of life.

Immunotherapy in allergic rhinitis and lower airway outcomes.

Allergic rhinitis and asthma constitute two clinical expressions of a single-condition, respiratory allergy. Allergen immunotherapy (AIT) is a form of treatment specifically aimed at modifying the response to sensitizing allergens. The inherent potential benefit of AIT is the simultaneous treatment of all clinical expressions of respiratory allergy. Current data support the effectiveness of subcutaneous and sublingual immunotherapy in rhinitis. Studies also provide proof for a beneficial effect in allergic asthma. Even more, substantial evidence points to the preventive effect on the progression from rhinitis to asthma. Despite the current knowledge on the basic mechanisms underlying the immunological effect of AIT is vast, the specific mechanisms for the preventive effect of primary sensitization or new sensitizations are poorly understood. This review aimed to provide a critical overview of the current knowledge on the effectiveness of AIT and its potential role in secondary prevention of respiratory allergy progression.

Management of chronic spontaneous urticaria in routine clinical practice: A Delphi-method questionnaire among specialists to test agreement with current European guidelines statements.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a frequent clinical entity that often presents a diagnostic and therapeutic challenge. OBJECTIVE: To explore the degree of agreement that exists among the experts caring for patients with CSU diagnosis, evaluation, and management. METHODS: An online survey was conducted to explore the opinions of experts in CSU, address controversial issues, and provide recommendations regarding its definition, natural history, diagnosis, and treatment. A modified Delphi method was used for the consensus. RESULTS: The questionnaire was answered by 68 experts (dermatologists, allergologists, and primary care physicians). A consensus was reached on 54 of the 65 items posed (96.4%). The experts concluded that CSU is a difficult-to-control disease of unpredictable evolution. Diagnostic tests should be limited and based on clinical history and should not be indiscriminate. Autoinflammatory syndromes and urticarial vasculitis must be ruled out in the differential diagnosis. A cutaneous biopsy is only recommended when wheals last more than 24h, to rule out urticarial vasculitis. The use of specific scales to assess the severity of the disease and the quality of life is recommended. In patients with severe and resistant CSU, second-generation H1-antihistamines could be used at doses up to four times the standard dose before giving second-line treatments. Omalizumab is a safe and effective treatment for CSU that is refractory to H1-antihistamines treatment. In general, diagnosis and treatment recommendations given for adults could be extrapolated to children. CONCLUSIONS: This work offers consensus recommendations that may be useful in the management of CSU.

Management of urticaria: not too complicated, not too simple.

In spite of being an old disease and apparently easy to diagnose, chronic spontaneous urticaria (CSU) is still perceived as an uncontrollable and difficult to manage disease. The perception of the patient is that his/her condition is not well understood and that is suffering from a disorder with hidden causes that doctors are not able to tackle. Sometimes patients go through a number of clinicians until they found some CSU expert who is familiar with the disease. It is surprising that myths and believes with no scientific support still persist. Guidelines are not widely implemented, and recent tools to assess severity are infrequently used. European and American recent guidelines do not agree in several key points related to diagnosis and treatment, which further contributes to confusion. With the aim to clarify some aspects of the CSU picture, a group of allergists and dermatologists from the Spanish Dermatology and Allergy societies developed a Frequent Asked Questions leaflet that could facilitate physicians work in daily practice and contribute to a better knowledge of common clinical scenarios related to patients with CSU.

Red flags for clinical suspicion of eosinophilic granulomatosis with polyangiitis (EGPA).

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA), is a rare ANCA-associated systemic vasculitis. Its overlapping features with other vasculitic or eosinophilic diseases, and the wide and heterogeneous range of clinical manifestations, often result in a delay to diagnosis. OBJECTIVE: To identify red flags that raise a suspicion of EGPA to prompt diagnostic testing and to present an evidence-based clinical checklist tool for use in routine clinical practice. METHODS: Systematic literature review and expert consensus to identify a list of red flags based on clinical judgement. GRADE applied to generate a strength of recommendation for each red flag and to develop a checklist tool. RESULTS: 86 studies were included. 40 red flags were identified as relevant to raise a suspicion of EGPA and assessed by the experts as being clinically significant. Experts agreed that a diagnosis of EGPA should be considered in a patient aged ≥6 years with a blood eosinophil level >1000 cells/µL if untreated and >500 cells/µL if previously treated with any medication likely to have altered the blood eosinophil count. The presence of asthma and/or nasal polyposis should reinforce a suspicion of EGPA. Red flags of asthma, lung infiltrates, pericarditis, cardiomyopathy, polyneuropathy, biopsy with inflammatory eosinophilic infiltrates, palpable purpura, digital ischaemia and ANCA positivity, usually anti-myeloperoxidase, among others, were identified. CONCLUSION: The identification of a comprehensive set of red flags could be used to raise a suspicion of EGPA in patients with eosinophilia, providing clinicians with an evidence-based checklist tool that can be integrated into their practice.

Co-factor-enhanced food allergy.

BACKGROUND: Alcohol, exercise or non-steroidal anti-inflamatory drugs (NSAID) are frequently mentioned as amplifiers of food allergic reactions but only individual cases or small series have been previously published. METHODS: Descriptive study including 74 cases of suspected co-factor enhanced food allergy, assessed by skin-prick tests, specific IgE and oral challenges. RESULTS: Anaphylaxis accounted for 85.1% of reactions. In 99% of cases culprit food allergens were plant-derived, mainly vegetables and cereals. NSAID were involved in 58%, exercise in 52.7% and alcohol in 12.2%. Lipid transfer protein was the most frequently involved allergen. CONCLUSIONS: Co-factor enhanced food allergy should be considered when assessing food, alcohol, exercise and NSAID allergic reactions.

Anti-ganglioside antibodies in patients with systemic lupus erythematosus and neurological manifestations.

INTRODUCTION: Anti-ganglioside antibodies (AGA) have been associated with several peripheral neuropathies, such as Miller-Fisher syndrome, Guillain-Barré syndrome and multifocal motor neuropathy. They have also been studied in patients with systemic lupus erythematosus (SLE), focusing on neuropsychiatric manifestations and peripheral neuropathy, but the results are contradictory. OBJECTIVE: To study the presence of AGA in a large cohort of patients with SLE and neuropsychiatric manifestations. PATIENTS AND METHODS: Serum from 65 consecutive patients with SLE and neuropsychiatric manifestations, collected from 1985 to 2009, was tested for the presence of AGA antibodies (GM1, GM2, GM3, asialo-GM1 GD1a, GD1b, GD3, GT1b, GQ1b) using a standard enzyme-linked immunosorbent assay ELISA test (INCAT 1999) and thin layer chromatography (TLC). RESULTS: Positive results for asialo-GM1 (IgM) were found in 10 patients, 6 were positive for asialo-GM1 (IgM and IgG), and 4 were positive for other AGA such as GM1, GM2, GM3, GD1b, GT1b, GD3, (mainly IgM). CONCLUSIONS: Clinical and statistical studies showed no correlation between AGA and neuropsychiatric manifestations of SLE. Although some patients showed reactivity to AGA, these antibodies are not a useful marker of neuropsychiatric manifestations in SLE patients.