From Allergy to Intolerance Barzin Khalili MD Adjunct Assistant Professor Allergy amp Immunology Oregon Health Sciences University Food Allergy Food allergy prevalence is increasing in US 34 of adults ID: 321630
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Slide1
Adverse Food Reactions:From Allergy to Intolerance
Barzin Khalili, MD
Adjunct Assistant Professor
Allergy & Immunology
Oregon Health Sciences UniversitySlide2
Food AllergyFood allergy prevalence is increasing in US:
3-4% of adults
6-8% of children
More people presenting to primary care with symptoms ascribed to food allergy.
More self-diagnosed patients
More misinformed patients due to lay press and inappropriate testingSlide3
Adverse Food ReactionsImmune
IgA
IgE
Class 1
Class 2
EosinophilMixed
Non-immune
Pharmacologic
Gastrointestinal
Toxins
Sensitivity to Additives
Intolerance
Lactose
GlutenSlide4
Immune MediatedIgA
IgE
Class 1
Class 2
Eosinophil
MixedSlide5
Celiac Sprue
IgA
mediated condition against
gliaden
component of gluten found in wheat, rye, and barley.
Prevalence of 1 in 300 in Western Europe, North America and Australia.10% prevalence in 1st degree relatives.
IgA
antibodies cause an inflammatory reaction that destroys intestinal
villi
.
Symptoms and complications include abdominal pain, diarrhea, bloating,
steatorrhea
, weight loss, bleeding (from low vitamin K) fatigue and weakness (from electrolyte losses) anemia, short stature in children, lymphoma and
adenocarcinoma
.Slide6
Celiac Sprue - PathophysiologySlide7
Celiac - TestingSmall bowel biopsy is gold standard
Serologic testing
Anti-
gliadin
antibodies –
IgA and IgGNonspecific -False positive in IBD, and present in healthy people.
Anti-
endomysial
antibodies –
IgA
Correlates with severity of villous atrophy
If partial atrophy could be
seronegative
, so we check AGA
IgA
.
Nearly 100% specific but not 100% sensitive (concordance with TTG
IgA
lacking).
Anti tissue
transglutaminase
antibodies –
IgA
Correlates with severity of villous atrophy
If partial atrophy could be
seronegative
, so we check AGA
IgA
.
False positives in presence of cirrhosis, diabetes, heart failure.
Total
IgA
Selective
IgA
deficiency occurs 10-15 times more common in celiac disease
SIgA
patients will lack
IgA
antibodies, hence AGA
IgG
. Slide8
Celiac GeneticsHLA DQ2 or
DQ8 gene expression
necessary but insufficient to develop disease.
Low specificity limits use in diagnosis
Present in 30% of normal population
High sensitivity helpful to rule out disease if negative.Optimal role in assessment:Someone already on gluten-free diet
To determine which family members should be screened.Slide9
Immune MediatedIgA
IgE
Class 1
Class 2
Eosinophil
T cells MixedSlide10
IgE Mediated Food Allergy
Symptoms –
Skin –
urticaria
,
pruritusGI – nausea, abdominal pain, diarrhea, Respiratory – dyspnea
, wheeze, laryngeal edema
Cardiovascular – chest pain, hypotension
Timing – usually within 1 hour of ingestion
Common foods –
usuals
plus sesame is on the rise
Pathophysiology – mast cell degranulation of histamine
Testing/diagnosis –
Skin prick tests
Serological
IgE
(ELISA)
Treatment – avoidance, education, epinephrine
autoinjectorSlide11
Prick Skin TestingEvaluate for IgE mediated food sensitizationSlide12
ELISASlide13
Question
If aeroallergen Immunotherapy is effective for
pollenosis
, why are we advocating food avoidance instead of food immunotherapy?Slide14
Subcutaneous Immunotherapy
Background:
Peanut allergy is prevalent and potentially fatal. Currently, preventative treatment consists of avoidance which is difficult.
Methods:
Six hypersensitive adult patients underwent peanut rush immunotherapy followed by 1 year of maintenance injections. Six peanut allergic patients served as untreated controls. All patients underwent 3 DBPC oral peanut challenges (before RIT, at 6 weeks, and 1 year).
Nelson HS, et al. Treatment of anaphylactic sensitivity to peanuts by immunotherapy with injections of aqueous peanut extract.
J Allergy
Clin
Immunol
1997;99:744-51.Slide15
Rush Immunotherapy Schedule
Day
Time (am)
Concentration
Dose (ml)
1
8
1:10,000 wt/vol.
0.05
9
0.10
10
0.20
11
0.40
2
8
1:1000 wt/vol.
0.05
9
0.10
10
0.15
11
0.20
3
8
0.30
9
0.40
10
0.50
11
1:100 wt/vol.
0.07
4
8
0.10
9
0.15
10
0.20
11
0.30
5
8
0.40
10
0.50Slide16
Oral Peanut Challenge Schedule
Dose No.
Amt of peanut
1
1 mg
2
5 mg
3
10 mg
4
20 mg
5
50 mg
6
100 mg
7
200 mg
8
500 mg
9
1 gm
10
2 gm
11
4 gm
12
8 gm
Doses delivered at 30 minute intervals until completion or reaction.
One peanut is equivalent to 432 mgSlide17
Results – Rush Immunotherapy
Subject No.
Injections
to maintenance
Cutaneous
reactions
Cutaneous
& Pulmonary
Epinephrine Injections
Inhaled Bronchodilator
1
63
5
29
39
7
2
30
7
2
3
0
3
36
3
2
3
0
4
23
3
6
5
4
5
35
9
5
7
1
6
21
2
2
21Mean34.74.87.79.82.2Median334.03.54.01.0
Repeat Epinephrine treatments were required 8 times.
Systemic Reaction Rate of 23%Slide18
Results – Maintenance Immunotherapy
Subject No.
Maintenance Injections
Cutaneous
reactions
Cutaneous
& Pulmonary
Epinephrine Injections
Inhaled Bronchodilator
Final Concentration
1
43
0
30
30
11
1:1000
2
43
0
18
7
6
1:100
3
36
0
13
16
11
1:100
4
34
7
7
5
4
1:100
5
32
11
5
18
0
1:100062103001:100
Two patients were unable to tolerate the dose achieved during RIT.
Median 13.5 reactions to 35 injections; Systemic reaction rate of 39%.Slide19
Results – Oral Challenges
Threshold Dose (mg)
Patients 1,4,5 received a reduced maintenance dose.Slide20
Subcutaneous Immunotherapy
Conclusions:
All 6 patients had increased tolerance to peanut at 6 weeks.
There was partial or complete loss of protection at 1 year in those who required dose reductions.
Most sensitive patient went from 16 mg (1/27
th) 7888 mg (18.3) 385mg (less than 1 peanut).
Clinical significance unknown
“The high rate of systemic reactions makes this form of treatment with the currently available peanut extract unacceptable.”Slide21
Oral Tolerance1829 – Populations of Native Americans ate poison ivy leaves to prevent contact hypersensitivity to
urushiol
.
1911 – Guinea pigs repeatedly fed hen’s egg protein were protected from anaphylaxis when injected with the protein.
2013 - We are still gaining more insight into mechanisms of oral tolerance.Slide22
Heated milk OFC
Tolerated
Reacted to regular milk
68%
Tolerated Regular milk
9%
Add milk to diet
Reacted
23%
Strict milk avoidance
Heated milk diet
Promoting Oral Food Tolerance
Can patients with milk allergy tolerate extensively-heated milk products?
Nowak-
Wegrzyn
A, et al. Tolerance to extensively heated milk in children with cow's milk allergy.
J Allergy
Clin
Immunol
.
2008;122:342-7.Slide23
Promoting Food Tolerance
Baseline median
3 month median
P value
Milk SPT wheal size
8
7
.001
Casein IgG4 mg/L
0.54
1.02
.005
Undetectable casein IgG4
6
0
0.27
Challenges notion that strict avoidance is necessary to
“outgrow a food allergy”
Demonstrates that eating extensively heated milk products is
safe and tolerated and may actually promote tolerance.
Strict milk avoidance may not be necessary for the majority of
patients with milk allergy.Slide24
Milk Oral immunotherapyIssue:
The main benefit of oral immunotherapy is to those patients with the most severe reactions.
Problem:
Patients with severe food allergies are often excluded from studies examining oral tolerance induction for fear of life-threatening conditions.
Solution:
Conduct the study overseas. Slide25
Milk Oral immunotherapy
Objective:
Is oral immunotherapy safe and effective for children with severe cow milk allergies?
Methods:
Inclusion Criteria
5-17 years oldMilk specific IgE > 85 kU
/L
History of at least 1 severe allergic reaction
Reaction Grade
Clinical Features
1
Mild
Localized
cutaneous
2
Mild
Generalized
cutaneous
3
Mild
1 or 2 plus GI symptoms
4
Moderate
Laryngeal
edema, mild asthma
5
Severe
Marked
dyspnea
, hypotension
Longo G, et al. Specific oral tolerance induction in children with very severe cow's milk-induced reactions.
J Allergy
Clin
Immunol
.
2008;121:343-7.Slide26
Milk Oral immunotherapyMethods Cont:
All patients underwent a DPPCFC. Only those who reacted to 8 ml or less of a 1:9 mix of
milk:amino
acid formula solution were randomized.
Group A – 30 received milk oral immunotherapy
Group B – 30 maintained a milk-free diet for 1 yearRepeat oral challenge was performed at 1 year.Slide27
Treatment GroupPhase 1 – In hospital
Day
Dilution
Doses
1
1 drop CM in 10 ml water
5 drops -10 ml
2
5 drop CM in 20 ml water
2 – 16 ml
3
1 ml CM in 20 ml water
2 – 12 ml
4
3 ml CM in 20 ml water
3 – 10 ml
5
10 ml CM in 20 ml water
3 – 9 ml
6
10 ml CM in 10ml water
3
– 9 ml
7
Whole milk
2 – 6 ml
8
Whole milk
4 – 10 ml
9
Whole milk
8 –
15 ml
10
Whole milk
13 – 20 ml
Phase 2 – At home
Increase by 1 ml every 2 days until 150 ml reached.Slide28
Milk Oral immunotherapy
Group A
Group B
Positive food challenges in all 30 cases
Difference between groups is statistically significant (P < 0.001)Slide29
Symptoms
In hospital patients
( total no. of reactions)
At home patients
(total no. of reactions)
Lip/mouth
pruritus
30 (355)
14 (85)
Perioral
urticaria
28 (37)
17 (22)
Generalized
urticaria
14 (17)
7 (13)
Abdominal pain
23 (47)
14 (32)
Rhinoconjunctivitis
18 (23)
3 (8)
Mild
Laryngospasm
14 (15)
3 (5)
Mild
bronchospasm
12 (28)
8 (19)
Administered Treatment
In hospital patients
( total no. of treatments)
At home patients
(total no. of treatments)
Oral steroids
8 (16)
17 (35)
Nebulized
epinephrine18 (22)6 (9)IM epinephrine4 (4)1 (1)Group B: 6 (20%) children had adverse reactions caused by accidental milk ingestion.Slide30
Milk Oral immunotherapy Conclusions:
90% of patients with severe milk allergy were able to ingest higher amounts (> 5ml) of cow’s milk without reaction.
No patient required IV fluids/epinephrine.
Increasing the threshold required to cause a reaction is so important in highly allergic patients where minute quantities can be life-threatening. Slide31
Peanut Oral Immunotherapy
Objective:
Investigate the efficacy and immunologic changes associated with OIT.
Hypothesis:
Subjects with peanut allergy who undergo OIT would be shifted toward a T
H1-type profile.Methods:
Open label study of 39 peanut allergic children undergoing an OIT protocol followed by food challenges. Immunologic parameters were followed.
Those with severe reactions excluded.
Jones SM, et al. Clinical efficacy and immune regulation with peanut oral immunotherapy.
J Allergy
Clin
Immunol
.
2009;124:292-300.Slide32
Peanut Oral ImmunotherapyResults:
29 subjects completed the peanut dose escalations and peanut challenge.
27/29 (93%) reached max dose of 3.9 g of peanut protein (equivalent to 16 peanuts).
Only mild symptoms reported.Slide33
Peanut-specific ImmunoglobulinsSlide34
Regulatory T CellsSlide35
Peanut Oral ImmunotherapyConclusions:
Humoral
and cellular responses suggest that OIT induces transition from short-term desensitization to long-term tolerance.Slide36
Peanut Oral ImmunotherapyObjective:
To investigate effectiveness of OIT in DBPC study.
Methods:
Peanut allergic children age 1-16 years received OIT with peanut flour or placebo. Oral food challenge done at 1 year.
Results:
16/16 treated subjects ingested 5000 mg (20 peanuts)9 placebo patients ingested average dose of 280 mg (range 0-1900 mg).
Conclusion:
Peanut oral immunotherapy induces desensitization.
Varshney
P, et al
. A randomized controlled study of peanut oral immunotherapy: Clinical desensitization and modulation of the allergic response. J Allergy
Clin
Immunol
.
2011;127:654-60.Slide37
Tolerance vs. Desensitization
Immunologic mechanism of oral IT unclear
Desensitization
A change in threshold of ingested food antigen needed to cause allergic symptoms. Continued exposure of antigen is required to maintain effect.
Tolerance
Long lasting immunity shift away from T
H
2 phenotype and not dependent upon ongoing therapy.Slide38
Egg Oral Immunotherapy
Objective:
Oral IT with egg white powder for treatment of children with egg allergy.
Methods:
DBPCRS of 55 kids age 5-11 years with egg allergy who received oral IT (40 children) or placebo (15).Escalation, build-up, and maintenance phases were followed by oral challenge with egg white powder at 10 and 22 months.
If passed OFC at 22 months, then egg avoidance and rechallenge
at 24 months to powder and cooked egg to evaluate for tolerance.
If passed OFC at 24 months, then egg back in diet ad lib and evaluated again at 30 and 36 months.
Burks AW, et al. Oral immunotherapy for treatment of egg allergy in children.
NEJM. 2012;367:233-43.Slide39
Egg Oral IT
ResultsSlide40
Egg Oral ImmunotherapyConclusions:
Oral IT can desensitize a significant proportion of children and induce sustained responsiveness in a subset.
Burks et al.
NEJM
2012Slide41
Immune MediatedIgA
IgE
Class 1
Class 2
Eosinophil
MixedSlide42
Class 2 Food AllergyAlso called Oral Allergy Syndrome (OAS)
Symptoms usually confined to oral mucosa and include:
soft palate itching
Mucosal swelling
Itching/tingling of tongue. lips, throat
Tongue swelling9% of the time can have systemic symptomsNausea, vomiting, diarrhea, abdominal pain
Urticaria
,
angioedema
1.7% experience anaphylaxisSlide43
Oral Allergy SyndromeDue to
IgE
cross reactivity between a prior aeroallergen sensitization and a plant derived protein found in food.
PR proteins – labile (cooked forms usually OK)
PR-10 is major birch tree pollen that can cross react with similar PR proteins in foods.
Profilins – labileInvolved in celery-
mugwort
-spice syndrome
Lipid transfer protein – stable to heat and proteolysis
Responsible for anaphylactic episodesSlide44
Oral Allergy SyndromeSlide45
Oral Allergy SyndromeTestingSkin prick test to actual food has highest sensitivity (70% - 80% depending on food)
PR proteins denatured during commercial processing
Specific
IgE
blood testing slightly inferior to skin test with fresh food.
Potential role for component resolved diagnostics (CRD).Slide46
CRD
Imagine this:
On a miniature scale (a biochip) using specific allergen recombinant
epitopes
rather than the whole protein.
ANDOnly requires 20ul of serum via capillary blood samplingSlide47Slide48
CRD - How it Can HelpComponent resolved diagnosis is valuable in the investigation of food allergy in children in whom it may be difficult to decide whether a sensitization may be caused by genuine allergy or a cross-reactivity.
IgE
to peanut protein
Ara
h8 (birch pollen homologue) indicative of cross reactivity and OAS.
IgE to Ara
h2 indicative of true food allergy and high risk for anaphylaxis.Slide49
Oral Allergy SyndromeTreatment as with Class 1 food allergy
Avoidance
Education
Injectable
epinephrine
Two potential pitfalls:Improper diagnosis of OAS in patient with anaphylaxisPotential to dismiss patient with OAS as having no risk of anaphylaxis.Remember 1.7% experience shockSlide50
QuestionIf OAS is initiated by a primary aeroallergen sensitization…is there a role for immunotherapy (IT)?Slide51
Oral Allergy Syndrome - Treatment
Objective:
Does SIT with birch pollen have an effect on OAS induced by apple or hazelnut?
Methods:
27 birch-allergic patients with OAS to apple or hazelnut underwent oral challenge with both foods at baseline. 15/27 were treated with SIT and 12 were not.
Bucher X, et al. Effect
o
f tree pollen specific, subcutaneous immunotherapy on the oral allergy syndrome to apple and hazelnut.
Allergy.
200459:1272-76.Slide52
Oral Allergy Syndrome - Treatment
Results:
13/15 (87%) in treated group could eat significantly more apple or hazelnut without symptoms after 1 year.
Avg
tolerated quantity increased from 12.6 to 32.6 g of apple. 1/12 (8%) untreated patients could consume more.
(128g = 2/3 of a medium apple)Conclusion: Although a positive impact – the amount of tolerated food is small.
Bucher et al.
Allergy
2004.Slide53
Oral Allergy Syndrome - Treatment
Background:
Birch IT does not consistently improve apple OAS symptoms. Can tolerance be achieved orally?
Methods:
Open, randomized trial of 27 allergic patients.
14 consumed increasing amounts of daily apple for 20 weeks, doubling amount Q 2-3 weeks.13 untreated
Endpoint:
Proportion of patients that were tolerant to 128gm of apple.
Results:
17/27 patients in active group and 0/13 in untreated group achieved
desensitization
. If apple not eaten daily, symptoms rapidly returned. Thus,
tolerance
not achieved.
Kopac
P, et al. Continuous apple consumption induces oral tolerance in birch-pollen-associated apple allergy.
Allergy.
2012:67:280-85.Slide54
Immune MediatedIgA
IgE
Class 1
Class 2
Eosinophil
MixedSlide55
Eosinophilic Esophagitis - History
Essentially a new disease
Described as a distinct clinical entity in 1993
10 patients with esophageal eosinophilia, unresponsive to acid blockade who improved with an elemental formula.
Prior to that time, symptoms were primarily attributed to uncontrolled reflux.
Anti-reflux measures were ineffective.Incidence: 10 per 100,000 per year
Prevalence: 43 - 104 per 100,000 Slide56
Eosinophilic Esophagitis - Presentation
Symptoms tend to vary depending on age;
Infants
Failure to thrive
Irritability
Food refusalYoung children vomiting
Regurgitation
E
pigastric pain
Abdominal Pain
Older children and adults
Dysphagia > 90%
Heartburn
Chest Pain
Food Impaction > 60%
Easy to see why symptoms often attributed to refluxSlide57
Eosinophilic Esophagitis - Diagnosis
Clinical
Feature
EE
GERD
Prevalence of atopy
Very high
Normal
Prevalence of food sensitization
Very high
Normal
Sex preference
Male
None
Abdominal pain and vomiting
Common
Common
Food impaction
Common
UncommonSlide58
Eosinophilic Esophagitis - DiagnosisEE is a
histo
-clinical diagnosis
Made by endoscopy and biopsy
Concentric rings
Linear
furrows
Mucosal lacerationSlide59
Eosinophilic Esophagitis - Diagnosis
Diagnostic criteria based on consensus recommendations:
Clinical symptoms of esophageal dysfunction
Greater than 15
eosinophils
per
hpf
< 10
eosinophils
often seen in reflux
Unlike other GI tissues, normal esophagus is devoid of
eosinophils
.
No improvement with high-dose PPI or normal pH probe.Slide60
Eosinophilic Esophagitis - Diagnosis
Average delay between symptom onset and first endoscopy.
Pediatrics 3 years
Adults 4 years
Most adults are diagnosed as a result of emergent presentation with food impaction
55% of patients presenting to the ECU with impaction have EE.Anyone with a food impaction should be scoped and biopsied.Visual inspection alone is unsatisfactory
1/3 of all cases have a normal appearance
Multiple biopsies are needed to enhance sensitivity due to patchy eosinophil distribution.Slide61
Eosinophilic Esophagitis - Pathophysiology
Link between EE and food allergy:
Complete symptom resolution and normalization of esophageal tissue when infants are placed on an amino acid diet.Slide62
Eosinophilic Esophagitis – Evaluation
Atopy
Patch Test
Evaluate for delayed T cell mediated reaction
Not yet standardized
Aluminum wells are filled with reconstituted dried powders or single-ingredient baby foods.Applied to upper backRemoved in 48 hours and read at 72 hours.
APT is complementary to SPT
Prick skin testing
Serologic testing
Food specific
IgE
testing has shown very poor specificity and positive predictive value.Slide63
Eosinophilic Esophagitis – Role of Food Allergy
Most common foods positive in skin tests (66% of patients react to 1 or more foods)
Cow’s milk
Egg
Peanut
Almonds
Soy
Rice
Beans
Pea
Mustard
Beef
Carrot
Most common foods positive on atopy patch tests
Cow’s milk
Egg
Beef
Lamb
Veal
Chicken
Oat
Rye
Rice
Corn
Wheat
Soy
Potato
PeasSlide64
Eosinophilic Esophagitis – Dietary Treatment
Elemental Diet
98% effective but not palatable, usually requires nasogastric tube for older children, not plausible in adults
Avoidance diet of the usual foods implicated EE
Egg, wheat, soy, cow’s milk, fish, shellfish, peanuts
75 % of patient had symptom improvementAvoidance diet based on skin and patch testing results.
NPV 88 – 100% (except for milk)
PPV 74% for milk, egg, and soy.
75 % of patient had improvement in symptoms and esophageal eosinophilia
These tests do identify causative foods that may contribute to EE.
Despite improvement with avoidance, relapse is common (50%) when diet is liberalizedSlide65
Eosinophilic Esophagitis – TreatmentSwallow Fluticasone
6 weeks of fluticasone 220ug, 4 puffs twice daily for adults does lead to complete symptom resolution
BUT………..
90% had recurrence in the first year
70% required repeat therapy within 3 years
20% required systemic steroids
28% had subsequent food impactions
22% underwent repeat dilation
Children's dose range is 440 – 880 ug per day
Risks – esophageal candidiasis, bone lossSlide66
Eosinophilic Esophagitis – TreatmentSwallowed Budesonide
Once daily suspension of budesonide solution with sucralose (nonabsorbable sugar).
Each 0.5 mg respule mixed with 5 packets of Splenda
< 10 years of age receive 1 mg
> 10 years of age receive 2 mg
All 20 patients had improved symptom scores and 16 had significant decrease in eosinophil count
Risks
No effect on AM cortisol levels
No increased risk of oral candidiasis
Aceves
SS, et al. Oral
viscous budesonide: A potential new therapy for
eosinophilic
esophagitis
in children.
Am J
of Gastroenterology
2007;102:2271-2279
.Slide67
Eosinophilic Esophagitis – Take Home Points
Increasing prevalence
Because family practitioners, pediatricians, internists are often on the front line for chronic illnesses, you must be familiar with the presentation and evaluation. You will see it.
Clinical presentation similar to reflux but does not respond to anti-reflux therapy
High index of suspicion especially in adults with food impaction
Specific IgE blood tests to foods are not helpful.
Relapses are commonSlide68
Immune MediatedIgA
IgE
Class 1
Class 2
Eosinophil
MixedSlide69
Mixed Cell mediated Food Allergy
Atopic Dermatitis
Allergic Contact Dermatitis
Heiner
Syndrome
Caused by precipitating antibodies (IgG) to cows milk Results in lower respiratory symptoms associated with:Pulmonary infiltrates
Pulmonary
hemosiderosis
in severe cases
Failure to thrive
Anemia
Milk elimination results in improvement within weeksSlide70
Mixed Cell mediated Food AllergyAllergic
Proctocolitis
Visible specks of blood in stool and lack of systemic symptoms
Generally occurs while breastfeeding and attributed to maternally ingested proteins.
Milk and soy are common offenders
Food Protein induced enterocolitis
Usually presents with emesis, diarrhea, lethargy, and failure to thrive
Heme
positive stools
Usual triggers are milk, soy, rice, oats and other cereals.Slide71
Non-Immune Mediated
Pharmacologic
Gastrointestinal
Toxins
Sensitivity to Additives
IntoleranceLactoseGlutenSlide72
Non-Immune Mediated
Pharmacologic
An
adverse reaction in which a chemical found in a food or food additive produces a drug-like
effect
e.g., caffeine causing "the jitters".Gastrointestinal
Foods that promote
peristalsis such as laxative
foods (
fresh
fruit,
juices) and sorbitolSlide73
Non-Immune mediatedPharmacologic
Gastrointestinal
Toxins
Sensitivity to Additives
Intolerance
LactoseGlutenSlide74
Toxin Food Reactions
Food poisoning: an
adverse reaction that does not involve the immune system. It can be caused by food that has been contaminated with
Toxins
Bacteria
Microorganisms Parasites An example is scombroid
fish poisoning, which can mimic anaphylaxis, but is due to excessive histamine in spoilt
fish.Slide75
Non-Immune MediatedPharmacologicGastrointestinal
Toxins
Sensitivity to Additives
Intolerance
Lactose
GlutenSlide76
Sulfite SensitivitySulfites in acidic medium can liberate a sulfurous gas that when inhaled can trigger
bronchospasm
in asthmatic individuals.
Sulfites in foods such as dried fruit can cause
sneezing, swelling of the throat, and hives
. Anaphalaxis and life threatening reactions are rare.Slide77
Non-Immune MediatedPharmacologic
Gastrointestinal
Toxins
Sensitivity to Additives
Intolerance
LactoseGlutenSlide78
Lactose Intolerance
Pathophysiology
Lactose must be hydrolyzed into glucose and
galactose
in the intestine by lactase found in tips of
villi.Unabsorbed lactose in the colon is fermented by colonic bacteria producing symptoms of LI includingLoose stools/diarrhea (due to increased osmotic load)
Bloating/flatulence
Abdominal cramping
Systemic symptoms reported between 20 – 86% of patients
Headache,
myalgias
, mouth ulcers, sore throat, arrhythmia
Pathophysiology unknown but maybe due to toxic metabolites such as acetaldehyde produced in colonic fermentation.Slide79Slide80
Lactose IntoleranceWhen systemic symptoms present consider:
LI
Coincidental
Cow’s milk allergy
Present in 20% of patients with symptoms of LI
Olivier et al. investigated 46 adult patients with LI and persistent symptoms despite lactose elimination who underwent cow’s milk IgE testingBetween
56 – 69% of patients exhibited sensitization to cow’s milk proteins. Slide81
Lactose Intolerance DiagnosisLactose Hydrogen Breath Test
Baseline breath sample
Oral lactose load
Breath samples taken at regular intervals to analyze for hydrogen gas in
ppm
Abnormal if rise of 20 ppm or more of hydrogen compared to baseline
Genetic testing may not detect all SNPs.Slide82
Lactose Intolerance DiagnosisLactose Hydrogen Breath Test
Assumption that if all lactose is absorbed, there should be no spillover to colon.
Lactose in colon is metabolized into hydrogen.
Hydrogen gas absorbed into circulation and excreted in lungs.
Small bowel overgrowth can lead to LI due to early exposure of lactose in the small bowel, not because of enzyme deficiency.
Recent antibiotic use can cause false negative results
So breath test identifies
malabsorption
, not intolerance. Intolerance is clinical diagnosis, so why test at all? Can try elimination diet.Slide83
Lactose IntoleranceDiagnosis DifficultiesSelf report questionnaires show patients commonly associate lactose containing products with abdominal symptoms, even with normal breath tests.
Nocebo
effect – symptoms after ingestion of an inert substance when negative expectations exist
Jellema
et al found that both lactose
malabsorbers and lactose absorbers reported symptoms during lactose hydrogen breath tests.Slide84
Lactose IntoleranceDose dependent symptoms due to lactose load and level of lactase remaining
Most people with LI can tolerate 12 gm of lactose (one glass of milk).
More symptoms with doses larger than 18 gm
Quantities over 50 gm elicit symptoms in most patients
Cow’s milk has solid and liquid phases
Liquid phase (whey) retains lactoseSolid phase (casein) as found in cheese has less lactose due to removal of wheySlide85
Lactose IntoleranceTreatmentLactase supplements
Lactose free or reduced milk products
Probiotics
– uncertainSlide86
Non-Immune MediatedPharmacologic
Gastrointestinal
Toxins
Sensitivity to Additives
Intolerance
LactoseGlutenSlide87
Non Celiac Gluten Sensitivity
Mankind exists for 2.5 million years
Wheat introduced roughly 10,000 years ago
Gluten is a relatively new introduction in our diet.
Gluten is a HMW storage protein found in wheat, rye, and barley.
Until recently, gluten only associated with celiac and wheat allergy. If patients presented with gluten induced symptoms and celiac work up and wheat IgE were negative then gluten not regarded as the cause.Slide88
Non Celiac Gluten Sensitivity “Gluten Intolerance”
Purported to cause variety of:
GI Symptoms
Extraintestinal
symptoms
Associations with
Bloating
Abdominal Pain
Diarrhea/Constipation
Headaches/Migraines
Lethargy/Tiredness
ADD
Autism
Bone and joint pain
SchizophreniaSlide89
Non Celiac Gluten SensitivityPathophysiology
not understood
normal intestinal permeability and no histological alterations
Maybe intestinal damage but not to point of villous atrophy?
Lacks definitive criteria for diagnosis
Gold standard for diagnosis is 2-3 month elimination followed by blinded oral challengeUnknowns:Is minimum amount tolerated?
Can it reverse after period of avoidance?
Long-term complications if gluten consumed?
Thus diagnosis is controversial!Slide90
NCGS and IBSMany symptoms of NCGS are similar to IBS.
AGA antibodies present in 12% of public, and 17% of patients with IBS.
Kaukinen
et al.
93 adults with IBS symptoms after eating gluten cereals
In those in whom celiac disease was excluded, 40% had AGA.Not cause and effect but suggests in susceptible individuals the consumption of gluten results in an immune response that is manifested by production of
antigliadin
Ab.
Can foods such as gluten cause low level inflammation?
Are
elevations in
antigliadin
antibodies an indication of immune activation?
Kaukinen
K, et al. Intolerance to cereals is not specific for coeliac disease
.
Scand
J
Gastroenterol
. 2000. 35:942-946.Slide91
NCGSObjective: To determine whether gluten ingestion can induce symptoms in non-celiac individuals and to examine the mechanism.
Methods:
DBPC randomized challenge in 34 patients with IBS in whom celiac disease was excluded and who were asymptomatic on gluten-free diet.
Received gluten or placebo bread daily for 6 weeks
Evaluated symptomatically and with markers of intestinal inflammation
Results:
68% in gluten group were symptomatic compared to 40% of placebo group.
Antigliadin
Ab
were not induced
No changes in intestinal inflammation
Conclusion: NCGS may exist but no clues on mechanism were elucidated.
Biesiekierski
JR, et al. Gluten causes gastrointestinal symptoms in subjects without celiac disease: A double-blind randomized placebo controlled trial
. Am J
Gastroenterol
. 2011;106:508-514.Slide92
Food Intolerance – IgG Testing
Patients are often heavily invested in the idea of a food allergy causing their symptoms.
If
IgE
testing is negative, disappointed patients seek confirmation elsewhere.
IgG food testing has taken off…but why?
Capacity for IgG4 to release histamine from
basophils
has not been established.
IgG4 has been shown to increase during the course of allergen immunotherapy and inhibits
IgE
activity.
IgG4 responses dominate in frequently stung beekeepers.
Induction of cow’s milk tolerance in milk allergic children is associated by increased specific IgG4 antibodies.
Persistent exposure to foods in the gut leads immune system to react with IgG4 response. But it is not pathologic, it is rather a marker of exposure and immunologic tolerance.Slide93
IgG in IBS
Background: Patients with IBS often feel they have a dietary intolerance. Dairy and wheat are common offenders.
Aim: Assess the therapeutic potential of dietary elimination based on
IgG
food testing.
Patients: 150 adults with IBS randomized to receive for 3 months either a diet excluding all IgG positive foods or a sham diet excluding the same number of foods but not those to which they had antibodies.
Methods: DBPC study. Primary outcome measure was change in IBS symptom severity.
Atkinson W, et al. Food elimination based on
IgG
antibodies in irritable bowel syndrome: a
randomised
controlled trial.
Gut.
2004;53:1459-1464.Slide94
IgG in IBS
Results:
True diet resulted in 10% greater reduction in symptom scores than sham
Fully compliant patients had a 26% greater reduction
Conclusion: Food elimination based on
IgG antibodies may be effective in reducing IBS symptoms.
Atkinson et al. Gut 2004.Slide95
IgG in IBS
Difference in outcomes can be explained by difference in diets.
True diet excluded milk products for 84% and wheat for 49% of patients.
Sham diet excluded them from 1.3% and 8% respectively.
Dairy and wheat are known to be subjective offenders in IBS. So improvement in true diet group reflects avoidance of common offending foods not value of
IgG testing. (Main endpoint was a subjective endpoint.)Slide96Slide97
IgG4 testing50 young adults with no history or signs of food reactions had specific IgG4 testing to 14 common foods.
92% had elevated specific IgG4 to at least one food.
Conclusion: The common occurrence of sIgG4 to foods in healthy persons argues against pathogenesis of these antibodies.
Kruszewski
J, et
al.
High serum levels of allergen specific IgG-4 for common food allergens in healthy blood donors.
Arch
Immun
Ther
Experim
. 1994;42:259.Slide98
IgG Food Testing
Positive results in absence of clinical symptoms.
EAACI position paper concludes IgG4 testing to foods is irrelevant for food allergy or intolerance.
Stapel
O, et al. Testing for IgG4 against foods is not recommended as a diagnostic tool: EAACI task force report.
Allergy
. 2008;63:793-96.Slide99
Food Allergy vs. Intolerance
Food Allergy
Immune system involvement
Reaction affects multiple organs and can be severe
Symptoms usually occur rapidly
Ingestion of small amounts of food can cause severe symptoms.
Avoidance is mainstay of therapy….thus far.
Food Intolerance
Immune system not involved.
Generally less severe and limited to GI symptoms.
Symptoms generally come on gradually
Can eat small amounts of the food without symptoms.
Treatment options do exist (lactase enzymes).Slide100Slide101
Bibliography
Nelson,HS
,
et al. Treatment of anaphylactic sensitivity to peanuts by immunotherapy with injections of aqueous peanut extract. J Allergy
Clin
Immunol 1997;99:744-51.
Vickery
BP, et al. Immunotherapy in the treatment of food allergy: focus on oral tolerance.
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Wegrzyn
A, et al. Tolerance to extensively heated milk in children with cow's milk allergy. J Allergy
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G, et al. Specific oral tolerance induction in children with very severe cow's milk-induced reactions. J Allergy
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O,
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