Background. Lymphocyte transformation test (LTT) has been widely used to evaluate non-immediate drug hypersensitivity reactions (NIDHRs). However, the lack of standardisation and the low sensitivity have limited its routine diagnostic use. The drug presentation by dendritic cells (DCs) and the assessment of proliferation on effector cells have shown promising results. Flow-cytometry-based methods can help apply these improvements. We aimed to assess the added value of using drug-primed-DCs and the determination of the proliferative response of different lymphocyte subpopulations in NIDHRs. Methods. Patients with confirmed NIDHR were evaluated by both conventional (C-LTT) and with drug-primed-DCs LTT (dDC-LTT) analysing the proliferative response in T-cells and other effector cell subpopulations by using the fluorescent molecule, carboxyfluorescein diacetate succinimidyl ester. Results. The C-LTT showed a significantly lower sensitivity (33.3%) compared with dDC-LTT (65.2%), which was confirmed analysing each particular clinical entity: SJS-TEN (62.5% vs 87.5%), MPE (14.3% vs 41.7%), and AGEP (33% vs 80%). When including the effector cell subpopulations involved in each clinical entity, CD3++CD4+Th1 cells in SJS-TEN, CD3++CD4+Th1+NK cells in MPE, and CD3++NK cells in AGEP, we could significantly increase the sensitivity of the in vitro test to 100%, 66.6%, and 100%, respectively. With an overall sensitivity of 87% and 85% of specificity in NIDHR. Conclusions. The use of a flow-cytometry-based test, DCs as drug presenting cells, and focussing on effector cell subpopulations for each clinical entity significantly improved the drug-specific proliferative response in NIDHRs with a unique cellular in vitro test.

Modern healthcare requires a proactive and individualized response to diseases, combining precision diagnosis and personalized treatment. Accordingly, the approach to patients with allergic diseases encompasses novel developments in the area of personalized medicine, disease phenotyping and endotyping and the development and application of reliable biomarkers. A detailed clinical history and physical examination followed by the detection of IgE immunoreactivity against specific allergens still represents the state of the art. However, nowadays, further emphasis focuses on the optimization of diagnostic and therapeutic standards and a large number of studies have been investigating the biomarkers of allergic diseases, including asthma, atopic dermatitis, allergic rhinitis, food allergy, urticaria and anaphylaxis. Various biomarkers have been developed by omics technologies, some of which lead to a better classification of the distinct phenotypes or endotypes. The introduction of biologicals to clinical practice increases the need for biomarkers for patient selection, prediction of outcomes and monitoring, to allow for an adequate choice of the duration of these costly and long-lasting therapies. Escalating healthcare costs together with questions on the efficacy of the current management of allergic diseases requires further development of a biomarker-driven approach. Here, we review biomarkers in diagnosis and treatment of asthma, atopic dermatitis, allergic rhinitis, viral infections, chronic rhinosinusitis, food allergy, drug hypersensitivity and allergen-immunotherapy with a special emphasis on specific IgE, microbiome and epithelial barrier. In addition, EAACI guidelines on biologicals are discussed within the perspective of biomarkers.

The “coronavirus disease 2019 (COVID-19)” outbreak was first reported in December 2019 (China). Since then, this disease has rapidly spread across the globe and in March 2020 the World Health Organization (WHO) declared the COVID-19 pandemic.1 Since the outbreak was first announced, our journal has extensively focused on the clinical features, outcomes, diagnosis, immunology, and pathogenesis of COVID-19 and its infectious agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We published our first COVID-19 article on 19 February, focusing for the first time on the clinical characteristics of 140 cases of human-to-human coronavirus transmission without any links to the Huanan Wet Market.2 Hypertension and diabetes were mentioned as risk factors and there was no increased prevalence in allergic patients. This early study reported that the main symptoms at hospital admission were fever (91.7%), cough (75.0%), fatigue (75.0%), gastrointestinal symptoms (39.6%), and dyspnea (36.7%). Lymphopenia and eosinopenia were also reported as important signs and biomarkers for monitoring and severity of the patients.2 The prevalent eosinopenia in COVID-19 patients and the possible anti-viral role of eosinophils were further discussed in several following publications inAllergy .3,4 Our second COVID-19 paper brought attention to the wide range of clinical manifestations of this disease, from asymptomatic cases to patients with mild and severe symptoms, with or without pneumonia as well as with only diarrhea.5Patients with common allergic diseases did not develop distinct symptoms and severe courses. Cases with pre-existing chronic obstructive pulmonary disease or complicated with a secondary bacterial pneumonia were severe. Another article, timely appearing in our journal, alerted the scientific community that even in experienced hands there was a 14.1% false negative polymerase chain reaction (PCR) diagnosis in COVID-19 cases and were later diagnosed positive after repeated tests.6 A pediatric article was also published extensively analyzing 182 cases and it was reported that children with COVID-19 showed a mild clinical course.7 Patients with pneumonia had a higher proportion of fever and cough and increased inflammatory biomarkers compared to those without pneumonia. There were 43 allergic patients in this series and there was no significant difference between allergic and non-allergic COVID-19 children in disease incidence, clinical features, laboratory, and immunological findings. Allergy was not a risk factor for disease and severity of SARS-CoV-2 infection and did not significantly influence the disease course of COVID-19 in children.7The immunology of COVID-19 was extensively reviewed in two articles from leading experts with a comprehensive discussion of the tip of the iceberg in COVID-19 epidemiology, anti-viral response, antibody response to SARS-CoV-2, acute phase reactants, cytokine storm, and pathogenesis of tissue injury and severity. 8,9Two studies timely reported the role of possible trained immunity in countries with a Bacillus Calmette-Guérin (BCG) vaccination programme and a relatively low COVID-19 prevalence and mortality rate.10,11 In an extensive RNA sequencing analyses of SARS-CoV-2 receptor and their molecular partners revealed that ACE2 and TMPRSS2 were coexpressed at the epithelial sites of the lung and skin, whereas CD147 (BSG), cyclophilins (PPIA and PPIB), CD26 (DPP4) and related molecules were expressed in both, epithelium and in immune cells.12Allergists, respiratory physicians, pediatricians, and other health care providers treating patients with allergic diseases are frequently in contact with patients potentially infected with SARS-CoV-2. Practical considerations and recommendations given by experts in the field of allergic diseases can provide useful recommendations for clinical daily work. Since the beginning of this current pandemic, our journal has disseminated clinical reports, 2,3,5,6,13 statements on the urgent need for accuracy in designing and reporting clinical trials in COVID-19,14 preventive measures,10,11,15 and Position Statements elaborated by experts in the field in close collaboration with the European Academy of Allergy and Clinical Immunology (EAACI) and its task force “Allergy and Its Impact on Asthma (ARIA) ”.16-28 (keynote information in table 1). A compendium answering 150 frequently encountered questions regarding COVID-19 and allergic diseases has been recently published by experts in their respective area.29 In addition, readers can put further questions regarding this “living ” compendium electronically to the authors and their answers will be available through a new category in the journal’s webpage.30Besides, EAACI in collaboration with ARIA, has provided recommendations on operational plans and practical procedures for ensuring optimal standards in the daily clinical care of patients with allergic diseases, whilst ensuring the safety of patients and healthcare workers.23Table 1: Examples of recently published recommendations, statements and Position Papers of the EAACI

Coronavirus disease 2019 (COVID-19), a respiratory tract infection caused by a novel human coronavirus, the severe acute respiratory syndrome coronavirus 2, leads to a wide spectrum of clinical manifestations ranging from asymptomatic cases to patients with mild and severe symptoms, with or without pneumonia. Given the huge influence caused by the overwhelming COVID-19 pandemic affecting over three million people worldwide, a wide spectrum of drugs is considered for the treatment in the concept of repurposing and off-label use. There is no knowledge about the diagnosis and clinical management of the drug hypersensitivity reactions that can potentially occur during the disease. This review brings together all the published information about the diagnosis and management of drug hypersensitivity reactions due to current and candidate off-label drugs and highlights relevant recommendations. Furthermore, it gathers all the dermatologic manifestations reported during the disease for guiding the clinicians to establish a better differential diagnosis of drug hypersensitivity reactions in the course of the disease.