On January 20th, 2015, President Obama announced the Precision Medicine Initiative® (PMI) (https://www.nih.gov/precision-medicine-initiative-cohort-program). Precision medicine (PM) is an emerging approach for disease prevention and treatment that takes into account people’s individual variations in genes, environment, and lifestyle. The reasons why PM is considered one of the most important advances in life science is mainly related to the availability of extremely efficient techniques of sequencing of the human genome [the next generation sequencing (NGS)], the improved technologies for biomedical analysis (including proteomics and metabolomics) and, finally the powerful new tools for using and probing large databases , including health-oriented datasets ,  and social networks . The terms of personalized, precision, targeted medicine are nowadays used interchangeably, and this will be the case in this article too . The impact of PM is not exclusively related to scientific or strictly medical programs. Programs based on PM have been officially launched by Governments for different chronic diseases , where long-term and expensive treatments are required, but the sustainability of the healthcare expenses should be preserved , . In this perspective, medicine will change, since the treatments (mainly the biotech ones) will be addressed to the molecular mechanisms of the disease or to a subgroup of patients with the same disease , and this implies the definition of the endotype of any single patient . In addition, the molecular events involved in determining the clinical disorders will be the specific target of the treatment. Accordingly, the PM approach will need a deep revision of the taxonomy of the diseases  thus, in a near future, medical students will approach their studies in this perspective. Overall, the sustainability of the healthcare costs will lead the process , . Allergy represents a field of clinical and laboratory research in which PM has already demonstrated its presence. In particular, the patient’s sensitization profile, represented by the results of skin prick tests and assays of specific IgE, is highly personalized and allergen immunotherapy (AIT), which represents an effective approach to the natural history of the allergic disease, is strictly based on the results of the sensitization repertoire. For this reason, allergy has been considered a prototype of PM (Figure 1). In recent years, a number of improvements in the field of molecular diagnostics of allergy have become available , ,  and, at present, the technical armamentarium of allergists is much more powerful that that of 20 years ago, and can be considered as virtually exhaustive. These outstanding progresses are based on genetic engineering and proteomics. Several documents have been produced in the past in order to share and extend this new knowledge to the professionals involved in allergy diagnosis and treatment , . Recently, the molecular based allergy diagnostics (MBAD) rapidly expanded, and the similarities with PM appeared much more robust. In addition, the “computer assisted diagnostics”, that has significantly modified the general behavior of doctors , identified new possibilities, because of the complexity of the interpretation of the IgE profile, in particular in polysensitized patients with sensitization to cross-reacting allergen components . All these improvements resulted also in the definition of new entities and characteristics listed in Table 1.
Biological and practical bases of molecular allergy diagnostics
The relationship between IgE and allergens are coded by both general and specific rules that are summarized in this review
The nature of the allergen
Allergens are usually proteins or polypeptides and more rarely aptens (e.g. penicillin). The allergens from plants are characterized by a large range of molecular weights (MW), between 7.5 kDa of the calcium binding proteins (CBP, such as Phl p 7 from Phleum pratense and Bet v 4, from Betula verucosa) to 60–65 kDa of 2S albumin and vicilins. Within animal-derived allergens, the smallest are parvalbumins (12 kDa), and the largest are albumins (such as Equ c 3, from Equus caballus or Can f 3 from Canis familiaris). Allergens are characterized by the presence of epitopes (which number is proportional to the MW of the protein). The smaller the protein, the more frequent are sequential epitopes, while in larger proteins, conformational epitopes are proportionally more represented. Because of their biochemical nature, allergens have specific chemical and physical characteristics. Allergens, as proteins, can be modified or denatured by heat, low pH or digestive peptidases, and also epitopes can be susceptible or resistant to those agents. These characteristics usually affect their biological activity. For instance, epitopes susceptible to heat or pH cause preferentially local reactions. In fact, Mal d 1, the PR-10 of apple, causes the oral allergy syndrome when the apple is eaten as fresh food. If the apple is cooked, the epitope is destroyed and no reaction occurs. In fact, Mal d 1 rarely cause systemic symptoms because it is susceptible to the low pH of the stomach and gastro-enteric peptidases. However, systemic reactions could occur in patients treated with anti-acids . The behavior of allergens (and epitopes) resistant to heat, low pH and peptidase is different. These epitopes can cause and oral allergy syndrome but, more frequently, systemic reactions in sensitized patients. Thus, lipid transfer proteins (LTPs), a common allergen of food, may cause both OAS and systemic (frequently severe) diseases (ranging from urticaria to anaphylaxis) in sensitized patients. LTPs remain intact in cooked foods.
The list of the most represented allergen families is shown in Table 2. It is well known that allergen families are homogeneous and for this reason, the positivity to a single component of a given family is often highly suggestive of sensitization to the whole family. By the use of cluster analysis, it has been shown that this is true for profilins, CBP and tropomyosins. On the contrary, PR-10 and LTPs have a more heterogeneous behavior, and a single positivity cannot be predictive of sensitization to all the components of the family .
Pan-allergen and cross-reacting allergens
Pan-allergens are widely distributed across different natural sources. Profilins and CBP are pan-allergens, since they are present and highly invariant in nature. One of the relevant characteristics of pan allergens is to be recognized by IgE raised against one component of the family. For example, in grass allergy, IgE anti Phleum components are raised, and profilin Phl p 7 is generally considered as a relevant sensitizer. Nonetheless, due to the high homogeneity of the different component of this family, IgE anti Phl p 7 can recognize other members, such as Bet v 2 from birch. Cross-reacting components have a slightly different nature: indeed, cross-reacting molecules can be detected in very different allergen sources. Table 3 shows the classification of four different sources of tropomyosins that can act as an allergen in humans. Thus, different components share epitopes that can be recognized by the same IgE, with different affinity. However, the sole binding (even at low affinity) of an IgE to the allergen can cause an allergic reaction in sensitized patients. The presence of pan allergens and cross-reacting components partly justifies the large number of positive results when skin prick tests (SPT) or specific IgE (sIgE) are carried out by using crude extracts. The main sensitizer remains often unknown and the identification of the allergen to be considered the target of an AIT approach is sometimes difficult.
The history of sIgE and the laboratory test for IgE
IgE were originally described in 1966 by K. Ishizaka  and in 1967, SGO Johansson described the first methods to evaluate their concentration in peripheral blood . Since then, several assays to evaluate the concentration of IgE specific for a given allergen were developed and used in laboratory medicine. These methods are mainly based on a solid substrate (originally Sephadex, then paper, and more recently a cellulose derivative enclosed in a capsule). Alternatively, allergens were adsorbed to plastic microwell or, better, linked to assay-specific coated bead trough a molecular bridge. All these tests were highly automated and, at present, the quality of the results, at least for the two main technologies (represented by Phadia ImmunoCAP and Siemens Immulite) are acceptable. The real improvement of MBAD was made in early 1990, when a group of scientists, headed by R. Valenta, cloned different allergen components and used them as reagents in immunoassays . It was immediately apparent that a more accurate dissection of the IgE profile could improve the diagnostic precision. In particular the reactivity of “genuine” allergens could be distinguished from that of cross-reacting components. In addition, a sensitization to particularly harmful components could also be detected. The implications of such an improvement became immediately clear to the scientific community. Recombinant allergens (in particular, those obtained by Escherichia coli) do not undergo post-translational modifications (such as glycosylation), but this fact had not apparent effects on the reactivity to IgE. On the contrary, the absence of glycosylation is, at present, a real advantage, because any cross-reactivity with cross-reactive carbohydrate determinant (CCD) is avoided . The evolution of the allergens was paralleled by the evolution of immunoassays and, at present, a wide armamentarium for the description of the patient’s IgE profile is available. In the light of the modern PM, this is one of the most interesting fields for a detailed diagnostic procedure. Indeed, not only the IgE repertoire is accurately defined (harmless and potentially dangerous molecules), but also, as described below, more proper indications for an effective AIT can be achieved.
The present resources for the description of IgE repertoire
Singleplexed diagnostics (SPD)
SPD tools have been implemented on few different platforms (Table 4), in particular the ImmunoCAP Phadia Immunosystem by Thermofisher and the Immulite by Siemens. Briefly, the Phadia platform uses an enzyme immune-assay characterized by a very large amount of allergen conjugated with the solid phase. Using this approach, the ImmunoCAP is able to detect both extremely low doses and extremely high doses of sIgE. Immulite is based on chemiluminescence. Also in this case, a large amount of allergen is conjugated to the solid phase by a “molecular bridge”. The SPD approach is highly dependent on the doctor’s habit and culture. In the hands of a skilled allergist, the more extensive component selection, the more robust is the information. SPD can also be used when after exhaustive SPT (and sIgE testing), the patient’s situation remains unclear and when AIT must be prescribed. Indeed, AIT needs 3–5 years of treatment to establish a perceivable clinical result. Therefore, a precise diagnosis for prescription is needed to justify the cost to benefit ratio.
Multiplexed diagnostics (MPD)
The multiplexed approach in allergy is based on allergens (both highly purified natural molecules or recombinant components) combined in a fixed panel. For this reason, the list of molecules included in the multiplexed assays depends on the relevance of allergens, on the real value in the diagnostic process and on the capacity of that given molecule to be linked to the solid phase. The first allergen microarray [Immuno Solid-Phase Allergen Chip (ISAC)] was described in 2002 . Since then the assay was improved, the number of components increased and its clinical use become widespread , , , . Recently, other platforms were developed and described: the MedALL  and the Microtest . The characteristics of the different platforms available are listed in Table 5. The multiplexed-based diagnostic approach offers both advantages and disadvantages . In particular, MPD, based on a predefined allergen list, gives also unrequested (or unexpected) results. This possibility has been considered, by allergist, as a disadvantage: indeed, the occurrence of unexpected results may be a source of confusion for the patient and pose a dilemma to the allergist who has to explain these results .
Allergen immunotherapy, molecular based diagnostics and PM
AIT involves the administration, subcutaneously or sublingually, of an extract of the allergen that is responsible for the clinical symptoms, in order to induce a “tolerance” thus decreasing the symptoms induced by the allergen itself . This is achieved through complex immune modifications that involve both humoral and cell-mediated immunity. As a paradigm AIT is “specific”. This means that the immune response is usually confined to the allergen (or allergenic source) to which the vaccination is performed. Thus, a detailed aetiological diagnosis is required for the prescription of AIT. This involves mandatorily a clear definition of the IgE mediate mechanims and the identification of the allergen, which is responsible of symptoms. Where allergen sources (e.g. plants) are few, and their pollen seasons are well defined and separated, a detailed clinical history, the knowledge of the local allergens and the standard diagnostic procedures are sufficient to identify the relevant allergen(s) . The allergen-oriented diagnosis, to prescribe AIT, becomes more complex, when the standard diagnostic tests exhibit a poly-sensitization profile, and the clinical history is not helpful. This may occur in a relatively high proportion of patients, since poly-sensitization is prevalent with respect to isolated sensitization. Nonetheless, the European approach to AIT is to desensitize only for few relevant allergens, whereas in USA, allergens are mixed together . In many cases, multiple positive results obtained with standard diagnostic procedures are due to the presence of cross-reactive molecules (pan-allergens) that are present in the diagnostic extracts used. Profilins, polcalcins, PR-10 are highly conserved in a wide variety of species, thus a patient sensitized to grasses may test positive for birch, due to the profilins contained in both extracts . The use of molecular based diagnostics allows to clearly identify genuine sensitizations and cross-reactivities, refining the prescription of AIT. Molecular diagnostics can also improve the selection of patients for hymenoptera venom AIT. Nowadays, there is increasing evidence that a MBAD can modify, improve or refine the prescription of AIT. Passalacqua et al. , in a population of 450 polysensitized subjects, found that the multiplexed approach could provide, based on the physicians’ judgement additional and useful information in more than 20% of subjects. Similarly, Sastre et al.  in 141 patients showed that the concordance between standard diagnostics and molecular diagnosis was about 60%. Consequently, the prescription of AIT was changed or modified in a large number of cases. Of note, it has been suggested that adverse reactions to AIT are partly related to the molecular sensitization profile. In particular, the occurrence of local or systemic reactions was higher in those patients sensitized to Phl p 1+Phl p 5 . Schmidt-Grendelmeier ,  reported that in a population of 737 allergic patients treated with AIT, the best clinical results were observed in those patients with only genuine sensitizations, and the worst results were more frequent in patients with sensitizations to cross-reacting components. It remains firm that molecular allergy diagnosis, especially with multiplexed instruments, remains a third-line approach, to be used only in patients with a complex poly-sensitization profile, and when the standard diagnostics are insufficient to choose the appropriate allergen(s) for AIT . On the other hand, a “tailored” AIT, using only the genuine sensitizers seems difficult to realize, since there are too many different sensitization profiles , , , and so far, commercial extracts (that are less expensive) perform as well as purified/recombinant molecules for AIT , . Allergen specific immunotherapy (AIT) is a well-documented effective treatment for respiratory and hymenoptera venom allergy , , , , , . Although AIT was empirically used the beginning of 1900, its efficacy has been later substantiated by several controlled studies ,  both for subcutaneous SCIT and sublingual SLIT routes of administration , , , . Some SLIT products, recently approved as drugs by EMA and food and drug administration (FDA), are available on the market and reimbursed. We recently described AIT, as a prototype of PM , . In fact a correct AIT is fulfilling the requirements for a defined PM approach . This is indeed true whenever some rules are respected: a correct specific allergy diagnosis with standardized extracts for skin tests and available specific AIT product documented in controlled studies or registered by the respective regulatory body. In both our papers we clearly pointed out MBAD to be crucial to prescribe a correct AIT, as previously reported in single trials , , . It has been defined in the global Consensus Document on MBAD  as a fruitful tool also in AIT prescription in daily clinical practice.
Molecular allergy diagnostics: interpretation of the results at the light of PM
The interpretation of SPD
SPD in general, does not require specific expertise for its interpretation. Indeed, when the testing of a single or a small number of components is required, it is clear, in the mind of the allergist, in which scenery these results will be used. For example, if a sensitization to tropomyosins is suspected, the evaluation of Der p 10, in a patient sensitized to mites, could explain the mite-shrimp syndrome recorded. In other word, sIgE to Der p 10 represent the molecular basis of the observed syndrome. On the contrary, if Der p 10 is negative and a sensitization to the extractive (whole) allergen of shrimps (or other foods expressing tropomyosins) has been observed, other molecular components of crustaceans, such as Pen m 2 (an arginine kinase) or Pen m 4 (a calcium binding protein) should be tested to detect a true sensitization to shrimp allergens. Similarly, if a sensitization to profilin is suspected in a patient sensitized to Phleum p., Phl p 7 should be assayed together with Phl p 1 and Phl p 5, two genuine grass components. The presence of IgE to Phl p 7 may explain several positivities observed in SPT and sIgE performed with allergen extracts, but should not modify the strategy for AIT. On the contrary, if Phl p 1 and Phl p 5 are negative and profilins are positive, AIT is not recommended, at least on the basis of the abovementioned reasons.
The interpretation of MPD and ISAC
ISAC, being a microarray containing 112 different components which include inhalant, food, contact and hymenopter allergens as well as genuine or cross-reacting components, requires a certain expertize for its interpretation . A general description of how to evaluate the whole result of an ISAC is given in the World Allergy Organization (WAO) consensus paper  and, in a greater detail, in the article describing the expert system Allergenius . Briefly, the presence of IgE to cross-reacting components should be immediately evaluated, as well as the presence of IgE to genuine components. In both cases, the presence of IgE to potentially dangerous allergens should be immediately evaluated. Finally, the evaluation of the relationships between the patient’s clinical picture and the results of ISAC should be carefully evaluated. Indeed, in Authors’ experience, the relationships between the ISAC results and symptoms are normally observed, while discrepancies between clinics and the IgE repertoire are rare. Interestingly, these discrepancies should be considered as an opportunity to ask patient further questions in the attempt to evaluate whether ISAC had identified a sensitization that was not recorded during the collection of the patient’s history.
Allergenius and the computer assisted diagnosis
Allergenius is a tool that helps allergist in the interpretation of ISAC . The work describes in great detail how and which rules were collected and what is the inferential engine activated by these rules. However, being an Expert System, Allergenius is not based on machine learning procedures: in other word, Allergenius cannot receive information from the external world and thus cannot be updated in real time. Only updates decided by the committee of experts in charge will be implemented in the future. From a practical point of view, it is difficult, also for experts, to remember the characteristics of 112 different components, the origin (recombinant or extractive), the relationships with other components, the membership of a component family, etc. In addition, calculations (such as evaluation of the fraction of cross-reacting components to assign the patient to a certain “component phenotype” , cannot be rapidly made in the allergist’s office. For all these reason, Allergenius works as a support to Allergists and clinical pathologists for the interpretation of ISAC. Notably, in the on line Allergenius report, selected words (such as profilins or Der p 10 or Birch) are modified to be links to special tables explaining the characteristics of that given object. This is a technique that Allergenius has introduced for the first time, in the laboratory report and should be easily exportable for all the assays that are new or not well known to the large majority of doctors.
Positive and negative for inhalants and food
Very recently, MBAD in food allergy has been endorsed . One of the problems of both SPD and MPD is that the range of positive results varies from 0.1 (or 0.35) to 100 units. Also naïve users of MAD realize that the common range for inhalants is from 0 to 100, while the common range for food allergen and components is 0–10. So, if a sensitization to mites results equal to 5.6 U (a low class result), the same result for a food (such as a lipid transfer protein) is highly representative of a clear sensitization. It is evident that it is extremely difficult to prepare standard curves for all the different components. So, Allergenius calculates the 95th percentile of all the positive results observe in the course of a 2-year survey and indicates this number together with the patient’s result. So, if the 95th percentile for Der f 2 is 85.3, it is clear that 5.6 is suggestive of a small number of reacting IgE. On the contrary, for Ara h 1, the 95th percentile is 8.2. Thus, a result of 5.6 U is clearly suggestive of a significant sensitization. It is a common notion that the relationship between a sIgE result and the clinical picture are not very strict, but allergists are aware that a strongly positive result is much more indicative than a weak IgE mediated immune-response.
Correlation between SPT, sIgE and MBAD
It is commonly said that SPD is not only highly specific but also highly sensitive, while ISAC results are specific but poorly sensitive. However, ISAC results may also be used for the interpretation of discrepancies observed between SPT or sIgE results and ISAC. For example, SPT and sIgE for Parietaria j. are positive but Par j 2 is negative. ISAC allows the interpretation of these results by evaluating other potentially related components. For example, Par j 3 (a profilin) and Par j 4 (a calcium binding protein) are well represented in the Parietaria whole extract. For this reason, SPT and sIgE could be positive in patients with a sensitization to these two cross-reacting components. Allergenius check whether other profilins or CBP are positive: if yes, the positive SPT and sIgE are explained but the negativity of Par j 2 (the LTP genuine component of this allergen) clearly indicates that no specific sensitization to Parietaria is evident: this is an important point for the administration of AIT .
In a world rapidly moving to the new rules of the PM, allergy represents a topic where not only these rules can be immediately applied, but also where many even if prototypic PM approaches have been developed in the past. So, for example, not only the sensitization profiles of patients were evaluated by means of SPTs since the beginning of the last century, but also the specific treatment, the AIT, at present the only therapeutic approach suitable to modify the natural history of the allergic patient, was based from its origin, on the results of sensitization tests. The discovery of the IgE as immunoglobulins responsible of the allergic reaction at cellular level, and, in the same time, the description of efficient laboratory methods to identify the specificity of these antibodies, has further addressed allergy diagnosis and allergy treatment in the direction of what will be, in present day the PM. Finally, the introduction of a even more sophisticated techniques, based on allergy components, had finally given the dignity of a PM approach to the whole management of the allergic patient. Along this line, the management of the allergic patient, when carried out using the extremely reliable data of modern molecular diagnostics, is strictly aligned with the principle of PM. Moreover, the accuracy of the diagnosis, based on the clear evidences of an immune-response directed to specific allergen components, implies that also the AIT proposed to the patient is also strictly in line with the rules of PM. However, this is the present. In a near future, the allergist and the clinical pathologist will be asked to face even more complex tasks, such as proteomics, metabolomics and, to some extend genomics (intended as collection of information by the routinely use of next generation sequencing) that, all together, will help clinicians not only in the accurate diagnosis of the allergic patient but also in the identification of specific genotypes (or phenotypes) known to benefit from specific and highly personalized therapies.
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About the article
Published Online: 2016-03-17
Published in Print: 2016-11-01
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: Giorgio W. Canonica, Giovanni Passalacqua and Giovanni Melioli were members of the Italian Board for ISAC (IBI) sponsored by ThermoFisher.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.