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JournalImmunoDiagnosticsScientific news,opinions and reports

Journal No. 4. 2013

3 CAPture

4 Clinical Utility o Peanut Components

CAPture and Peanut sensitization phenotypesCAPture highlights three recent articles; the rst shows that wheata/b/g-gliadins are importantmarkers in wheat-dependent exercise induced anaphylaxis (WDEIA), and the second demonstratesthat also in the Mediterranean area storage proteins are the major severity markers in peanut allergy.The last article reviewed describes how sensitization in grass allergy spreads on the component levelduring childhood.

With the advent o recombinant peanut components the diagnosis o peanut allergy has beenimproved by allowing the discrimination o patients o dierent sensitization patterns. That thesesensitization phenotypes correlate with dierent clinical maniestations o the allergy gains more andmore support rom studies published, which is reviewed in this issue.


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ImmunoDiagnostics Journal No. 4. 013

CONTENTS

3 CAPture A selection o recentallergy papers

4 Clinical Utility o Peanut Components Background

Sensitization Phenotypes o Peanut Allergy

Combining tests or increased perormance

Confrm or exclude peanut allergy

Literature list

ImmunoDiagonstics Journal is the Journal o

Thermo Fisher Scientifc

This issue is published by Thermo Fischer Scientic -Phadia ABP.O. 6460, SE-75137 Uppsala, Sweden

EditorMalin Berthold

Contributor(s)

Jan Hed, Anita Kober

Peanut Allergy Focus

For almost 40 years,Thermo Fisher Scientic

ImmunoDiagnostics,previously known asPhadia, have maintainedglobal leadership in allergytesting and become oneo the worlds leadingautoimmune disease testproviders. Through clinical

excellence, laboratory eciency and our dedication,we strive to deliver the highest quality and clinicalvalue in our diagnostic tests, as well as providing

clinical expertise and scientic inormation.This ourth issue o Immunodiagnostics Journalincludes a CAPture section with summaries o somerecent interesting publications in the eld o allergy,ollowed by an article summarizing the clinical utility opeanut components.

With the introduction o allergen components thediagnosis o peanut allergy has been dramaticallyimproved. Peanut sensitization patterns revealdierent phenotypes o peanut allergy that are

associated with dierent clinical maniestations. Notonly can component resolved diagnosis help toidentiy those patients who run a high risk o severereactions, but they may also contribute to minimizingthe need or oral ood challenges as suggested inseveral publications. The review gives reerences torecent papers supporting the concept o MolecularAllergology in peanut allergy and gives an overviewo the peanut components that orm the basis or thedierent sensitization phenotypes. The benet ocombining peanut extract tests and components oran optimal combination o sensitivity and specicity isdescribed based on published results.

I hope that the ImmunoDiagnostics Journal providesyou with an easy way to catch up with or learn moreon topics o interest to you.


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3


CAPture A selection o recent allergy papers

SYNOPSISCombined testing o sIgE to a/b/g-gliadin andw5-gliadinincreased the sensitivity to 100% in a population o

WDEIA patients

Serum IgE tow5-gliadin has earlier been shown to have an 80% sensitivity todetect wheat-dependent exercise-induced anaphylaxis (WDEIA). The aim o thepresent study was to analyze the IgE sensitization proles o adult WDEIA patients(n=17) using well characterized puried wheat allergen components on theImmunoCAP platorm. The diagnosis o WDEIA was based on clinical history andchallenge tests o most patients.

The sensitivity o serum IgE to either w5-gliadin or a/b/g-gliadin was both 82%(14/17) when a cut o at 0.35 kUA/l was applied. Three patients negative tow5-gliadin were all positive to a/b/g-gliadin, indicating that by combined testingor specic IgE to w5-gliadin and a/b/g-gliadin would increase the test sensitivityto 100% in this population. Analyzing sIgE to HMW (high molecular weight glutenin)in addition to w5-gliadin did not increase the sensitivity o testing, and serum IgEto HMW on itsel was shown to have a sensitivity o 59%. Only one patient haddetectable serum IgE to wheat LTP and AAI dimer in this study.

The authors conclude that by using combined testing o IgE to w5-gliadin anda/b/g-gliadin, the gap in the in vitro diagnostics o WDEIA might be closed.

Citation: Hofmann SC et al. IgE detection toa/b/g-gliadin and its clinicalrelevance in wheat-dependent.

Allergy 2012; 67:1457.

Citation: Pedrosa M et al. Peanut seed storage proteins are responsible forclinical reactivity in Spanish peanut-allergic children.Pediatr Allergy Immunol. 2012;23:654-9.

Adultpatients(agerange17-60y)withtypicalhistoryoWDEIA

wererecruited.

Infvepatientsco-actorssuchasaspirin,alcoholand/orinection

wereinvolvedinelicitingsymptoms.

IgEtowheatextractandtow5-gliadinwerequantifedwithcommerciallyavailableImmunoCAPtestsusingacutoat

0.35kUA/l.(PhadiaLaboratorySystem,ThermoFisherScientifc,

Uppsala,Sweden).

SerumIgEtoa/b/g-gliadin,high-molecular-weightglutenin(HMW-glutenin),alpha-amylaseinhibitordimer(AAI)andwheatLTP

wereanalyzedusingexperimentalImmunoCAP.

Theresultswerebasicallyconfrmedinamicroarraytechnology

platorm.

SYNOPSISThe majority o peanut allergic children in the

Mediterranean area are sensitized to storage proteins

and not LTP

Previous studies have shown geographical variations in the sensitization prolesand clinical phenotypes in peanut ood allergy. The most established conclusionhas been that sensitization to storage proteins dominates worldwide except in theMediterranean area where sensitization to lipid transer protein (LTP) related topeach allergy is common.

The aim o the present study was to see i this could be conrmed by comparing

sera rom unselected peanut allergic Spanish children and peanut tolerantchildren with suspected ood allergy using the ImmunoCAP ISAC microarray.Sensitization to storage proteins was more common than sensitization to LTP(76% vs. 47%) in Spanish peanut allergic children. IgE to storage proteinswas signicantly (p


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4


Clinical Utility o Peanut Components

phenotypic characterization o peanut

allergic patients

Background

Peanut allergy is one o the most common ood allergiesin childhood in many parts o the world, oten appearingalready during the rst two years o lie. The prevalence hasbeen estimated to be 1- 2% but this gure varies widelybetween studies rom dierent countries and also dependson how the diagnosis is made e.g. reported disease vs.

challenge veried disease(1, 2).

Peanut allergic inants oten have a concomitant allergy to otheroods e.g. egg and milk. Unlike milk and egg allergy, peanutallergy used to be considered a lielong disease. However, itis now reported that approximately 20% o peanut allergicchildren develop tolerance within the rst ve years o lie, andthat in those with low peanut-specic IgE levels as many as50-60% may outgrow their peanut allergy(3, 4).

The requency o peanut allergy appears to have increasedduring recent years and as allergy to peanut and tree nutsoten lead to severe systemic reactions and anaphylacticshock, they have received much attention(5-9). In the ewcases where peanut allergy leads to atal reactions, mainlyadolescents and young adults with concomitant asthma are

aected(10, 11).

Peanut allergen components have since several yearsbeen used in clinical studies, showing the relationbetween dierent sensitization phenotypes and clinicalmaniestations o peanut allergy. Some o the previousconclusions drawn on prevalence, incidence and tolerancedevelopment in peanut allergy based on peanut extracttests may have to be re-evaluated with these new tools.


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5


Sensitization Phenotypes o Peanut AllergyRecombinant DNA technology allows the ecientproduction o pure peanut allergen components that todayare used or component resolved diagnosis (CRD) inpatients with a suspicion o peanut allergy. CRD helps toidentiy the most serious sensitization phenotypes where

the allergic patients runs the risk o anaphylactic reactions,and to distinguish these rom those who will react only withmild, i any, symptoms. Patients previously diagnosed aspeanut allergic may thereby be relived rom daily anxiety aswell as unnecessary dietary restrictions.

Peanut allergy related to storage proteins

Peanut allergy associated with sensitization to the storageproteins Ara h 1, Ara h 2 and/or Ara h 3 is the most seriousorm o peanut allergy, and has now been described all overthe world Europe, USA, Asia and Australia(13-17) andrecently also in the Mediterranean area, where previouslypeanut allergic children and adults were shown to mainly beo other sensitization phenotypes(18).

The sensitization to storage proteins oten appears early inlie, even beore the age o one year, and can be shownin patients with clinical allergy also to other legumes suchas soy(19, 20) and lentils(21) but also to tree nuts(22) andvarious seeds such as sesame seeds(22-24). Children whosuer rom severe atopic dermatitis and who are sensitizedto egg and milk during their rst year o lie appear to beat higher risk o sensitization to peanut and soy storageproteins(15, 25-27).

Peanut allergic patients who develop tolerance over time

may be those sensitized to storage proteins, as the diseaseonset precedes that o sensitization to aeroallergens.Ho et al. showed that low levels (< 3 kUA/l) o IgE topeanut extract in the rst 2 years or decreasing levels bythe age o 3 predict likely remission o peanut allergy(28).A similar decrease in sensitization requency during therst three years o lie has been shown also in soy extract

sensitized inants(29). This indicates that sensitizationto storage proteins, although associated with severesymptoms, still may be outgrown in early lie. Recurrenceo peanut allergy has been shown at older age in somestudies however i this phenomenon is due to the samestorage protein dependent phenotype or is due to an onseto a new, pollen related phenotype, has not been shown(3).

Storage proteins are very stable to heat, low pH andprotease activity in the gastrointestinal tract, explaining whythis peanut sensitization phenotype is highly associated withallergic anaphylaxis and even death.

It is well known that many more individuals are peanutsensitized than who actually have allergic symptoms topeanut. In the MAAS birth cohort, or example, it wasshown that 11.8% o 8 years old children were sensitizedto peanut extract while only 22.4% o the sensitized

children reacted in peanut challenge tests(12). Thus, eightypercent o those showing positive peanut extract testswere not peanut allergic in this non-selected childhoodpopulation. In the same study peanut storage proteincomponents could discriminate between serious and lessserious sensitization phenotypes o peanut allergy.

Component Protein type Comments

Arah1 Storageprotein

7Svicilin-likeglobulin

Peanutspecifcmarker


2Salbumin,conglutinin

Peanutspecifcmarker


11Sglobulin

Peanutspecifcmarker

Arah5 Proflin Markerograsspollencross-reactivity,

lowclinicalrelevance


2Salbumin,conglutinin

Peanutspecifcmarker

HighlysimilartoArah2

Arah8 PR-10protein Markerotreepollencross-reactivity

Arah9 nsLTP Markeropeachcross-reactivity

Peanut allergen components


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LTP-related peanut allergy

The LTP (lipid transer protein) phenotype o peanut allergy,characterized by sensitization to Ara h 9, has mainly beendescribed in the Mediterranean area and is suggestedto be caused by cross-reactivity in patients sensitized topeach LTP(17, 30). In contrast to storage protein-relatedpeanut allergy, this orm o peanut allergy seems to startsomewhat later in lie, apparently when sensitizations aretriggered by inhalant allergens(17). Patients with LTP-relatedpeanut allergy are seldom reported to be under 10 yearso age and are usually older(30, 31).

LTPs are very stable in the gastrointestinal tracts (low pH,proteases) and thereore LTP sensitization is also a riskactor or serious systemic reactions in peanut allergic

(lip swelling, stomach cramping and tiredness), possibly dueto sensitization to other storage proteins such as Ara h 6 (38).

As always, in assessing the risk o severe reactions to anyallergen it is important to be aware o the act that allergicsymptoms are not only based on the allergen specic IgEconcentrations but also on the dose o the allergen per se,as well as other contributing actors such exercise, NSAIDdrugs and inections.

Grass pollen related allergy

Grass sensitization is the most common cause o prolinand cross-reactive carbohydrate determinant (CCDs)sensitization in ood allergic patients, and both prolinand CCD antibodies are highly cross-reactive with peanutprolin (Ara h 5) and CCDs(39). It is however broadlyaccepted that the clinical relevance o these sensitizationsis generally low, which is true also in peanut allergy (40-46).

As or other pollen allergens, sensitization to prolin is

mainly detectable ater inancy (> 2 years o age). Whenusing recombinant components in the diagnostic testing,sensitization to CCDs is not detected, and thus theseclinically irrelevant antibodies do not obscure the testresults.

Tree pollen-related peanut allergy

Extract based peanut specic IgE tests are oten positive inpatients living in areas rich in birch due to cross-reactivitybetween Bet v 1 in birch and its homolog Ara h 8 inpeanut. In other geographic areas, PR-10 proteins romother tree pollen such as alder, beech or oak may giverise to the same type o cross-reactivity(36, 37). PR-10sensitization thereore coincides with the development oinhalation allergies and is mostly seen in children older than

2 years o age.Food allergic reactions caused by PR-10 sensitization areusually restricted to the oral cavity which can be ascribedto their unstable nature; already in the mouth the allergen isdegraded and heated oods are oten tolerated.

Thus, the PR-10 dependent sensitization phenotype inpeanut allergy is considered a mild orm, with low riskor severe reactions. This was nicely and convincinglydemonstrated in a clinical study rom Sweden whereAsarnoj et al. showed that 90% o children sensitized only

to Ara h 8 (the level o sensitization to storages proteinsAra h 1, Ara h 2 and Ara h 3 was below 0.35 kUA/l) didnot react in peanut challenge while 9.7% reacted with OASat the rst two, but not subsequent challenge doses. Onlyone single individual reported other symptoms

patients, although in this phenotype it is also common thatonly local reactions are elicited.

Although peach allergy is suspected to be the predominantcause o LTP sensitization in the Mediterranean area, up to

25% o the peanut allergic patients are in act suggested tohave primary sensitization to something else than peach(31).Gao et al. recently showed that in Chinese peach allergicpatients the primary driver o LTP-sensitization diereddepending on the geographical location and exposureto dierent possible triggers(32), and already previouslymugwort and plane tree pollen were suggested to drive LTPsensitization(32-35). In conclusion, there are uncertaintiesregarding the primary source o LTP sensitization.

Labile protein low amount

Stable protein high amount

Ara h 5 Ara h 8 Ara h 9 Ara h 1

Ara h 2

Ara h 3

PR-10 LTPProfilinStorageProteins

Likelihood of

asymptomatic

sensitization

Two peanut sensitization phenotypes can give rise to serious systemic reactions; those caused by sensitization to storage proteins and to lipid transer

proteins (LTP), respectively. These are both stable proteins and abundant in peanuts. The proflin and PR-10 phenotypes may be asymptomatic or eliciting

mainly local reactions, as these proteins are readily degraded, heat sensitive and o low abundance in peanuts.


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Combining tests or increased perormance

Improved clinical sensitivity

Increased sensitivity o the ImmunoCAP technology nowenables reliable quantication o allergen-specic IgE downto 0.1 kUA/l, as compared to previously 0.35 kUA/l. As aconsequence, the clinical sensitivity has also improved, as

shown in recently published studies. In a selected populationand using the lower limit o detection (0.1 kUA/l), a 100%sensitivity(47) was obtained when diagnosing peanut allergyas compared to 90-96% sensitivity in similar populationswhen the higher cut o level was applied(48, 49).

Peanut allergic patients o all phenotypes - storage protein,LTP, PR-10 and prolin - are positive in peanut extracttests when using the 0.1 kUA/l cut-o

(12, 31, 50), and thus anegative test excludes peanut allergy with a high degree ocertainty, i.e. the NPV is high.

Ideally, in vitrodiagnostic tests should provide results thatenable complete separation o patients in those who havea disease and those who do not, leaving no cases ounclear diagnosis - in other words the positive and negativepredictive values should both be 100%. This is howevernever the case or any allergy test as many dierent actorsinfuence the clinical symptoms and there is no singlemeasurable marker that alone can discriminate betweenclinical disease and no disease.

O importance or the clinical situation is that predictivevalues depend not only on the sensitivity and specicityo the test, but also to a high degree on the prevalence odiseased patients in the tested population. As soon as thesensitivity and specicity are less than 100% the positiveand negative predictive values decrease rapidly as theprevalence decreases. This means that specic IgE testingnever should be used as a screening test in a generalpopulation but only be used as an aid or the clinician whenthere is a suspicion o allergy.

Increasing clinical specifcity

A high specicity is needed to obtain a high positivepredictive value o a diagnostic test, especially i theprevalence o the disease is low. Increasing the specicitywhile maintaining the sensitivity improves the test, and in

the case o peanut allergy this is now achieved by usingCRD in combination with extract based testing. A negativetest (below 0.1 kUA/l) or the storage protein Ara h 2excludes storage protein related peanut allergy with a veryhigh probability (although it cannot be ully excluded), andadditional testing o IgE antibodies to other storage proteins- Ara h 1, Ara h 3 and Ara h 6 - increases thecertainty(15, 18, 51-53).

AnegativeIgEtest(


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Confrm or exclude peanut allergyThe use o peanut extract based tests

The cut-o o 15kUA/l or extract based peanut IgE testshas been widely used in studies and clinical routine tominimize the number o challenges perormed(49, 54, 55).However, this decision point is based on data rom aselected population at an allergy specialist level and haslow sensitivity since roughly 50% o patients sensitizedbelow this level are clinical reactive(12, 47, 56). This indicatesthat test designs solely based on peanut extract can onlyreplace a certain number o ood challenges in the clinicalroutine.

Storage proteins as discriminators

Through many studies it is now well established thatsensitization to the storage protein Ara h 2 has the highest

potential o the three storage proteins or discriminatingbetween symptomatic and non-symptomatic peanutallergy(12, 47, 53, 57-61). Decision points o both 100%sensitivity and specicity have been determined in dierentstudies by quantiying IgE to Ara h 2 down to 0.1kUA/l

(53,

57, 58, 62). However it must be noted that such decisionpoints also or components are dependent on the kind opatients tested and o the prevalence o the disease in thetested population.

Addition o Ara h 1, Ara h 3 and Ara h 6 specic IgE testswill increase specicity and sensitivity to some degree, asnot all patients who develop symptoms show sensitizationto Ara h 2(15, 18, 52, 53). In accordance with this,Ebisawa et al. showed that a combination o all threecomponents increased the specicity but decreased thesensitivity, underlining the dominating role o Ara h 2 orclinical symptoms(15).

SerumIgEtoArah2isthebestdiscriminatorosymptomaticandnon-symptomaticsensitizationinthe

storageproteinphenotype

ThetestcombinationIgEtopeanutextract(highsensitivity)andtoArah2(highspecifcity)would

decreasetheneedooodchallengetestwith50-100%

IgEtestingtoadditionalstorageproteins(Arah1,Arah3,Arah6)mightleadtoimprovedrisk

assessment

Furthermore, it has been shown that both epitope diversitywithin an allergen component as well as diversity including

concomitant sensitization to several dierent componentsis associated with a more severe orm o storage proteinrelated peanut allergy(63). This indicates that measuringsensitization to all storage proteins could have additionalclinical value or risk assessment(47, 55, 59).

In order to achieve an accurate and sae diagnosis o peanutallergy, it is vital to quantiy also very low levels o peanutcomponent specic IgE, as suggested by a study on apopulation o peanut allergic inants where roughly 20 % othose with clinical peanut allergy were shown to have Ara h 2levels below 0.35 kUA/l

(52).

It is essential to veriy a suspected diagnosis o storageprotein related peanut allergy. Equally important, asSicherer et al recently pointed out, is to be able to excludea hidden storage protein dependent allergy in pollensensitized patients who have mild peanut-associatedreactions(64).


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Reduced need or ood challenges

In ood allergy, double blind placebo controlled oodchallenge (DBPCFC) is considered the gold standard or anaccurate diagnosis; in practice however open challengesare mostly perormed. DBPCFC are cumbersome,expensive and potentially dangerous, and thereore thereis a strong need to reduce the number o challenges stillreaching a sae and accurate diagnosis. CRD has beenshown in several publications to be an aid in ullling thisneed in peanut allergy.

In the study o Codreanu, a cut o o 0.23 kUA/l or IgE toAra h 2 was calculated that distinguished between clinicalpeanut allergy and non-symptomatic sensitization with asensitivity and specicity o 93% and 96% respectively,and they concluded that by combining the high sensitivityo the peanut extract based test with the high specicity o

the Ara h 2-IgE test, oral challenges could be replaced(52).A similar testing strategy, reducing the need o oodchallenge was proposed by Lieberman et al. who showeda specicity o 91% using the cut o value 0.35 kUA/l

(47).A third study that propose an analogous strategy is byDang et al. where the need o ood challenge is shown to

Clinical Utility of peanut CRD

Helpstoexcludeclinicalpeanutallergy

Helpstoconfrmclinicalpeanutallergy Identifespatientsathighriskorsystemicreaction(phenotyping)

Reducesneedoroodchallengetestinthediagnosticprocess

decrease by two thirds i inants rst are tested with IgEpeanut extract and then Ara h 2, and only those withAra h 2 - specic IgE levels between 0.1 and 1.0 kUA/lare selected or challenge test(14). Hong et al. could denean optimal cut o point with a 99.1% sensitivity and98.3% specicity with only 1.2% misclassication(28), andin a patient population studied by Eller at al. the need oood challenge tests decreased with 55% when using a cuto or Ara h 2 at >1.63 kUA/l.

Taken together, these studies suggest that the optimalstrategy is to combine extract based peanut IgE tests withquantication o Ara h 2-specic IgE antibodies down to0.1 kUA/l. Application o this diagnostic workup woulddecrease the need o ood challenge test with 50-100%depending on the tested population.

The best guess based on what has been reported up totoday is that a decision point with high predictive value(above 95%) or diagnosing storage protein related peanutallergy would be somewhere between 0.25-1.5 kUA/ldepending on the selected population.


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