Cashew allergy, 2S albumins, and risk predictions based on IgE antibody levels

Risk prediction by assessing the probability of an event is a thought process common to the study of politics, economics, the humanities and last but not least, the natural sciences. This can be exemplified by a researcher?s curiosity for examining how a particular parameter such as allergen-specific IgE relates to the prediction of risk for manifesting a clinical allergic response. Lange et al 1 exhibit this curiosity by studying the ability of IgE antibody specific for cashew's 2S albumin storage protein (Ana o 3) to provide clarity on the need for an oral cashew challenge to prove disease. They report that IgE antibody levels >2 kUA/l to Ana o 3 improved their prediction (95% probability) of a positive oral food challenge after cashew consumption in comparison with IgE against the whole cashew extract. In other words, increased analytical specificity of molecular Ana o 3-specific IgE testing 2 reportedly translates into an improved diagnostic efficacy and a superior prediction for a positive oral cashew challenge. Three issues are raised by the study: (A) the report supports other studies that suggest a quantitative IgE measurement specific for a 2S albumin can serve as a biomarker of clinical response, (B) there are implications regarding other potentially cross-reactive food allergens, and (C) the study may only be narrowly valid for a selective population because there are additional factors that determine the relationship between a quantitative measurement of allergen-specific IgE and clinical presentation of allergic symptoms. Following paragraphs expand on these issues and discuss the advantages and limitations of the use of a quantitative IgE measurement as a biomarker of allergic disease. (A) Several research groups have reported that the ability of molecular allergen-specific IgE antibody testing to potentially distinguish a clinically relevant from a silent IgE sensitization is one of molecular allergen based assays' notable strengths 2. Thus, this outcome in their report expands on the original conclusions of Sampson et al. 3 for single allergens and it is not a surprise. Seed storage proteins, in particular 2S albumins 4 in legumes, tree nuts, and oil seeds, are known to be highly abundant and stable. Their extraordinary thermal and digestive resistance allows them to effectively trigger severe anaphylactic reactions. Increased levels of IgE antibodies to a number of the 2S albumins (e.g., Ara h 2 5, 6 and 6 7, 8 from peanut, Gly m 8 9, 10 from soy, Cor a 14 6, 11 from hazelnut, Jug r 1 12 from walnut, Ber e 1 13 from brazil nut, Ses i 1 14 from sesame, and others) seem to generally indicate an increased risk concerning severe reactions in a sensitized individual following exposure to the offending allergen source. (B) What about other related foods in this situation? Does the presence of IgE antibody specific for cashew 2S albumin indicate an increased risk from exposure to other potentially cross-reactive 2S albumin-containing plant foods? Due to fairly limited cross-reactivity among these different storage proteins 4, 15, IgE levels in any given patient are expected to vary considerably if different 2S albumins from these various sources are tested. Ideally, a clear negative result to a 2S albumin of one source could potentially rule out serological as well as clinical cross-reactivity. Thus, totally negative results using a singleplex IgE assay can be considered of value in ruling out sensitization! Moreover, the highest IgE antibody level against one of a panel of these different 2S albumins would likely point to the 'primary sensitizer' which would also be helpful for counseling on avoidance. Clearly, a more accurate indication of the responsible allergen that initiated the 2S albumin-specific IgE antibody response detectable in a patient's serum can provide helpful information as a result from a diagnostic allergy work-up. One might ask whether it is of value to test a patient's serum for IgE antibody to as many 2S albumins as are available in the routine clinical immunology laboratory. Could placing 2S albumin-specific IgE levels from a panel of different specificities (i.e., Ara h 2, Gly m 8, Cor a 14, Ana o 3, Jug r 1, Ber e 1, and Sesi 1) in a hierarchical order from highest to lowest aid in distinguishing clinically relevant from silent sensitizations and cross-reactivities? This question unfortunately has not yet been systematically addressed and awaits a convincing answer. By utilizing a singleplex IgE antibody assay with an optimal analytical sensitivity, it will be possible to answer this better as more 2S albumins become available in the diagnostic allergy laboratory. One general rule of thumb in molecular allergy diagnostics advocates for limited testing in the case of highly cross-reactive allergen families (i.e., profilins, polcalcins, nonspecific lipid transfer proteins, tropomyosins, parvalbumins, lipocalins, PR10-like proteins, and serum albumins) 2. Testing IgE antibody to more than one candidate of these broadly cross-reactive allergen families tends to duplicate a previously detected positive or negative serology to one member of the family and unlikely adds any useful additional information. In contrast, limited cross-reactivity within one allergen (sub)family (i.e., 2S albumins) could represent a unique case where broad testing of many family members would be beneficial in identifying the potentially significant from the insignificant (negative) cross-sensitizations. But how does one interpret the case where specific IgE antibody levels are not entirely negative to the other 2S albumins, but rather positive to a subset of those allergens with shared allergenic epitopes 15 in comparison with the presumed primary sensitizer? Clinically valid information from the patient's medical history and/or a supervised oral challenge would thus be absolutely necessary to successfully work-up such a case and clarify the clinical significance of the patient's serological sensitization pattern. In addition, the following assumptions should be kept in mind when considering the predictive value of an allergen-specific IgE antibody result: The difficulty in extrapolating from 'sensitization' to 'clinical allergy' is also highlighted by a recent study, showing that IgE antibody responses to common foods were detected in 26% of a representative cohort in south India. This contrasted with the (self-reported) clinical food reactions that occurred in only 1.2% of these subjects 29. The authors did not provide total serum IgE levels, but mention the concern about high total IgE levels in the Indian cohort as one potential confounding factor for the disappointing low positive predictive value of allergen-specific IgE. The high total serum IgE levels in this population could result from wide-spread nematode parasitism that is common throughout South India and/or be associated with highly prevalent low-affinity IgE to cross-reactive carbohydrate determinants (CCDs). Returning to the cashew study by Lange and colleagues 1, how would its predictive value turn out if IgE anti-Ana o 3 were measured in this South India region where high total serum IgE levels are common? Would one expect similar cutoff levels for Ana o 3 specific IgE? Importantly, more than one variable, not only allergen-specific IgE or the specific to total IgE ratio as in the case of the cashew study 1 should be considered to understand its predicative value in relation to the observed IgE-mediated hypersensitivity reaction. Total IgE is a rarely requested analyte that should be routinely integrated into diagnostic testing plans to adequately interpret the intra- and interindividual significance of an allergen-specific IgE measurement 30. In conclusion, predictions on allergic clinical outcomes using a single IgE antibody analysis involving components such as a 2S albumin would be nice to have, but they are not as straight forward as many studies such as cashew component investigation of Lange et al. 1 suggest. A successful diagnostic allergy work-up still requires individually planned diagnostic steps and proper interpretation, while always taking into consideration the historical context of the patient on a case-by-case basis. Both authors have contributed to the ideas and writing of this editorial. Dr. Kleine-Tebbe reports personal fees from diagnostic companies (Dr. Fooke Laboratories, Germany; ThermoFisher/Phadia, Sweden/Germany; different laboratories, Germany) for scientific and educational presentations on laboratory diagnosis in allergic conditions for physicians and grants from diagnostic companies (Dr. Fooke Laboratories; ThermoFisher/Phadia, Sweden/Germany) for contract research on new laboratory tests for diagnosing allergic conditions, outside the submitted work.