Ocular surface disease in moderate-to-severe atopic dermatitis patients and the effect of biological therapy.

Atopic dermatitis (AD) is a chronic inflammatory skin disease for which new targeted therapies are currently available. Due to the increased rates of ocular surface disease (OSD) reported during treatment with these new targeted treatments, more insight into the occurrence and pathomechanism of OSD in moderate-to-severe AD patients is needed. Therefore, this review's first part highlights that most patients with moderate-to-severe AD already have characteristics of OSD before starting targeted treatment. Remarkably, not all AD patients with OSD report ocular symptoms. OSD in AD is associated with less conjunctival goblet cells (GC) compared to healthy controls. In addition, OSD severity in AD patients is associated with high AD activity, the presence of eyelid and/or facial eczema, and high levels of AD-related severity biomarkers in tear fluid. The second part of this review highlights that pre-existing ocular pathology (e.g. in combination with the use of ophthalmic medication or eyelid eczema) may be associated with the development of dupilumab-associated ocular surface disease (DAOSD). During dupilumab treatment, DAOSD (which can be new-onset OSD or worsening of pre-existing OSD) is observed in approximately one-third of the dupilumab-treated AD patients. Anti-inflammatory ophthalmic treatment improves DAOSD, and dose reduction of dupilumab may also be an effective treatment option. The pathomechanism of DAOSD is still not fully elucidated. In a prospective study low, but stable conjunctival GC numbers were observed in moderate-to-severe AD patients, before and during dupilumab treatment. However, the Mucin 5 AC (MUC5AC) expression of GCs decreased during dupilumab treatment, suggesting an impairment of the GC function by dupilumab treatment. In addition, higher dupilumab tear fluid levels were found in dupilumab-treated AD patients with moderate-to-severe OSD compared to patients with no or mild OSD, whereas the dupilumab serum levels are similar. Clinicians should be aware of the frequent occurrence of OSD in moderate-to-severe AD patients, and a low-threshold referral to an ophthalmologist is recommended.

EAACI guidelines on the diagnosis of IgE-mediated food allergy.

This European Academy of Allergy and Clinical Immunology guideline provides recommendations for diagnosing IgE-mediated food allergy and was developed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Food allergy diagnosis starts with an allergy-focused clinical history followed by tests to determine IgE sensitization, such as serum allergen-specific IgE (sIgE) and skin prick test (SPT), and the basophil activation test (BAT), if available. Evidence for IgE sensitization should be sought for any suspected foods. The diagnosis of allergy to some foods, such as peanut and cashew nut, is well supported by SPT and serum sIgE, whereas there are less data and the performance of these tests is poorer for other foods, such as wheat and soya. The measurement of sIgE to allergen components such as Ara h 2 from peanut, Cor a 14 from hazelnut and Ana o 3 from cashew can be useful to further support the diagnosis, especially in pollen-sensitized individuals. BAT to peanut and sesame can be used additionally. The reference standard for food allergy diagnosis is the oral food challenge (OFC). OFC should be performed in equivocal cases. For practical reasons, open challenges are suitable in most cases. Reassessment of food allergic children with allergy tests and/or OFCs periodically over time will enable reintroduction of food into the diet in the case of spontaneous acquisition of oral tolerance.

Measurement of IgE to hazelnut allergen components cannot replace hazelnut challenge in Dutch adults.

BACKGROUND: Component-resolved diagnostics (CRD) help predict hazelnut allergy (HA) in children, but are of unknown diagnostic value in adults. This study aimed to evaluate the diagnostic accuracy of IgE to hazelnut extract and components in adults. METHODS: A Dutch population of consecutively presenting adults suspected of HA, who underwent a double-blind placebo-controlled food challenge, were included. Serum IgE to hazelnut extract and Cor a 1, 8, 9, and 14 was measured on ImmunoCAP. Diagnostic accuracy was assessed by area under the curve (AUC) analysis. RESULTS: Of 89 patients undergoing challenge, 46 had challenge-confirmed HA: 17 based on objective and 29 based on subjective symptoms. At commonly applied cutoffs 0.1 and 0.35 kUA /L, high sensitivity was observed for IgE to hazelnut extract and Cor a 1 (range 85-91%), and high specificity for IgE to Cor a 8, 9 and 14 (range 77-95%). However, the AUCs for hazelnut extract and components were too low for accurate prediction of HA (range 0.50-0.56). Combining hazelnut extract and component IgE measurements did not significantly improve accuracy. Higher IgE levels to Cor a 9 and 14 were tentatively associated with HA with objective symptoms, but the corresponding AUCs still only reached 0.68 and 0.63, respectively. CONCLUSIONS: Although hazelnut allergic adults are generally sensitized to hazelnut extract and Cor a 1, and hazelnut tolerant adults are usually not sensitized to Cor a 8, 9, or 14, challenge testing is still needed to accurately discriminate between presence and absence of HA in adults from a birch-endemic country.

Non-Digestible Oligosaccharides Can Suppress Basophil Degranulation in Whole Blood of Peanut-Allergic Patients.

Background: Dietary non-digestible oligosaccharides (NDOs) have a protective effect against allergic manifestations in children at risk. Dietary intervention with NDOs promotes the colonization of beneficial bacteria in the gut and enhances serum galectin-9 levels in mice and atopic children. Next to this, NDOs also directly affect immune cells and low amounts may reach the blood. We investigated whether pre-incubation of whole blood from peanut-allergic patients with NDOs or galectin-9 can affect basophil degranulation. Methods: Heparinized blood samples from 15 peanut-allergic adult patients were pre-incubated with a mixture of short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides (scGOS/lcFOS), scFOS/lcFOS, or galectin-9 (1 or 5 µg/mL) at 37°C in the presence of IL-3 (0.75 ng/mL). After 2, 6, or 24 h, a basophil activation test was performed. Expression of FcεRI on basophils, plasma cytokine, and chemokine concentrations before degranulation were determined after 24 h. Results: Pre-incubation with scGOS/lcFOS, scFOS/lcFOS, or galectin-9 reduced anti-IgE-mediated basophil degranulation. scFOS/lcFOS or 5 µg/mL galectin-9 also decreased peanut-specific basophil degranulation by approximately 20%, mainly in whole blood from female patients. Inhibitory effects were not related to diminished FcεRI expression on basophils. Galectin-9 was increased in plasma after pre-incubation with scGOS/lcFOS, and both NDOs and 5 µg/mL galectin-9 increased MCP-1 production. Conclusion and clinical relevance: The prebiotic mixture scFOS/lcFOS and galectin-9 can contribute to decreased degranulation of basophils in vitro in peanut-allergic patients. The exact mechanism needs to be elucidated, but these NDOs might be useful in reducing allergic symptoms.

n-3 Long-chain PUFA reduce allergy-related mediator release by human mast cells in vitro via inhibition of reactive oxygen species.

Increased n-6 and reduced n-3 long-chain PUFA (LC-PUFA) intake in Western diets may contribute to the increased prevalence of allergic diseases. Key effector cells in allergy are mast cells (MC). The aim of the present study was to investigate the effects of n-6 v. n-3 LC-PUFA on MC phenotype. Human MC lines (LAD2 and HMC-1) were incubated for 24 h with either arachidonic acid (AA, n-6 LC-PUFA) or the n-3 LC-PUFA EPA or DHA. The effects of these three LC-PUFA on degranulation, mediator secretion and reactive oxygen species (ROS) generation were assessed. ROS, mitogen-activated protein kinase (MAPK) or NF-κB inhibitors were used to unravel signalling pathways involved in cytokine secretion. AA, EPA or DHA did not reduce IgE-mediated degranulation by LAD2 cells. However, AA increased PGD2 and TNF-α secretion by ionomycin/phorbol 12-myristate 13-acetate-stimulated HMC-1, whereas EPA and DHA more prominently inhibited IL-4 and IL-13 secretion. Suppression of IL-4 and IL-13 release by LC-PUFA correlated with reduced ROS generation. IL-4 and IL-13 release by activated HMC-1 was abrogated using ROS inhibitors. Inhibition of MAPK signalling, but not NF-κB, downstream of ROS reduced IL-13 secretion by activated HMC-1. Combined incubation of EPA or DHA with MAPK inhibitors further suppressed IL-13 secretion. In conclusion, the n-6 LC-PUFA AA enhanced pro-inflammatory mediator production by MC, while the n-3 LC-PUFA EPA as well as DHA more effectively suppressed ROS generation and IL-4 and IL-13 release. This suggests that dietary supplementation with EPA and/or DHA may alter the MC phenotype, contributing to a reduced susceptibility to develop and sustain allergic disease.

Anaphylaxis to cow's milk formula containing short-chain galacto-oligosaccharide.

BACKGROUND: On the basis of the proven prebiotic effects of oligosaccharides in cow's milk formula (CMF) in infants, CMFs are supplemented with oligosaccharides. OBJECTIVE: We present a series of 5 cases of cow's milk-tolerant but atopic patients with a history of respiratory allergies. All had anaphylaxis after the ingestion of CMF supplemented with short-chain galacto-oligosaccharide (scGOS). The allergen trigger was investigated. METHODS: Clinical histories were collated. Skin prick tests (SPTs) and basophil activation tests (BATs) were carried out with the eliciting CMF that triggered anaphylaxis, with or without supplemented prebiotics (scGOS) and with scGOS fractions containing oligosaccharides of different chain lengths. RESULTS: The median age of presentation was 6 years (range, 5-38 years). Anaphylaxis occurred within 30 minutes of the first known exposure to CMF supplemented with prebiotics in all patients. Only 1 patient was subjected to oral challenge, which resulted in an anaphylactic reaction. All patients demonstrated IgE sensitization through SPTs and BATs to scGOS and fractions of scGOS containing 3 sugar units or greater but not to cow's milk or long-chain fructo-oligosaccharide. Eight child control subjects tolerant to regular ingestion of scGOS-supplemented CMF and 1 adult volunteer were found to have negative results to scGOS through SPTs and BATs. In addition, in vitro BATs with donor basophils sensitized with sera from 2 of the 3 reported cases showed reactions to scGOS. The scGOS-induced basophil activation was inhibited in the presence of wortmannin, a phosphatidylinositol 3-kinase inhibitor. CONCLUSIONS: This study describes an unusual form of IgE-mediated anaphylaxis triggered by low-molecular-weight oligosaccharides in scGOS. The primary sensitizer for this phenomenon requires further investigation.

Narrowband ultraviolet B and medium-dose ultraviolet A1 are equally effective in the treatment of moderate to severe atopic dermatitis.

BACKGROUND: Phototherapy may be effective in atopic dermatitis (AD). Medium-dose (MD) ultraviolet (UV) A1 was introduced for the treatment of AD. Few immunohistochemical data are available pertaining to phototherapy in AD. Regulatory T cells may play a role in clearing AD. OBJECTIVES: We sought to compare the clinical and immunohistochemical effects of narrowband (NB) UVB and MD UVA1 treatment in patients with AD. METHODS: Thirteen adult patients with AD were included in this randomized investigator-blinded half-sided comparison study between NB UVB and MD UVA1. Disease activity was measured using the Leicester sign score. Skin biopsy specimens were taken before and after phototherapy. Regulatory T cells were stained with the forkhead box protein P3 (FoxP3). RESULTS: NB UVB and MD UVA1 both significantly decreased AD severity (P < .01) and the dermal cellular infiltrate. The percentage of FoxP3(+)CD3(+) T cells did not change after NB UVB or MD UVA1 treatment. LIMITATION: MD UVA1 therapy was given 3 times per week instead of the preferred regimen of 5 times per week. This was necessary to achieve good blinding of the study. CONCLUSIONS: NB UVB and MD UVA1 seem equally effective in the treatment of patients with moderate to severe AD. Neither MD UVA1 nor NB UVB had an effect on the percentage of FoxP3(+)CD3(+) T cells.