What molecular allergy teaches us about genetics and epidemiology of allergies.

PURPOSE OF REVIEW: To delineate pertinent information regarding the application of molecular allergology within the realm of both genetic and epidemiological facets of allergic diseases. RECENT FINDINGS: The emergence of molecular allergy has facilitated the comprehension of the biochemical characteristics of allergens originating from diverse sources. It has allowed for the exploration of sensitization trajectories and provided novel insights into the influence of genetics and environmental exposure on the initiation and development of allergic diseases. This review delves into the primary discoveries related to the genetics and epidemiology of allergies, facilitated by the application of molecular allergy. It also scrutinizes the impact of environmental exposure across varied geoclimatic, socioeconomic, and lifestyle contexts. Additionally, the review introduces specific models of molecular allergy within the realms of plants and animals. SUMMARY: The utilization of molecular allergy in clinical practice holds crucially acknowledged diagnostic and therapeutic implications. From a research standpoint, there is a growing need for the widespread adoption of molecular diagnostic tools to achieve a more profound understanding of the epidemiology and natural progression of allergic diseases.

IgE to cyclophilins in pollen-allergic children: Epidemiologic, clinical, and diagnostic relevance of a neglected panallergen.

BACKGROUND: Cyclophilins are ubiquitous panallergens whose epidemiologic, diagnostic, and clinical relevance is largely unknown and whose sensitization is rarely examined in routine allergy practice. OBJECTIVE: We investigated the epidemiologic, diagnostic, and clinical relevance of cyclophilins in seasonal allergic rhinitis and its comorbidities. METHODS: We examined a random sample of 253 (25%) of 1263 Italian children with seasonal allergic rhinitis from the Panallergens in Pediatrics (PAN-PED) cohort with characterized disease phenotypes. Nested studies of sensitization prevalence, correlation, and allergen extract inhibition were performed in patients sensitized to birch pollen extract but lacking IgE to Bet v 1/2/4 (74/1263) or with highest serum level of IgE to Bet v 1 (26/1263); and in patients with sensitization to various extracts (ragweed, mugwort, pellitory, Plantago, and plane tree), but not to their respective major allergenic molecule, profilins, and polcalcins. IgE to cyclophilin was detected with recombinant Bet v 7, and extract inhibition tests were performed with the same rBet v 7. RESULTS: IgE to rBet v 7 was detected in 43 (17%) of 253 patients. It was associated with asthma (P < .028) and oral allergy syndrome (P < .017) in univariate but not multivariate analysis adjusted for IgE to profilins (Phl p 12), PR-10s (Bet v 1), and lipid transfer proteins (Pru p 3). IgE to rBet v 7 was also highly prevalent (47/74, 63%) among patients with unexplained sensitization to birch pollen extract. In patients with unexplained sensitization to ragweed, mugwort, pellitory, Plantago and plane tree pollen, the levels of IgE to those extracts correlated with the levels of IgE to rBet v 7, and they were also significantly inhibited by rBet v 7 (inhibition range 45%-74%). CONCLUSIONS: IgE sensitization to cyclophilin is frequent in pollen-allergic patients living in temperate areas and can produce "false" positive outcomes in skin prick and IgE tests to pollen extracts. Molecular diagnostic guidelines should include this panallergen family.

Optimization of the diagnosis and characterization of gibberellin-regulated protein sensitization: An Italian cohort study.

BACKGROUND: Pru p 7 was the first gibberellin-regulated protein (GRP) to be identified as a food allergen as the basis of a pollen food allergy syndrome. OBJECTIVE: To clinically and biologically characterize a group of patients with suspected allergy to Pru p 7 to optimize the diagnostic workup of GRP sensitization. METHODS: Allergy to Pru p 7 was suspected in the presence of a systemic allergic reaction to plant food, positive skin prick test results for cypress pollen and lipid-transfer protein-enriched peach extract, and absence of Pru p 3-specific immunoglobulin E. Controls were patients with food allergies, patients sensitized to Pru p 3, and patients with cypress allergy without food allergy. Diagnostic workup included skin tests, basophil activation test, Western blot, and single and multiplex assays. RESULTS: In total, 23 patients and 14 controls were enrolled. The most implicated food was peach (91.3%). Approximately 70% of patients reacted to multiple foods. Mueller 4 reactions were 8.7%. In 26.1% of cases, a cofactor triggered the reaction. The basophil activation test results were positive for rPru p 7 in 87% of the patients. Specific immunoglobulin E to Pru p 7 was detected in 95.7% by singleplex and in 73.9% by multiplex assays in patients with suspected allergies; 73.9% of them also reacted to cypress pollen GRP (Cup s 7) in Western blot analysis. CONCLUSION: Patients with Pru p 7-Cup s 7 allergy in our cohort confirm a mild-to-severe clinical syndrome characterized by pollen and food allergy. The diagnosis may benefit from the proposed selection criteria that can be used as preliminary steps to further characterize the cross-reactive GRP sensitization.

Phl p 5 levels more strongly associated than grass pollen counts with allergic respiratory health.

BACKGROUND: Studies have linked daily pollen counts to respiratory allergic health outcomes, but few have considered allergen levels. OBJECTIVE: We sought to assess associations of grass pollen counts and grass allergen levels (Phl p 5) with respiratory allergic health symptoms in a panel of 93 adults with moderate-severe allergic rhinitis and daily asthma hospital admissions in London, United Kingdom. METHODS: Daily symptom and medication scores were collected from adult participants in an allergy clinical trial. Daily counts of asthma hospital admissions in the London general population were obtained from Hospital Episode Statistics data. Daily grass pollen counts were measured using a volumetric air sampler, and novel Phl p 5 levels were measured using a ChemVol High Volume Cascade Impactor and ELISA analyses (May through August). Associations between the 2 pollen variables and daily health scores (dichotomized based on within-person 75th percentiles) were assessed using generalized estimating equation logistic models and with asthma hospital admissions using Poisson regression models. RESULTS: Daily pollen counts and Phl p 5 levels were each positively associated with reporting a high combined symptom and medication health score in separate models. However, in mutually adjusted models including terms for both pollen counts and Phl p 5 levels, associations remained for Phl p 5 levels (odds ratio [95% CI]: 1.18 [1.12, 1.24]), but were heavily attenuated for pollen counts (odds ratio [95% CI]: 1.00 [0.93, 1.07]). Similar trends were not observed for asthma hospital admissions in London. CONCLUSIONS: Grass allergen (Phl p 5) levels are more consistently associated with allergic respiratory symptoms than grass pollen counts.

Role of Neutrophil-to-Lymphocyte Ratio (NLR) in Patients with Mycosis Fungoides.

BACKGROUND: The neutrophil/lymphocyte ratio (NLR) at baseline has been demonstrated to correlate with higher stages of disease and to be a prognostic factor in numerous cancers. However, its function as a prognostic factor for mycosis fungoides (MF) has not been yet clarified. OBJECTIVE: Our work aimed to assess the association of the NLR with different stages of MF and to outline whether higher values of this marker are related to a more aggressive MF. METHODS: We retrospectively calculated the NLRs in 302 MF patients at the moment of diagnosis. The NLR was obtained using the complete blood count values. RESULTS: The median NLR among patients with early stage disease (low-grade IA-IB-IIA) was 1.88, while the median NLR for patients with high-grade MF (IIB-IIIA-IIIB) was 2.64. Statistical analysis showed positive associations of advanced MF stages with NLRs higher than 2.3. CONCLUSIONS: Our analysis demonstrates that the NLR represents a cheap and easily available parameter functioning as a marker for advanced MF. This might guide physicians in recognizing patients with advanced stages of disease requiring a strict follow-up or an early treatment.

Multiplex Proteomic Evaluation in Inborn Errors with Deregulated IgE Response.

(1) Background: Atopic dermatitis constitutes one of the most common inflammatory skin manifestations of the pediatric population. The onset of many inborn errors occurs early in life with an AD-like picture associated with a deregulated IgE response. The availability of proteomic tests for the simultaneous evaluation of hundreds of molecules allows for more precise diagnosis in these cases. (2) Methods: Comparative genomic hybridization microarray (Array-CGH) analysis and specific IgE evaluation by using allergenic microarray (ISAC) and microarray (ALEX2) systems were performed. (3) Results: Proteomic investigations that use multiplex methods have proven to be extremely useful to diagnose the sensitization profile in inborn errors with deregulated IgE synthesis. Four patients with rare diseases, such as recessive X-linked ichthyosis (RXLI, OMIM 308100), Comel-Netherton syndrome (NS, OMIM256500), monosomy 1p36 syndrome (OMIM: 607872), and a microduplication of Xp11.4 associated with extremely high levels of IgE: 7.710 kU/L, 5.300 kU/L, 1.826 kU/L, and 10.430 kU/L, respectively, were evaluated by micro- and macroarray multiplex methods. Polyreactivity to both environmental and food allergens was observed in all cases, including the first described case of association of X-chromosome microduplication and HIE. (4) Conclusions: Extensive use of proteomic diagnostics should be included among the procedures to be implemented in inborn errors with hyper-IgE.

IgE Sensitization Profile in Patients with Netherton Syndrome.

BACKGROUND: Scant data are currently available on the allergen-specific immunoglobulin (Ig)E sensitization profile in primary immunodeficiencies with hyper IgE. Netherton syndrome (NS, OMIM 266500) is an extremely rare form of congenital ichthyosis characterized by congenital scaly erythroderma, hair abnormalities, and deregulated IgE reactivity associated with severe atopic manifestations. OBJECTIVE: The aim of this study was to evaluate the feasibility and reliability of a multiplex proteomic approach in the detection of specific IgE in NS. METHODS: Specific IgE was evaluated in 10 individuals with an established molecular diagnosis of NS using an allergenic molecules microarray (immuno-solid-phase allergen chip). RESULTS: Polireactivity to airway allergens, mainly house dust mites and olive tree pollen, and food allergens were observed in NS. Eighty per cent of patients were responsive to LTP or profilins. A clinical history suggestive of severe egg, milk, and fish allergy was confirmed by reactivity to the thermostable molecules Gal d 1, Bod 8, and parvalbumin Gad c 1, respectively. Latex reactivity was associated with Hev b 5 and 6 reactivity. Two distinct clusters of reactivity were observed after hierarchical analysis. Extremely high IgE levels (> 10,000 kU/L) do not affect the results obtained with microarrays. CONCLUSION: IgE multiplex evaluation allows (i) to profile IgE polyreactivity pictures, in the presence of LTP and profilin sensitization, (ii) to verify the clinical history of food allergy to milk, egg, and seafood, (iii) to confirm the allergic events associated with latex exposure, and (iv) to disclose the presence of preclinical sensitizations in patients affected by primary immunodeficiencies with hyper IgE, such as the NS.

Mollusk allergy in shrimp-allergic patients: Still a complex diagnosis. An Italian real-life cross-sectional multicenter study.

Introduction: Shellfish allergy is an important cause of food allergies worldwide. Both in vivo and in vitro diagnostics failure nowadays is caused by the poor quality of the extracts associated with the scarce availability of allergenic molecules in the market. It is known that not all patients with shellfish allergies experience adverse reactions to mollusks. It is still unclear how to detect and diagnose these patients correctly. Aim: To investigate the features of shrimp-allergic patients either reactive or tolerant to mollusks, with the currently available diagnostic methods. Methods: Nineteen centers, scattered throughout Italy, participated in the real-life study, enrolling patients allergic to shrimp with or without associated reactions to mollusks. Patients underwent skin tests using commercial extracts or fresh raw and cooked shrimp and mollusks, and IgE reactivity to currently available allergenic extracts and molecules was measured in vitro. Results: Two hundred and forty-seven individuals with a self reported adverse reactions to shrimp participated in the study; of these 47.8% reported an adverse reaction to mollusks ingestion (cephalopod and/or bivalve). Neither of the tests used, in vivo nor in vitro, was able to detect all selected patients. Accordingly, a great heterogeneity of results was observed: in vivo and in vitro tests agreed in 52% and 62% of cases. Skin tests were able to identify the mollusk reactors (p < 0.001), also using fresh cooked or raw food (p < 0.001). The reactivity profile of mollusk reactors was dominated by Pen m 1, over Pen m 2 and Pen m 4 compared to tolerant subjects, but 33% of patients were not detected by any of the available molecules. Overall, a higher frequency of IgE rectivity to shrimp was recorded in northern Italy, while mollusk reactivity was more frequent in the center-south. Conclusion: The current diagnostic methods are inadequate to predict the cross-reactivity between crustaceans and mollusks. The detection of mollusks hypersensitivity should still rely on skin tests with fresh material. The exclusion of mollusks from shrimp allergic patients' diets should occur when clinical history, available diagnostic instruments, and/or tolerance tests support such a decision.

A comprehensive molecular approach in fish allergy: Usefulness in daily clinical practice.

BACKGROUND AND AIMS: Diagnosis of fish may represent an important challenge for the allergists. This study aimed to evaluate the diagnostic sensitivity of an in vitro multiplex assay using a comprehensive panel of fish allergens and the cross-reactivity patterns between different molecular components. METHODS: 56 subjects with fish allergy were enrolled. All patients underwent specific IgE measurement using the Allergy Explorer-Alex 2™ multiplex assay (Macroarray Diagnostics, Vienna, Austria) RESULTS: The single ß-parvalbumins Clu h 1, Cyp c 1, Gad m 1, Sal s 1, Sco s 1, Thu a 1 and Xyp g 1 scored positive in 75.0%, 67.8%, 62.5%, 80.3%,80.3%, 78.8% and 73,2% patients, respectively. 14.3% scored positive for the α-parvalbumin (Raj c-parvalbumin), and 16.1% for the aldolase + enolase (Gad m 2 + 3) components. 92.8% reacted to at least one ß-parvalbumin and 96.4% to at least one of the allergens tested. Overall sensitivity was higher than that obtained using commercial extracts of cod, salmon and tuna for skin prick test (75.8%) and IgE detection (92.3%). CONCLUSIONS: The Alex 2 showed high diagnostic sensitivity and it might be used as an additional assay to investigate the cross-reactivity patterns between different molecular components, looking for potentially safe fish species.

Genetically Driven CD39 Expression Affects Sezary Cell Viability and IL-2 Production and Detects Two Patient Subsets with Distinct Prognosis.

Sézary syndrome (SS) is a rare and aggressive variant of cutaneous T-cell lymphoma. It is characterized by the copresence of CD4+ neoplastic lymphocytes, named Sezary cells, mainly in the blood, lymph nodes, and skin where they induce chronic inflammation that in turn impairs the patient's QOL and fuels neoplastic cells. SS is not readily cured, but immunotherapy is becoming an effective option for this lymphoma. In this study, we investigated, in a large cohort of patients with SS, the expression and function of the immune checkpoint molecule CD39, which degrades proinflammatory extracellular adenosine triphosphate. We showed that the SNP rs10748643 A/G within the ENTPD1 gene coding for the CD39 protein controls its expression level. Patients carrying the A/G‒G/G genotype showed a significantly higher frequency of clonal CD4+CD39+ SS cells than those carrying the A/A genotype. Different from other cancers, high CD39 expression correlates with a better prognosis. Comparing primary G/G with A/A lymphoma cells, we observed that G/G SS cells have a higher ability to degrade adenosine triphosphate, increased apoptotic susceptibility, and upon activation, reduced IL-2 production. Accordingly, CD39 enzymatic inhibition enhances SS cell viability and IL-2 production on activation. These results strongly suggest a special caution for SS treatment with therapeutic inhibitors of CD39.

Continuous low-dose gemcitabine in primary cutaneous T cell lymphoma: A retrospective study.

The aim of our retrospective study was to evaluate the efficacy of a continuous therapy with a lower dosage of gemcitabine compared to those usually administered in patients with cutaneous T cell lymphomas (CTCL). Twenty-two patients received different dosages of gemcitabine. Dosage and schedule of the drug were chosen on the basis of clinical features. Gemcitabine was given at 1000 mg every 15 days in 13 patients (four mycosis fungoides [MF], nine Sezary syndrome [SS]); at 1000 mg at days +1, +8, +15 in six cases (three MF, three SS). All patients had been previously treated: four patients had received both skin directed and systemic treatments. Eighteen patients had received photopheresis, IFN, chemotherapy and immunotherapy. The objective response rate (CR + PR) among all patients was 54.5% (12 of 22 patients) with a CR of 4.5% (one of 22 patients) and a PR of 50% (11 of 22 patients). Patients with SS had an ORR of 61.5% (eight of 13 patients) with one CR (7%) and seven PR (53.8%); patients with MF showed an ORR of 55.6% (five of nine patients) but no patients experienced CR (0%). The schedule with the highest efficacy and the lowest toxicity profile was 1000 mg every 15 days. Median progression free survival and overall survival in all patients were 17 and 45 months respectively. Gemcitabine was generally well tolerated. We have demonstrated that a much lower dose of gemcitabine (1000 mg once every 15 days) in patients with advanced-stage and refractory CTCL can lead to a durable response, with tolerable and manageable adverse effects.

Multiple Roles for Cytokines in Atopic Dermatitis: From Pathogenic Mediators to Endotype-Specific Biomarkers to Therapeutic Targets.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, which generally presents with intense itching and recurrent eczematous lesions. AD affects up to 20% of children and 10% of adults in high-income countries. The prevalence and incidence of AD have increased in recent years. The onset of AD mostly occurs in childhood, although in some cases AD may persist in adult life or even manifest in middle age (adult-onset AD). AD pathophysiology is made of a complex net, in which genetic background, skin barrier dysfunction, innate and adaptive immune responses, as well as itch contribute to disease development, progression, and chronicization. One of the most important features of AD is skin dehydration, which is mainly caused by filaggrin mutations that determine trans-epidermal water loss, pH alterations, and antigen penetration. In accordance with the "outside-inside" theory of AD pathogenesis, in a context of an altered epidermal barrier, antigens encounter epidermal antigen presentation cells (APCs), such as epidermal Langerhans cells and inflammatory epidermal dendritic cells, leading to their maturation and Th-2 cell-mediated inflammation. APCs also bear trimeric high-affinity receptors for immunoglobulin E (IgE), which induce IgE-mediated sensitizations as part of pathogenic mechanisms leading to AD. In this review, we discuss the role of cytokines in the pathogenesis of AD, considering patients with various clinical AD phenotypes. Moreover, we describe the cytokine patterns in patients with AD at different phases of the disease evolution, as well as in relation to different phenotypes/endotypes, including age, race, and intrinsic/extrinsic subtypes. We also discuss the outcomes of current biologics for AD, which corroborate the presence of multiple cytokine axes involved in the background of AD. A deep insight into the correlation between cytokine patterns and the related clinical forms of AD is a crucial step towards increasingly personalized, and therefore more efficient therapy.

Peanut allergy in Italy: A unique Italian perspective.

Background: Peanut allergy has not been well characterized in Italy. Objective: Our aim was to better define the clinical features of peanut allergy in Italy and to detect the peanut proteins involved in allergic reactions. Methods: A total of 22 centers participated in a prospective survey of peanut allergy over a 6-month period. Clinical histories were confirmed by in vivo and/or in vitro diagnostic means in all cases. Potential risk factors for peanut allergy occurrence were considered. Levels of IgE to Arachis hypogea (Ara h) 1, 2, 3, 6, 8, and 9 and profilin were measured. Results: A total of 395 patients (aged 2-80 years) were enrolled. Of the participants, 35% reported local reactions, 38.2% reported systemic reactions, and 26.6% experienced anaphylaxis. The sensitization profile was dominated by Ara h 9 (77% of patients were sensitized to it), whereas 35% were sensitized to pathogenesis-related protein 10 (PR-10) and 26% were sensitized to seed storage proteins (SSPs). Sensitization to 2S albumins (Ara h 2 and Ara h 6) or lipid transfer protein (LTP) was associated with the occurrence of more severe symptoms, whereas profilin and PR-10 sensitization were associated with milder symptoms. Cosensitization to profilin reduced the risk of severe reactions in both Ara h 2- and LTP-sensitized patients. SSP sensitization prevailed in younger patients whereas LTP prevailed in older patients (P < .01). SSP sensitization occurred mainly in northern Italy, whereas LTP sensitization prevailed in Italy's center and south. Atopic dermatitis, frequency of peanut ingestion, peanut consumption by other family members, or use of peanut butter did not seem to be risk factors for peanut allergy onset. Conclusions: In Italy, peanut allergy is rare and dominated by LTP in the country's center and south and by SSP in the north. These 2 sensitizations seem mutually exclusive. The picture differs from that in Anglo-Saxon countries.

Lipid transfer protein allergy: A review of current controversies.

Sensitization to lipid transfer protein (LTP), the most frequent cause of food allergy in southern Europe, still shows several controversial, but also intriguing, aspects. Some of these include the degree of cross-reactivity between LTPs from botanically distant sources, the definition of risk factors, the role of some cofactors, clinical outcomes, geographical differences and the identification of the primary sensitizer in different areas. This review article tries to analyse and comment on these aspects point by point suggesting some explanatory hypotheses with the final scope to stimulate critical thoughts and elicit the scientific discussion about this issue in the readership.

A qualitative and quantitative comparison of IgE antibody profiles with two multiplex platforms for component-resolved diagnostics in allergic patients.

BACKGROUND: Clinically complex phenotypes require more and more sophisticated and comprehensive diagnostic approaches, able to discriminate genuine sensitizations from cross-reactivity. Interpretative complexity of multiplex diagnostic arrays has somewhat limited their diffusion. This study compares two currently available methods, namely ISAC® test and ALEX2® test. METHODS: In total, 140 allergic individuals, with a history of atopic dermatitis, adverse food reactions, allergic rhinitis and/or bronchial asthma were studied by Allergy Explorer-ALEX2® macroarray and ImmunoCAP ISAC112® . Lin's concordance correlation coefficient, intraclass correlation coefficient and Bland-Altman plots were used to verify the agreement between continuous values. Cohen's kappa coefficient (k) was assessed for the molecules available in both tests. The degree of relationship was analysed using Spearman's correlation (quantitative variables) and Pearson's χ2 or Fisher's exact test (categorical variables). RESULTS: A substantial agreement (κ = 0.795) was observed between the two methods with 94,3% concordant results when results were dichotomized as negative or positive, but if double-negative results were discarded, the agreement dropped to 71%. Conversely, little or no concordance was observed comparing raw data. Considering the 102 molecules shared by both systems, 28/102 (27%) showed an almost perfect agreement (k > 0.81), and concordance was good (k > 0.61) in a further 32 (31%) cases. A perfect to substantial agreement was observed by comparing species-specific aeroallergens. Heterogeneous results emerged comparing panallergens (co-recognition ranging from 30% for tropomyosin/serum albumins to 70% for PR-10/profilin). The correlation among LTP, profilin and PR-10 assayed with ISAC® was better than ALEX2® , but the latter identified more positive cases due to the wider number of molecules available. The CCD blocker provided by ALEX® test abolishes the carbohydrate determinants signal in 60% of the 33 cases reactive to MUXF3 on the ISAC® test. CONCLUSION: Despite the excellent concordance of the species-specific markers, the analysis of the panallergens provided in both methods suggests a better performance of the ISAC® test on those components, while the ALEX2® test, which includes a larger number of allergens, allowing a broader molecular detection.

Erratum to "IgE allergy diagnostics and other relevant tests in allergy, a World Allergy Organization position paper" [World Allergy Organ J 13/2 (2020) 100080].

[This corrects the article DOI: 10.1016/j.waojou.2019.100080.].

May Bacterial Infections Trigger Bullous Pemphigoid? Case Report and Review of Literature.

Bullous pemphigoid (BP) is an autoimmune blistering skin disease, mainly observed in the elderly. Infections have been suggested as possible disease triggers. However, infections may even heavily influence the disease clinical course and mortality. A 75-year-old woman was admitted to hospital for severe erythematosus blistering disease, accompanied by hyper-eosinophilia and hyper-IgE. The culture of bullous fluid was positive for Enterococcus faecalis, the blood culture was positive for Staphylococcus aureus, and the urine culture was positive for Proteus mirabilis and Escherichia coli. Moreover, circulating anti-BP180 IgG was present and the histopathological/ultrastructural examination of a lesional skin biopsy was compatible with BP. High eosinophil levels (up to 3170/µL) were found throughout the clinical course, while values below 1000/µL were associated with clinical improvement. The total IgE was 1273 IU/mL, and specific anti-G/V-penicillin/ampicillin IgE antibodies were positive. The patient had a complete clinical recovery in two months with methyl-prednisolone (40 then 20 mg/day) and low-dose azathioprine (50 mg/day) as a steroid-sparing agent. The steroid treatment was tapered until interruption during a one-year period and intravenous immunoglobulins have been administered for three years in order for azathioprine to also be interrupted. The patient stopped any treatment five years ago and, in this period, has always been in good health. In this case, the contemporaneous onset of different bacterial infections and BP is suggestive of bacterial infections acting as BP trigger(s), with allergic and autoimmune pathways contributing to the disease pathogenesis.

Non-specific lipid-transfer proteins: Allergen structure and function, cross-reactivity, sensitization, and epidemiology.

BACKGROUND: Discovered and described 40 years ago, non-specific lipid transfer proteins (nsLTP) are present in many plant species and play an important role protecting plants from stressors such as heat or drought. In the last 20 years, sensitization to nsLTP and consequent reactions to plant foods has become an increasing concern. AIM: The aim of this paper is to review the evidence for the structure and function of nsLTP allergens, and cross-reactivity, sensitization, and epidemiology of nsLTP allergy. MATERIALS AND METHODS: A Task Force, supported by the European Academy of Allergy & Clinical Immunology (EAACI), reviewed current evidence and provide a signpost for future research. The search terms for this paper were "Non-specific Lipid Transfer Proteins", "LTP syndrome", "Pru p 3", "plant food allergy", "pollen-food syndrome". RESULTS: Most nsLTP allergens have a highly conserved structure stabilised by 4-disulphide bridges. Studies on the peach nsLTP, Pru p 3, demonstrate that nsLTPs are very cross-reactive, with the four major IgE epitopes of Pru p 3 being shared by nsLTP from other botanically related fruits. These nsLTP allergens are to varying degrees resistant to heat and digestion, and sensitization may occur through the oral, inhaled or cutaneous routes. In some populations, Pru p 3 is the primary and sole sensitizing allergen, but many are poly-sensitised both to botanically un-related nsLTP in foods, and non-food sources of nsLTP such as Cannabis sativa, Platanus acerifolia, (plane tree), Ambrosia artemisiifolia (ragweed) and Artemisia vulgaris (mugwort). Initially, nsLTP sensitization appeared to be limited to Mediterranean countries, however more recent studies suggest clinically relevant sensitization occurs in North Atlantic regions and also countries in Northern Europe, with nsLTP sensitisation profiles being broadly similar. DISCUSSION: These robust allergens have the potential to sensitize and provoke symptoms to a large number of plant foods, including those which are raw, cooked or processed. It is unknown why some sensitized individuals develop clinical symptoms to foods whereas others do not, or indeed what other allergens besides Pru p 3 may be primary sensitising allergens. It is clear that these allergens are also relevant in non-Mediterranean populations and there needs to be more recognition of this. CONCLUSION: Non-specific LTP allergens, present in a wide variety of plant foods and pollens, are structurally robust and so may be present in both raw and cooked foods. More studies are needed to understand routes of sensitization and the world-wide prevalence of clinical symptoms associated with sensitization to these complex allergens.

Pleomorphicskin eruptions in a COVID-19 affected patient: Case report and review of the literature.

The coronavirus disease (COVID-19), during its course, may involve several organs, including the skin with a petechial skin rash, urticaria and erythematous rash, or varicella-like eruption, representing an additional effect of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as commonly observed in other viral diseases. Considering that symptomatic patients with COVID-19 generally undergo multidrug treatments, the occurrence of a possible adverse drug reaction presenting with cutaneous manifestations should be contemplated. Pleomorphic skin eruptions occurred in a 59-year-old Caucasian woman, affected by a stable form of chronic lymphocytic leukemia, and symptomatic SARS-CoV-2 infection, treated with a combination of hydroxychloroquine sulfate, darunavir, ritonavir, sarilumb, omeprazole, ceftriaxone, high-flow oxygen therapy devices, filgrastim (Zarzio®) as a single injection, and enoxaparin. The patient stopped all treatment but oxygen and enoxaparin were continued and the patient received a high-dose Desametasone with complete remission of dermatological impairment in 10 days. It is very important to differentially diagnose COVID-19 disease-related cutaneous manifestations, where is justified to continue the multidrug antiviral treatment, from those caused by an adverse drug reaction, where it would be necessary to identify the possible culprit drug and to start appropriate antiallergic treatment.