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• W2107760269 abstract "Peanut allergy is a common food allergy and currently affects approximately 1.5% of UK children [1]. The prevalence of tree nut allergy in the general population has not been independently assessed, but studies of adults and children with peanut allergy suggest a high co-prevalence of tree nut allergy [2, 3]. Peanut and tree nut allergy are particularly troublesome food allergies as they are infrequently outgrown and are associated with considerable morbidity and mortality [4, 5]. There is evidence that the prevalence of peanut allergy is increasing among high-risk atopic infants [6], as well as among children in the general population [1]. Peanuts and tree nuts, often generically referred to as ‘nuts’, are now the most frequent cause of food-induced anaphylaxis. Community-based anaphylaxis admissions among the general UK population have doubled over the period 1991–95 [7, 8]. Therefore individuals with either peanut allergy and/or tree nut allergy are currently advised to avoid all tree nuts and peanuts. Inadequate or unclear product labelling and cross contamination of nut products makes a strong case for blanket nut avoidance. However, the elimination of all nuts is difficult and may have a negative impact on the lifestyle of the affected individual as well as that of their family [9]. In addition, nuts are an important source of dietary protein, particularly for individuals who cannot afford, or choose to avoid, animal protein sources. In this issue of the Journal, Clark and Ewan [10] present a large observational cross-sectional study of children and adults referred to a specialist allergy clinic, all having experienced an allergic reaction to at least one nut. History, skin prick test (SPT) and nut-specific IgE (CAP) tests were performed for peanut and up to four tree nuts (Brazil nut, almond, hazelnut and walnut extracts). In the absence of an oral food challenge (OFC), the authors chose to clarify the interpretation of SPT and specific IgE tests using a clear history. The detailed clinical history was graded for severity and all equivocal nut allergy cases, either on clinical grounds, or if the food was not known with certainty to contain nut, were excluded. The study highlights both the advantages and limitations of the diagnostic modalities currently available to clinicians for the diagnosis of peanut and tree nut allergies. These modalities include: clinical history, physical examination, SPT, specific IgE assays and OFC. The clinical history is important when making the diagnosis of peanut and tree nut allergy, but the performance of this investigation when compared to OFCs may not be optimal. In general, studies that make use of the OFC to establish a diagnosis of food allergy reveal that a comprehensive clinical history may only be validated in less than 50% of patients [11]. This much-disputed discrepancy between a detailed history of food allergy and OFC outcome is somewhat surprising. One potential explanation is that food allergy studies frequently include young children with egg and cow's milk allergy. Egg and cow's milk allergy usually resolve early in life [12–14]; therefore, unless OFCs are performed within the first few years of life, negative results are to be expected. Other reasons for negative OFCs in the face of a suggestive history include: confusing histories, misidentification of food in the history, and non-allergic causes of symptoms. The physical examination is also an important diagnostic modality, as the ‘allergic phenotype’ of the individual influences not only the choice of allergy test, but also the interpretation thereof. Patients with Atopic Eczema Dermatitis Syndrome (AEDS) are commonly peanut allergic [15] and characteristically have high total IgE [16], both factors are known to influence the predictive performance of allergy tests. In addition, extensive eczematous lesions may limit the opportunity to perform a SPT on unaffected skin. A clinical diagnosis of asthma is also an important physical finding, as most patients with fatal or near fatal anaphylaxis have concomitant asthma [17, 18]. SPTs have been used as an in vivo allergy investigation for over a hundred years, but are seldom performed by non-allergists. Specific IgE tests are therefore usually performed for the diagnosis of peanut and tree nut allergy. The initial radioallergosorbent tests (RAST) have largely been superseded by the use of enzyme-linked immunosorbent assays (ELISA). Recent predictive studies have made use of the CAP specific IgE assays (CAP System FEIA; Pharmacia-Upjohn Diagnostics, Uppsala, Sweden), shown to be reproducible, standardized and quantifiable across a broad range of IgE values [19]. Despite the availability of all these diagnostic modalities, it remains difficult to make a confident diagnosis of peanut and tree nut allergy for patients with a negative or equivocal history of a nut reaction, and with SPT or specific IgE values which fall in an intermediate poorly predictive range. For these ‘grey zone’ patients, diagnostic certainty can only be gained through performing an OFC. The OFC remains the gold standard investigation for the diagnosis of nut allergy, particularly the double-blind placebo-controlled food challenge (DBPCFC). For each individual with suspected nut allergy, a careful selection of nut challenges is required as multiple challenges are labour intensive and younger children may not tolerate the large food volumes. In addition, if blanket nut avoidance is to be recommended multiple challenges become unnecessary once a single nut allergy is confirmed. While Clark and Ewan's study [10] does not make use of OFCs, the authors make the point that 10 000 OFCs would have been required to analyse the five nut allergic status of 1000 patients (n=1000, five nut challenge with placebo). Instead they therefore rely on a very careful history. In their study population peanut was responsible for the majority of index reactions (58%) followed by Brazil nut (16%) and hazelnut (6%). Peanut reactions were more likely to be classified as mild (61%) and Brazil nut allergy moderate to severe (68%). An important finding is that 46% of patients who were sensitized to a non-index nut reported histories of tolerance to that nut. Up to 55% of patients allergic to one nut were able to tolerate another type of nut. In keeping with existing peanut allergy data, for the four tree nuts considered, Clark and Ewan [10] could establish no correlation between severity of reaction and magnitude of SPT diameter or specific IgE CAP level. Interestingly, for Brazil nut alone, there was an increase in SPT diameter if severe reactions were compared to all mild to moderate reactions. (P=0.0005). Brazil nut-allergic patients with the most severe reactions had larger SPT weals. The selective relationship seen between Brazil nut clinical reactivity and the magnitude of SPT result could in theory be explained by the characteristics of the allergens within the Brazil nut SPT solution. Brazil nut is an uncommon example of an allergen source where a single major allergen (2S Albumin) is responsible for clinical reactivity [20]. This is in contrast to most allergenic foods (e.g. egg, cow's milk and peanut) where several major and minor allergens are responsible for clinical symptoms [21]. Thus, if we were to use standardized SPT solutions containing known amounts of major allergen, we might expect to see correlations emerge between severity of the allergic response and size of the test result. Studies to date demonstrate that by careful interpretation of the magnitude of SPT and specific IgE responses, the need to perform OFCs can be reduced by 40% or more [22–25]. These studies have mainly been performed for egg, milk and peanut. There is general consensus that negative SPTs or negative specific IgEs to these foods, in the presence of negative or equivocal history, have a high negative predictive value (NPV). However, no NPV is sufficiently high if it does not reach 100%, and any discrepancy between a positive history and negative SPT or specific IgE must be adjudicated by an OFC, or one must assume the history to be correct. The Clark and Ewan study [10] highlights this principle, as false negative SPT and specific IgE results were demonstrated for all five nuts tested. Confirmation of these findings will be required using OFCs in the future. Not all studies to date agree on the cut off SPT and specific IgE values required to achieve high positive predictive values (PPV). Sporik et al. [25] demonstrated a PPV of >95% for peanut SPT weal diameters of 8 mm. Sampson and Ho [24] set the threshold value for peanut-specific IgE concentrations at 15 kUA/L for a PPV of 95%. In a subsequent prospective study Sampson [23] demonstrated that the threshold value of 14 kUA/L achieved a PPV of 95%. Rance et al. [22], in a larger study population, achieved a sensitivity of 44% and a specificity of 95.2% for the same threshold value of 14 kUA/L for their study population, only if the raw peanut SPT extract induced a weal diameter of 16 mm or if the specific IgE was 357 kUA/L, could they be quite certain that the child was allergic to peanut (PPV 100%, sensitivity of 27.7% and a specificity of 100%). Although the purpose of Clark and Ewan's study [10] was not to establish predictive values, they interestingly obtain similar specific IgE and SPT results to Sampson [23] and Sporik et al. [25]. In addition, Clark and Ewan [10] establish similar predictive cut-off SPT and specific IgE values for all five nuts tested (peanut, Brazil nut, almond, hazelnut, walnut). The observations that the same allergy tests perform differently between centres may be due to many factors. Firstly, although the sensitivity, specificity and efficiency of a diagnostic test provide information about the ability of allergy tests to identify nut allergy, most clinicians prefer working with positive and negative predictive values. The calculation of predictive values is, however, influenced by the population prevalence of nut allergy, which may differ between tertiary allergy centres [26]. The performance of predictive values may therefore not be applicable across all populations. For example, Rance et al.'s [22] study population had a peanut allergy prevalence of 48.8%, Sampson's [23] was 81% and Clark and Ewan's study [10] population had a peanut and tree nut allergy prevalence of 100%, as this was the principal reason for referral. Likelihood ratios, on the other hand, although less frequently utilized for the interpretation of allergy results, have the advantage of being independent of the population prevalence of the condition being studied [27]. The population prevalence of peanut allergy is influenced by the allergic phenotype of the study population. The highest prevalence of peanut and tree nut allergy is found in children with moderate to severe AEDS [16, 28, 29], whereas patients with chronic idiopathic urticaria share the same food allergy prevalence as the general population [30]. The allergic phenotype varies between published predictive studies; for example, Rance et al.'s [22] study was conducted among a population of children with a wide range of symptoms (AEDS, urticaria, angioedema, asthma and anaphylactic reactions) typical of those seen in patients with peanut allergy. Sampson and Ho's [24] retrospective study population of 196 children and adolescents all had AEDS and approximately 50% had asthma and allergic rhinitis [25]. Sampson's prospective study [23] consisted of children with a mix of AEDS (61%) and asthma (≈50%). Different reference standards used to make the diagnosis of peanut allergy between studies may also account for the different performance of allergy tests. Most predictive studies have made use of either an OFC or DBPCFC as the reference standard. However, most allergy centres are reluctant to perform OFCs on patients younger then 3 years, and will, in addition, exclude individuals with a history of severe anaphylaxis, recent allergic reaction, and uncontrolled asthma. Although these precautions are clinically prudent, the omission of highly allergic individuals may bias the sample, as it is unknown which patients among those excluded will pass or fail an OFC. Predictive studies make use of different diagnostic modalities; for example, Sampson's prospective study [24] of 68 children made the diagnosis of peanut allergy by means of OFC in only 2% of patients, on the basis of a suggestive history for 13% and on the basis of a convincing history for 85%. In contrast, Rance's study population [22] of 363 children all underwent DBPCFCs. Clark and Ewan [10] made use of a clear history for the diagnosis of peanut and tree nut allergy. The age of the study population may also be important when establishing predictive SPT and specific IgE values. Sporik et al. [25] determined that for children aged 2 years or younger, 100% specificity was reached at a lower SPT weal diameter of 4 mm. SPT histamine weal diameters are also known to increase by 125% from 4 days to 2 years, and 50% from ages 2–18 years [31]. Variations in specific IgE levels may also need to be considered when establishing predicative cut-offs, as they are characteristically low at birth (<2 kIU/L) and increase until 10–15 years of age [32]. Although Clark and Ewan's [10] study enrolled children and adults, 58% were less than 10 years of age and 36% were under 5 years old. In contrast, the Rance et al. [22], Sampson [23] and Sporik et al. [25] study populations all share a slightly younger median age of approximately 3 years. The young age of these study populations reflects the usual age of onset of peanut allergy at around 14 months, and tree nut allergy at around 36 months of age [33]. The different performance of SPTs between studies may also be due to the unique characteristics of the SPT extracts used. That Rance et al. [22] obtained larger peanut SPT weal diameters when using raw extracts (median 6 mm, range 0–25 mm) compared to commercial extracts (median 3 mm, range 0–16 mm) is interesting, as most commercial extract manufacturers make use of raw peanut proteins (personal communication). The performance characteristics of the two extracts also differ when compared with DBPCFC proven peanut allergy; commercial SPT extracts were falsely negative in 18% of 32 subjects (sensitivity 82%) whereas raw SPT extracts were always positive (sensitivity 100%). Variability in SPT extracts is not unique to smaller research laboratories, as commercial peanut SPT solutions may vary by as much as 2-logs [34]. Given that nut extracts are a complex mixture of proteins, lipids, carbohydrates and pigments with varying allergen concentrations, purity and degree of contamination, it is not surprising that variability occurs. Even the choice of peanut plant species may influence the quality and quantity of extract allergens [35]. The process of roasting or frying has been shown to significantly alter the allergenic properties of peanut [36]. Maleki et al. [37] demonstrated that roasted peanut samples are less soluble, more resistant to digestion, bind significantly higher levels of serum IgE from peanut-allergic individuals, and result in larger weal diameters than raw peanut extracts. Many of these novel characteristics are attributable to the Maillard reaction, a heat-induced, non-enzymatic biochemical reaction between reducing sugars and amino acids [37]. Therefore, given that humans generally consume peanuts after boiling, frying or roasting, it may be clinically more relevant to make use of roasted peanut extracts for SPT and specific IgE testing. This may however, not be true for patients with oral allergy syndrome (OAS), a condition characterized by oro-pharyngeal symptoms secondary to cross-reactivity between ingested labile allergens and aeroallergens [38]. For example, patients allergic to birch pollen may show symptoms after the ingestion of raw vegetables and fruits such as potatoes, carrots, celery, apples, pears and kiwi [14]. Of note is that tree nuts such as hazel [39], almond [40] and walnut [14,41], have been incriminated as cross-reactive OAS allergens. For these patients, SPT reactivity may only be demonstrated if use is made of fresh SPT extracts or by performing the SPT in a prick plus prick method [42]. Specific IgE assays are also subject to variability with the result that many of the commercial assays available are not always interchangeable or equivalent. Even the CAP (Pharmacia) system, which achieves greater quantification and better interassay agreement through standardized calibration schemes, remains subject to a degree of variability [32, 43]. Given all these variables, it may be necessary to standardize SPT extracts and reagents used in specific IgE assays not only with respect to major allergen content but also with respect to the processed form of the protein. The use of recombinant allergens for allergy testing certainly offers benefits with respect to the standardization of major allergens. However, as these proteins lack natural post-translational modification such as glycosolation, they may respond differently to heat processing when compared to native allergens, rendering them less biologically relevant. We therefore need to continue in our efforts to optimize our clinical and laboratory diagnosis of peanut and tree nut allergies. For the time being, performance characteristics of these allergy tests will need to be established in each tertiary allergy centre, using the results of OFC as the reference standard. International collaborative efforts between these centres and allergy associations using standardized histories, challenge protocols and allergen reagents should be pursued. This will advance our diagnostic ability in the field of allergic disease and extend the applicability of allergy testing." @default.
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• W2107760269 title "Optimizing the diagnosis of peanut and tree nut allergy" @default.
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