Pollen

Nuts

Eggs

Cat

Mould

Milk

Drug Allergy

Fish

Wheat

Peanut

An approach to the Diagnosis of an Allergy

Your consulting pathologistsPR0520005200431www.ampath.co.za

AN APPROACH TO DRUG ALLERGY

AN APPROACH TO DRUG ALLERGY DIAGNOSIS - MADE EASY WITH A FLOW DIAGRAM

HISTORY COMPATIBLE WITH DRUG ALLERGY

POS

IMMEDIATE

NEG POS

NEG POS

DRUG IMPORTANT?PROVOCATION POSSIBLE?

REFER TO SPECIALIST

YES

DRUG PROVOCATION

NO AVOIDANCE

NEG

SPT DRUGINTRA-DERMAL TEST

ImmunoCap® CAST

• AVOID• EDUCATE• DOCUMENT

NO

POS

DELAYED

NEGPOS

NEGPOS

DRUG IMPORTANT?PROVOCATION POSSIBLE?

REFER TO SPECIALIST

DRUG PROVOCATION

NO AVOIDANCE

NEG

SPT DRUGPATCH TEST

INTRA-DERMAL TEST

CASTMELISA

• AVOID• EDUCATE• DOCUMENT

NOYES

DRUG ALLERGY CONFIRMED

• AVOID• EDUCATE• IDENTIFY SAFE ALTERNATIVE

YES

TIMING OF REACTION

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AN APPROACH TO DRUG ALLERGY

•Whentestingforpenicillinallergy,patientsshouldbetestedtothepenicillinring,major andminordeterminantsandrelevantside-chains.•Abetalactamringisalsofoundincephalosporins(2-5%penicillincross-reactivity), carbapenems(1%penicillincross-reactivity)andmonobactams(nocross-reactivity)•Quinolonesfrequentlycausedrugallergyandcross-reactswithotherquinolones.•Macrolidesdon’toftencauseallergiesandcross-reactivitybetweenmacrolidesis uncommon.•NSAIDallergyiscommon.Aspirin,diclofenacandibuprofenarethebestindicatorsof NSAIDallergy.PleasedistinguishbetweenAspirinallergyandAspirinexacerbated respiratorydisease,wherecox-inhibitionleadstogreatlyinducedleukotrineproduction. Thisisnotatrueallergyandpatientsmaypresentwithnasalpolypsandasthma.•Localanaestheticallergyiscommon,butpatientsmaytolerate1/morealternatelocal anaesthetics.•Radiocontrastmediumallergyiscausedbyanimmunologicalreactiontoquaternary iodinecomponents.Thisdoesnotcross-reactwithiodatedtablesaltorseafood.

CLINICAL PEARLS

AN APPROACH TO ECZEMA AND DERMATITIS

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FOOD ALLERGENS

ECZEMA

INFANT: Pruritic, red scaly and crusty lesions on cheeks, scalp and exterior surfaces

CHILDREN AND ADULTS: Plaques in the flexure areas, especially antecubital and popliteal fossea, volar aspects of wrists, ankles and neck

USUAL DISTRIBUTION

IF NEGATIVE

• Consider food challenge• Consider different mechanism: CAST - foods - contact aero-allergens (pets, house dust mite) - latex - colourants and preservatives MELISA - Foods - contact aero-allergens - metals

• Consider other eczematous disorders - Seborrheic dermatitis - Drug reations - Scabies - Hyper IgE syndrome - Wiscott Aldrich - Nutritional Deficiency

UNUSUAL DISTRIBUTION

PATCH TESTING - European baseline, cosmetic, hairdressing or sunscreen series.MELISA TESTING - Metals (i.e. gold, nickel, platinum, mercury) - Latex

Also consider skin prick testing or lgE testing to inhalants including pollens and

moulds

• Pet allergens• House dust mite• Latex IgE (If exposed)

CONTACT ALLERGENS

FOOD ALLERGENS• SPT/ImmunoCap® food mix (milk, egg, wheat, peanuts, cod)

+

IF HISTORY OF ASTHMA/ALLERGIC RHINITIS

AN APPROACH TO ECZEMA AND DERMATITIS

•Patientswitheczemahaveanintrinsic/impairedskinbarrierdefect,butallergenexposure causesflaresinatopicpatients.•Commonallergensarefoodallergensorcontactinhalantallergenslikedustmiteor animaldanders.•PatientswithveryhighIgElevels,asiscommonlyseeninatopiceczema,canleadto multiplepositiveallergytests(cross-reactivityandnon-specificbinding).AnISACtestis notinfluencedbynon-specificbindingandcanidentifycross-reactivity,thereforeis recommendedinthesepatients.•Patientswithanunusualdistributionoftheirrashshouldbeinvestigatedforcontact dermatitits(patchtesting).

CLINICAL PEARLS

THE FOLLOWING FLOW-DIAGRAMS ASSISTS WITH AN APPROACH TO ACUTE AND CHRONIC URTICARIA:

ACUTE URTICARIA FLOW-DIAGRAM:

CHRONIC URTICARIA FLOW-DIAGRAM:

Underlying disease?

Drug allergy testing Investigate and treat disease

Recent acute infection?

Symptomatic treatmentAvoidance Consider Challenge

Positive Negative

• SPT/Specific IgE• CAST

YES

Recent Drug?

NO

• Treat symptomatically. • If no resolution, investigate as for chronic urticaria

PHYSICAL URTICARIANO UNUSUAL FEATURES

• SKIN BIOPSY (HISTOLOGY)

• INVESTIGATIONS TO DETERMINE CAUSE

URTICARIAL VASCULITIS

LABORATORY INVESTIGATES TO IDENTIFY UNDERLYING /TREATABLE MEDICAL CONDITIONS

• IDENTIFY BY CHALLENGE TESTING

• IF COLD URTICARIA DO CRYOGLOBILINS

AN APPROACH TO URTICARIA

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OBVIOUS REACTION TO FOOD/FOOD ADDITIVE

ACUTE URTICARIA

• HISTORY• APPEARANCE OF LESIONS

CHRONIC URTICARIA

AN APPROACH TO URTICARIA

•Urticariamaybetriggeredbymultiplefactorsingeneticallysusceptibleindividuals, e.g.infections,autoimmunity,malignancies,hypersensitivityandphysicalorpsychological factors.•Allergyisrarely(5-10%)thecauseofchronicurticaria.•Themostcommonallergensimplicatedaredrugs,foods,colourantsandpreservatives.•Urticariaisitchy,notpainful.Itmaybeassociatedwithangioedema.•Suspiciousfeaturesofurticarialvasculitisispainfulornon-itchylesionsthatlast>24hours onthesamespotandhealwithbruisingorscarring.•Physicalurticariasincludedermatographism,delayedpressureurticaria,cholinergic urticaria,aquagenicurticariaandvibrationalurticariaandshouldbediagnosedfromclinical history.

CLINICAL PEARLS

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ANGIOEDEMA

Associated urticaria

Investigate as chronic urticaria

? ACE inhibitors? Statins? NSAIDS? PPI

Trial of substitution/ discontinuation of drug

drugsC1 inhibitorC4 levels

Positive family or history of onset at a young age No family history/ later onset

HISTORY OF ONSET, FAMILY HISTORY

AN APPROACH TO ANGIOEDEMA

FBC and Diff + ESRANA, ds DNA, ENAC4C1qIgG, A, MProtein electrophoresis B2 microglobulinUrinary Bence-Jones proteinsExamine for lymphadenopathy/ splenomegalyConsider chest/ abdominal CT

AN APPROACH TO ANGIOEDEMA

•Angioedemaisnotitchy,but“tingly”,burningorpainful.•Ifurticaria/itchisprominent,investigateandmanageasforurticaria.•Hereditaryangioedema(HAE)usuallypresentsearlyorwithapositivefamilyhistory.•AngioedemawithurticariaisnotHAE.•ThemostcommoncauseofangioedemainadultsisACEinhibitorsorNSAIDS.•Angioedema(withouturticaria)isnotanallergyandpatientsshouldbeinvestigatedfor anunderlyingdisease,.e.g.autoimmunityormalignancy.

CLINICAL PEARLS

AN APPROACH TO THE DIAGNOSIS OF ANAPHYLAXIS

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ANAPHYLAXIS

•Mostcelltryptase(alwaysdo abaselineafter24hours)•C3,C4

•Repeatmastcelltryptase•SpecificImmunoCap®IgE/CAST dependingonhistory: • Venoms - Bee/Wasp • Foods - Nuts,seeds,legumes - Fishandshellfish - Egg -Milk - Anyfood,includingfruit,vegetables andadditives • Drugs - Antibiotics - Radiocontrastmedia - Analgesics - Anaestheticagents,especiallymuscle relaxants - Biologicals • Latex

Latertests(after2or3weeks)ImmediateTests

•Mastcelltryptaseisveryimportanttodiagnoseanaphylaxisandispositiveinanaphylactic (IgEmediated)andanaphylactoid(non-IgEmediated)reactions.•Alwaysdoabaselinetryptaselevelatleast24hourslater.•Donotinvestigatefortheanaphylaxistriggerwithin2-3weeksofthereactionas basophilsinCASTtestsmayhaveincreasedbackgroundactivationandIgEmaybe negativeduetoincreasedconsumption.•Considerco-factordependantanaphylaxise.g.wheatinduced–exercise–induced anaphylaxis(LTP/Ω–5–gliadin),NSAIDoralcoholco-factoranaphylaxis.

CLINICAL PEARLS

AN APPROACH TO INHALANT ALLERGY

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HISTORY SUGGESTIVE OF INHALANT ALLERGY

* ALLSA/NPG panel: Bermuda grass, Rye grass, Alternaria (mould), Cladosporium (mould), Aspergillus (mould), D.pteronyssinus (mite), B.tropicalis (mite), cat, dog** Request specific allergen breakdown if CAST inhalant mix is positive and phadiatop is negative.

Phadiatop Inhalant Screen

Break down in ALLSA/NPG panel*ANDallergy tree mix/individual trees

Highveld, Free State, NorthwestKZNWestern Cape

Consider adding:• Epicoccum (mould)• Cockroach (German)

Consider adding:• Maize Pollen• Eucalyptus• Weed Mix (Cosmos, Kakhibos)

Consider adding:• Cockroach (Oriental)

Phadlatop Inhalant Screen

WHERE DOES THE PATIENT LIVE?

Symptoms worse in SpringSymptoms all year round

Break down in ALLSA/NPG panel*

Positive Negative Negative Positiveif negative

Or SPT panel

? OTHER MECHANISMCAST inhalant mix **Nasal eosinophils

AN APPROACH TO INHALANT ALLERGY

•ThemajorityofinhalantallergiesareIgEmediated,thereforeIgEmediatedtesting,e.g. Phadiatop/skinpricktestsarerecommendedasfirstlinetests.•InpatientswithahistoryhighlysuggestiveofinhalantallergiesandnegativeIgEallergy tests,consider. a) Anothermechanism -DoCASTinhalantscreen. -Donasalmucussmearforeosinophils. b) Anotherallergen -?Treepollen,animal,weed,occupationalallergen.•ThemostallergenictreepollensinSouthAfricaareplanetree,oak,olive,cypress, eucalyptus,pine,acacia,willow,poplar,mulberryashandelder.•Screeningtests(Phadiatop)forinhalantallergiesshouldalwaysbebrokendownif positive,soindividualallergenscanbeidentifiedforavoidanceorimmunotherapy.•Patientsareoftensensitizedtocross-reactivecomponentsthatoccurinpollensand foodsofplantorigin.Testforthesecomponents,nl.LTP,PR-10,ProfilinandCCDin patientssensitizedtopollensandfoodsofplantorigin.

CLINICAL PEARLS

AN APPROACH TO FOOD ALLERGY

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THE FOLLOWING DIAGNOSTIC TOOLS ARE KEY IN THE ASSESSMENT OF A POSSIBLE FOOD ALLERGY:

HISTORY SUGGESTIVE OF FOOD ALLERGY

Negative

Food allergen screen on ImmunoCap® or SPT food panel

If food IgE is positive do dietary component testing to indicate risk, severity and for dietary advice

Egg: ovomucoid Milk: casein Wheat: Ω5gliadin Soy: glym5,6storageprotein Peanut: Arah1,2,3storageprotein Codfish:parvalbumin

NB!Ifsoy,wheatandpeanutsarepositive,considerfood-pollensyndromeAdd:

•GrassmixIgE •CCD•Proflin •LTP•PR-10

Positive

Breakdown in •Eggwhite •Milk •Wheat •Soya •Peanut •Codfish

Clear history indicates a specific food

Food allergen IgE or SPT

NegativePositive

? Other allergen •Otherfood IgE/SPT’s

Specific food allergens not implicated

? Other mechanism CAST test •Foodmix •Colourants •PreservativesMELISA/patch test

? Other disease, e.g. Coelliacs disease •HLADQ2+8 •lgA •TTGlgA •EndomysiallgA •DeamidatedGliadinlgA

? Non Immunological Mechanism i.e.lactasedeficiency•H-breathtest•Stoolreducingsubstances

? Other mechanism CAST test •Foodmix •Colourants •PreservativesMELISA/patch test

? Other disease, e.g. Coelliacs disease •HLADQ2+8 •lgA •TTGlgA •EndomysiallgA •DeamidatedGliadinlgA

? Non Immunological Mechanism i.e.lactasedeficiency•H-breathtest•Stoolreducingsubstances

AN APPROACH TO FOOD ALLERGY

•Itisimportanttodistinguishbetweenimmediate(<2hours)hypersensitivityreactions, whichareusuallyIgE/basophilmediatedanddelayedreactions,whichmayinclude otherimmunemechanisms.Testingshouldberequestedaccordingly.•Screeningwithafoodmix(IgEorCAST)shouldalwaysbebrokendownifpositive.•Considerallergytofoodadditiveslikecolourantsandpreservativesinadditiontothe specificfoodallergens.•Inpatientswithsymptomssuggestiveofwheathypersensitivityandnegativeallergy tests,pleaseconsidertestingforCoeliacdisease.•Oralallergysyndrome(OAS)isusuallycausedbypollen-foodcross-reactivity.Testfor pollenallergyandcross-reactivepollencomponents:IgEtoLTP,PR-10,profilinandCCD.•Relevantcomponentsshouldberequestediffood-specificIgEispositivetoadviseon risk,avoidanceandprognosis.•ISACtestingshouldbeconsideredinpatientswithmultiplefoodandinhalantallergies.

CLINICAL PEARLS

THE MOST IMPORTANT ALLERGEN COMPONENTS:

•Mainwheyproteins•Heatlabile•Patientsreactmoreseverely tofreshmilk.Maytolerateboiled/ bakedmilk,long-lifemilk, hardcheeseandyoghurt.

•Heatstable•Mostimportantallergen•Severeandpersistent allergy•Cross-reactsbetween mammals(eg:goats milk)

•Occursinmilkand beef/redmeat.•Heatlabile,maytolerate wellcookedmilkand dairy.•Cross-reactionwithother mammals.

•Heatlabile.•Maybeusedasa preservativeinbeef andnasalsprays.

EGG WHITE EGG YOLK

Ovomucoid Ovalbumin Conalbumin Lysozyme EggserumalbuminGald1 Gald2 Gald3 Gald4 Gald5

•Highlyallergenic •Heatlabile •Occursineggyolk,chicken•Heatstable •Maytoleratewell-cookedegg meatandfeathers•Severeandpersistent allergy

MILK Casein αlactalbumin βlactoglobin Bovineserumalbumin LactoferrinBosd8 Bosd4 Bosd5 Bosd6 Bosdlactoferrin

FISH SHELLFISHCodpavalbumin Carpparvalbumin TropomyosinCypc1 Gadc1 Pena1

•Heatstable•Broadcross-reactivity,markerforgeneralfishsensitization.•Parvalbumincontentofdifferentfishspeciesmayvary,e.g.lowerlevels intuna.

•Heatstablemuscleprotein.•Foundincrustaceans,molluscs, insectsandmiteswithclinical cross-reactivity.

MILK

FOOD ALLERGEN COMPONENTS: EGG, MILK, FISH, SHELLFISH

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Profilin

•Heatlabile•OAS

PR-10

•Heatlabile•OAS•Mildto severe symptoms

LTP

•Heatstable•OAS•Severe clinical symptoms or anaphylaxis

CCD

•Usuallyno clinical symptoms

PEANUT

•Stabletoheatanddigestion•Riskofanaphylaxis•Cross-reactivewithothernutsandseeds

Profilin PR-10 LTP CCDStorage Proteins

Ara h 1 Ara h 2 A ra h 3 Ara h 6 Ara h 5 Ara h 8 Ara h 9 CCD

SOYA

•Associatedwithseverereactions•Heatstable

Profilin Gly m 4 LTP CCDStorage Proteins

Gly m 5 Gly m 6 PR-10

•Mayhave severe reactions

WHEAT

•Riskmarkerforsystemic reactions•Wheatallergypersistence•Wheatdependentexercise inducedanaphylaxis

Profilin PR-10 Tri a 14LTP

CCDΩ 5 GliadinTri a 19

B WGliadins

•Markerofseverereactions•Markerofwheatallergy persistence.

Wheat dependent exercise induced anaphylaxis.

POLLEN CROSS REACTIVE

FOOD ALLERGEN COMPONENTS: POLLEN, PEANUT, SOYA, WHEAT

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