Diagnosis of Food Allergy and Intolerance - Vickerstaff：食物过敏和不耐受诊断维克斯塔夫

1、Diagnosis and Dietary Management of Food Allergies and IntolerancesClinical ApplicationsTests for Adverse Reactions to FoodsRationale and Limitations3Standard Allergy Tests Skin testsScratch or prickAllergen extract applied to skin surface of arm or backSkin is scarified (scratched) or pricked with

2、lancetAllergen encounters mast cells below skin surfaceIf allergen-specific IgE is present, allergen plus antibody causes release of mediators (mast cell degranulation), especially histamineHistamine causes reddening and swelling: “wheal and flare” reaction of the skin testSize of reaction measured

3、(usually 1+ to 4+)4Standard Allergy Tests Skin tests continuedIntradermal testsAllergen extract is injected into dermisRationale: release of histamine produces wheal and flareNote: many countries do not approve this type of testing because of increased risk of anaphylaxis as allergen introduced dire

4、ctly into blood streamControls for all skin tests:Negative: medium in which allergen is suspended (usually saline)Positive: measured amount of histamine5Wheal and Flare ReactionSkin prick tests6Value of Skin Tests in PracticePositive predictive accuracy of skin tests rarely exceeds 50%Many practitio

5、ners rate them lower Negative skin tests do not rule out the possibility of non-IgE-mediated reactionsDo not rule out non-immune-mediated food intolerances7Value of Skin Tests in PracticeTests for highly allergenic foods thought to have close to 100% negative predictive accuracy for diagnosis of IgE

6、-mediated reactionsSuch foods include: Egg Milk Fish Wheat Tree nuts Peanut8Reasons for False Positive Skin TestsDegranulation of skin mast cells by stimuli that do not degranulate mast cells in the digestive tractDifferences in the form in which the food is applied to the skin compared to that whic

7、h encounters immune cells in the digestive tract Raw form in extract may be degraded during cooking Digestion by gastric acid and digestive enzymes can degrade antigensAllergen extract contains histamine9False Negative Skin TestsChildren younger than 2-3 years are more likely to have a negative skin

8、 test and positive food challenge than adultsAdverse reaction is not mediated by IgECommercial allergen may contain no material that the immune system can recognizeProcessing of food leads to degradation of allergen (e.g. crushing produces phenols and catabolic enzymes)10Other Skin TestsPrick-to-Pri

9、ckSterile needle is inserted into raw food, and the patients skin is pricked with the same needleUsed for suspected contact allergye.g. oral allergy syndromeEspecially where allergen is easily denatured by heat and acidCrushing plant tissue during preparation of allergen extracts releases phenols th

10、at rapidly cause break-down of proteinPrick-to prick test transfers “native” allergen11Other Skin TestsPatch Test for Contact AllergiesInvolves Type IV (delayed) hypersensitivity reaction, requiring cell-to-cell contactExamples: Poison ivy rash Nickel contact dermatitis Preservatives, dyes and perfu

11、mes in cosmeticsAllergen is placed on the skin, or applied as an impregnated patch, which is kept in place by adhesive bandage for up to 72 hoursLocal reddening, swelling, irritation, indicates positive response12Other Skin TestsDIMSOFT (dimethylsulphoxide test) for delayed reaction to foodFood extr

12、act is suspended in 90% dimethylsulfoxideAids in skin penetration of allergenPatch held in place 48-72 hoursEspecially useful in skin and gastrointestinal reactions which may not have immediate onset symptomsEspecially useful for milk and cereal grains13Risks associated with skin testsHigh number of

13、 false positive and false negative tests creates risk of diagnostic inaccuracyAll tests must be considered together with:Clear medical history Exclusion of non-allergic causesConfirmation by elimination and challenge of suspect foodsDanger of sensitisation to allergens through the skin:Initial expos

14、ure via the digestive tract most likely to lead to toleranceInitial exposure via the skin more likely to lead to sensitization and initiation of allergy especially if inflammation exists (e.g. eczema)14Standard Allergy TestsBlood TestsRAST: radioallergosorbent test (e.g. ImmunoCap-RAST; Phadebas-RAS

15、T)FAST; Fluorescence allergosorbent testELISA: enzyme-linked immunosorbent assayDesigned to detect and measure levels of allergen-specific antibodiesUsed for detection of levels of allergen-specific IgEMay measure total IgE - thought to be indicative of “atopic potential”Some practitioners measure I

16、gG (especially IgG4) by ELISA15Value of Blood Tests in PracticeBlood tests have about the same sensitivity as skin tests for identification of IgE-mediated sensitisation to food allergensAnti-food antibodies (especially IgG) are frequently detectable in all humans, usually without any evidence of ad

17、verse effectIgG production likely to be the first stage of development of oral tolerance to a foodStudies suggest that IgG4 indicates protection or recovery from IgE-mediated food allergy16Value of Blood Tests in PracticeThere is often poor correlation between high level of anti-food IgE and symptom

18、s when the food is eatenMany people with clinical signs of food allergy show no elevation in IgEReasons for failure of blood tests to indicate foods responsible for symptoms are the same as those for skin tests17Tests for Intolerance of Food AdditivesThere are no reliable skin or blood tests to dete

19、ct food additive intoleranceSkin prick tests for sulphites are sometimes positiveA negative skin test does not rule out sulphite sensitivityHistory and oral challenge provocation of symptoms are the only methods for the diagnosis of additive sensitivity at presentCaution: Challenge may occasionally

20、induce anaphylaxis in sulphite-sensitive asthmatics18Unorthodox TestsMany people turn to unorthodox tests when avoidance of foods positive by conventional test methods have been unsuccessful in managing their symptomsTests include:Vega test (electro-dermal)Biokinesiology (muscle strength)Analysis of

21、 hair, urine, salivaRadionicsALCAT (lymphocyte cytotoxicity)19Controversial TestsElectro-Dermal (Vega) TestMeasures change in electrical potential on skinCircuit linking Patient holding a metal rod Vial containing food, or other material being testedMeter to measure energy levelTechnician holding pr

22、obe held at acupuncture point on patients other handDisturbance in energy flow to meter indicates reactivity20Controversial TestsBiokinesiologyAssumption: muscles become weak when influenced by the allergen to which the patient reactsPatient holds a vial containing the suspect allergen (food)Practit

23、ioner tests the strength of the patients other arm in resisting downward pressureWeakening of resistance indicates a positive (allergic) reaction21Drawbacks of Unreliable TestsDiagnostic inaccuracyTherapeutic failureFalse diagnosis of allergyCreation of fictitious disease entitiesFailure to recogniz

24、e and treat genuine diseaseInappropriate and unbalanced diets22Consequences of Mismanagement of Adverse Reactions to FoodsMalnutrition; weight loss, due to extensive elimination dietsEspecially critical in young children where nutritional deficiency at a crucial stage in development can cause perman

25、ent damageFood phobia due to fear that “the wrong food” will cause permanent damage, and in extreme cases, deathFrustration and anger with the “medical system” that is perceived as failing themDisruption of lifestyle, social and family relationshipsElimination and Challenge Protocols24Identification

26、 of Allergenic FoodsRemoval of the suspect foods from the diet, followed by reintroduction is the only way to:Identify the culprit food componentsConfirm the accuracy of any allergy testsLong-term adherence to a restricted diet should not be advocated without clear identification of the culprit food

27、 components25Food Intolerance: Clinical DiagnosisSymptoms DisappearElimination Diet: Avoid Suspect FoodSymptoms PersistIncrease RestrictionsReintroduce Foods Sequentially or Double-blindSymptoms ProvokedNo SymptomsDiagnosis ConfirmedDiagnosis Not Confirmed26Elimination and ChallengeStage 1: Exposure

28、 DiaryRecord each day, for a minimum of 5-7 days:All foods, beverages, medications, and supplements ingestedComposition of compound dishes and drinks, including additives in manufactured foodsApproximate quantities of eachThe time of consumption27Exposure Diary (continued)All symptoms graded on seve

29、rity: 1 (mild); 2 (mild-moderate) 3 (moderate) 4 (severe)Time of onsetHow long they lastRecord status on waking in the morning.Was sleep disturbed during the night, and if so, was it due to specific symptoms?28Elimination DietBased on:Detailed medical historyAnalysis of Exposure DiaryAny previous al

30、lergy testsFoods suspected by the patientFormulate diet to exclude all suspect allergens and intolerance triggersProvide excluded nutrients from alternative sourcesDuration: Usually four weeks29Selective Elimination DietsCertain conditions tend to be associated with specific food componentsSuspect f

31、ood components are those that are probable triggers or mediators of symptomsExamples:Eczema: Highly allergenic foodsMigraine: Biogenic aminesUrticaria/angioedema: HistamineChronic diarrhea:Carbohydrates; DisaccharidesAsthma: Cyclo-oxygenase inhibitors SulphitesLatex allergy:Foods with structurally s

32、imilar antigens to latexOral allergy syndrome: Foods with structurally similar antigens to pollens30Few Foods Elimination DietWhen it is difficult to determine which foods are suspects a few foods elimination diet is followedLimited to a very small number of foods and beveragesLimited time: 10-14 da

33、ys for an adult7 days maximum for a childIf all else fails use elemental formulae:May use extensively hydrolysed formula for a young child31Expected Results of Elimination DietSymptoms often worsen on days 2-4 of eliminationBy day 5-7 symptomatic improvement is experiencedSymptoms disappear after 10

34、-14 days of exclusion32ChallengeDouble-blind Placebo-controlled Food Challenge (DBPCFC)Lyophilized (freeze-dried) food is disguised in gelatin capsulesIdentical gelatin capsules contain a placebo (glucose powder)Neither the patient nor the supervisor knows the identity of the contents of the capsule

35、sPositive test is when the food triggers symptoms and the placebo does not33Challenge (continued)Drawback of DBPCFCExpensive in time and personnelCapsule may not provide enough food to elicit a positive reactionPatient may be allergic to gelatin in capsuleMay be other factors involved in eliciting s

36、ymptoms, e.g. taste and smell34Challenge (continued)Single-blind food challenge (SBFC)Supervisor knows the identity of the food; patient does notFood is disguised in a strong-tasting “inert” food tolerated by the patient: lentil soup apple sauce tomato sauce 35Challenge Phase continuedOpen food chal

37、lengeSequential Incremental Dose Challenge (SIDC)Each food component is introduced separatelyStarting with a small quantity and increasing the amount according to a specific scheduleThis is usually employed when the symptoms are mild, and the patient has eaten the food in the past without a severe r

38、eactionAny food suspected to cause a severe or anaphylactic reaction should only be challenged in suitably equipped medical facility36Open Food ChallengeEach food or food component is introduced individuallyThe basic elimination diet, or therapeutic diet continues during this phaseIf an adverse reac

39、tion to the test food occurs at any time during the test STOP. Wait 48 hours after all symptoms have subsided before testing another food37Incremental Dose ChallengeDay 1: Consume test food between mealsMorning: Eat a small quantity of the test foodWait four hours, monitoring for adverse reaction If

40、 no symptoms:Afternoon: Eat double the quantity of test food eaten in the morning Wait four hours, monitoring for adverse reaction If no symptoms:Evening: Eat double the quantity of test food eaten in the afternoon38Incremental Dose Challenge (continued)Day 2:Do not eat any of the test foodContinue

41、to eat basic elimination dietMonitor for any adverse reactions during the night and day which may be due to a delayed reaction to the test food39Day 3:If no adverse reactions experienced Proceed to testing a new food, starting Day 1If the results of Day 1 and/or Day 2 are unclear :Repeat Day 1, usin

42、g the same food, the same test protocol, but larger doses of the test food Day 4:Monitor for delayed reactions as on Day 2Incremental Dose Challenge(continued)40Sequential Incremental Dose ChallengeContinue testing in the same manner until all excluded foods, beverages, and additives have been teste

43、dFor each food component, the first day is the test day, and the second is a monitoring day for delayed reactions41Sequence of TestingMilk and Milk ProductsTest 1: Casein proteinsTest 2: Annatto, biogenic amines, plus caseinTest 3: Casein plus whey proteinsTest 4: Lactose in addition to casein and w

44、hey proteinsTest 5: Modified milk componentsTest 6: Whey proteins (lactose-free)Test 7: Lactose (in whey)Test 8: Complex milk products (e.g. ice cream)42Sequence of Testing:WheatTest 1: Pure cereal grainTest 2: Wheat Cracker without yeastTest 3: White BreadTest 4: Whole Wheat BreadMaintenance Diet44

45、Final DietMust exclude all foods and additives to which a positive reaction has been recordedMust be nutritionally complete, providing all macro and micro-nutrients from non-allergenic sourcesThere is no benefit from a rotation diet in the management of food allergyA rotation diet may be beneficial

46、when the condition is due to dose-dependent food intolerance45Important Micronutrients in Common Allergenic FoodsMineralsMilkEggPeanutSoyFishWheatRiceCornCalcium+Phosphorus+Iron+Zinc+Magnesium+Selenium+Potassium+Molybdenum+Chromium+Copper+Manganese+46VitaminsMilkEggPeanutSoyFishWheatRiceCornA+Biotin

47、+Folacin (folate; folic acid)+B-1 (thiamin)+B-2 (riboflavin)+B-3 (niacin)+B-5 (pantothenic acid)+B-6 (pyridoxine)+B-12 (cobalamin)+D+E (alpha-tocopherol)+K+Current Areas of ResearchPromotion of Tolerance to Foods48Prevention of Food Allergy in Clinical PracticeSignificant change in directives within

48、 the past 3 years:Previously: Avoidance of allergen to prevent sensitization (allergen-specific IgE)Current: Active stimulation of the immature immune system to induce tolerance of the antigens in food_Rautava et al 200549Diet During Pregnancy and LactationThere is no convincing evidence that women

49、who avoid highly allergenic foods, or other foods during pregnancy and breast-feeding lower their childs risk of allergiesCurrent directive: the atopic mother should strictly avoid her own allergens and replace the foods with nutritionally equivalent substitutesThere are no indications for mother to

50、 avoid other foods during pregnancyA nutritionally complete, well-balanced diet is essential_Kramer et al 200650Introduction of FishHistorically, fish consumption during infancy was considered to be a risk factor for allergyRecent research indicates otherwise:Regular fish consumption during the firs

51、t year of life associated with a reduced risk for allergic disease by age 4 years (n=4089)1Babies of mothers who frequently consumed fish (2-3 times per week or more) during pregnancy had one third less food sensitivities than those whose mothers did not consume fish during pregnancy2_1Kull et al 20

52、06_2Calvani et al 200651Introduction of Fish Babies who were fed fish before nine months of age were 24% less likely to develop eczema by age 1 year1Children less likely to develop allergy to fish if the mother consumes fish two or three times a week during pregnancy2 Regular fish consumption during

53、 the first year of life was associated with a reduced risk for allergic disease by age four3 _Alm et al 2009_Calvani et al 2006_Kull et al 200652Recent Evidence for Early Introduction of SolidsDelaying initial exposure to cereal grains until after 6 months may increase the risk of wheat allergy1Rese

54、arch suggests that high risk for celiac disease occurs if gluten-containing grains are introduced before 3 months or after 7 months2_1Poole et al June 2006_2Norris et al 2005 53Introduction of PeanutsStudy (n=10,786) among primary school age Jewish children in UK and IsraelPrevalence of peanut aller

55、gy (PA):In UK:1.85%In Israel:0.17%Median monthly consumption of peanut in infants aged 8 14 months:In UK:0In Israel:7.1 gDifference not due to atopy, genetic background, social class, or peanut allergenicityIsraeli infants consume peanuts in high quantities during the first year of life_Du Toit et a

56、l 200854Development of Tolerance25% of infants lost all food allergy symptoms after 1 year of ageMost infants will outgrow milk allergy by 3 years of age, but may have become intolerant to other foods in the meantimeTolerance of specific foods :After 1 year:26% decrease in allergy to: Milk Soy Peanu

57、t Egg Wheat2% decrease in allergy to other foods_Bishop et al 199055PrognosisAge at which milk was tolerated by milk-allergic children:Diverse studies report different statisticsAllergy to some foods more often than others persists into adulthood: Peanut Tree nuts Shellfish Fish28% by 2 years 156% b

58、y 4 years78% by 6 years56% at 1 year 277% at 2 years87% at 3 years19% by 4 years 342% by 8 years64% by 12 years79% by 16 years_1Bishop et al 19902Host and Halken 19903Skripak et al 200756Induction of Oral ToleranceAllergy to a specific food can be induced by oral administration of the offending food

59、 (SOTI: specific oral tolerance induction)Starting with very low dosagesGradually increasing daily dosage up to the equivalent of the usual daily intakeFollowed by daily maintenance dose_Niggemann et al 200657Desensitization to Cows Milk18 children with confirmed CMA 4 years of age underwent SOTISta

60、rting dose 0.05 ml cows milkIncreased to 1 ml on first dayIncreasing dosage weekly up to a daily dose of 200-250 mlResults: 16/18 tolerated 200-250 ml milkLength of process median 14 weeks (range 11-17 weeks)Tolerance has been maintained for 1 year_Zapatero et al 200858Oral Tolerance Induction to Mi