Phase 1

Report
Adverse Food Reactions:
From Allergy to Intolerance
Barzin Khalili, MD
Adjunct Assistant Professor
Allergy & Immunology
Oregon Health Sciences University
Food Allergy
• Food 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 testing
Adverse Food Reactions
• Immune
– IgA
– IgE
• Class 1
• Class 2
– Eosinophil
– Mixed
• Non-immune
–
–
–
–
–
Pharmacologic
Gastrointestinal
Toxins
Sensitivity to Additives
Intolerance
• Lactose
• Gluten
Immune Mediated
• IgA
• IgE
– Class 1
– Class 2
• Eosinophil
• Mixed
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.
Celiac Sprue - Pathophysiology
Celiac - Testing
• Small bowel biopsy is gold standard
• Serologic testing
– Anti-gliadin antibodies – IgA and IgG
• Nonspecific -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.
Celiac Genetics
• HLA 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.
Immune Mediated
• IgA
• IgE
– Class 1
– Class 2
• Eosinophil
• T cells
• Mixed
IgE Mediated Food Allergy
• Symptoms –
–
–
–
–
•
•
•
•
Skin – urticaria, pruritus
GI – 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 autoinjector
Prick Skin Testing
• Evaluate for IgE mediated food sensitization
ELISA
Question
If aeroallergen Immunotherapy is effective for
pollenosis, why are we advocating food
avoidance instead of food immunotherapy?
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.
Rush Immunotherapy Schedule
Day
Time (am)
Concentration
Dose (ml)
1
8
1:10,000
wt/vol.
0.05
2
3
9
0.10
10
0.20
11
0.40
8
5
0.05
9
0.10
10
0.15
11
0.20
8
0.30
9
0.40
10
0.50
11
4
1:1000 wt/vol.
1:100 wt/vol.
0.07
8
0.10
9
0.15
10
0.20
11
0.30
8
0.40
10
0.50
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 mg
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
2
1
Mean
34.7
4.8
7.7
9.8
2.2
Median
33
4.0
3.5
4.0
1.0
• Repeat Epinephrine treatments were required 8 times.
• Systemic Reaction Rate of 23%
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
1:1000
6
21
0
3
0
0
1:100
• Two patients were unable to tolerate the dose achieved during RIT.
• Median 13.5 reactions to 35 injections; Systemic reaction rate of 39%.
Results – Oral Challenges
9000
Threshold Dose (mg)
8000
7000
6000
5000
Baseline
4000
1 Month
12 Months
3000
2000
1000
0
1
2
3
4
Patients 1,4,5 received a reduced maintenance dose.
5
6
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 (1/27th)  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.”
Oral Tolerance
• 1829 – 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.
Promoting Oral Food Tolerance
Can patients with milk allergy tolerate extensively-heated milk products?
Reacted
23%
Strict milk avoidance
Reacted to regular milk
68%
Heated milk OFC
Heated milk diet
Tolerated
Tolerated Regular milk 9%
Add milk to diet
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.
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.
Milk Oral immunotherapy
• Issue: 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 lifethreatening conditions.
• Solution: Conduct the study overseas.
Milk Oral immunotherapy
• Objective: Is oral
immunotherapy safe
and effective for
children with severe
cow milk allergies?
• Methods:
– Inclusion Criteria
• 5-17 years old
• Milk 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.
Milk Oral immunotherapy
• Methods 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
year
– Repeat oral challenge was performed at 1 year.
Treatment Group
Phase 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.
Milk Oral immunotherapy
Group A
Unrestrict
ed Diet (7)
Group B
• Positive food challenges in
all 30 cases
Maximum
Tolerance
(4)
Partial
Tolerance
(16)
Failure (3)
Difference between groups is statistically significant (P < 0.001)
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)
In hospital patients
( total no. of treatments)
At home patients
(total no. of treatments)
Oral steroids
8 (16)
17 (35)
Nebulized epinephrine
18 (22)
6 (9)
4 (4)
1 (1)
Administered Treatment
IM epinephrine
Group B: 6 (20%) children had adverse reactions caused by accidental milk ingestion.
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 lifethreatening.
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 TH1-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.
Peanut Oral Immunotherapy
• Results:
– 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.
Peanut-specific Immunoglobulins
Regulatory T Cells
Peanut Oral Immunotherapy
• Conclusions: Humoral and cellular responses
suggest that OIT induces transition from shortterm desensitization to long-term tolerance.
Peanut Oral Immunotherapy
• Objective: 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.
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 TH2
phenotype and not dependent upon ongoing
therapy.
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.
Egg Oral IT
Results
Egg Oral Immunotherapy
• Conclusions: Oral IT can desensitize a
significant proportion of children and induce
sustained responsiveness in a subset.
Burks et al. NEJM 2012
Immune Mediated
• IgA
• IgE
– Class 1
– Class 2
• Eosinophil
• Mixed
Class 2 Food Allergy
• Also 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 swelling
• 9% of the time can have systemic symptoms
– Nausea, vomiting, diarrhea, abdominal pain
– Urticaria, angioedema
• 1.7% experience anaphylaxis
Oral Allergy Syndrome
• Due 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 – labile
• Involved in celery-mugwort-spice syndrome
– Lipid transfer protein – stable to heat and proteolysis
• Responsible for anaphylactic episodes
Oral Allergy Syndrome
Oral Allergy Syndrome
• Testing
– Skin 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).
CRD
Imagine this:
On a miniature scale (a biochip) using specific
allergen recombinant epitopes rather than the
whole protein.
AND
Only requires 20ul of serum via capillary blood
sampling
CRD - How it Can Help
• Component 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.
Oral Allergy Syndrome
• Treatment as with Class 1 food allergy
– Avoidance
– Education
– Injectable epinephrine
• Two potential pitfalls:
– Improper diagnosis of OAS in patient with anaphylaxis
– Potential to dismiss patient with OAS as having no risk
of anaphylaxis.
• Remember 1.7% experience shock
Question
• If OAS is initiated by a primary aeroallergen
sensitization…is there a role for
immunotherapy (IT)?
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 of tree pollen specific, subcutaneous immunotherapy on the oral allergy syndrome to apple and hazelnut.
Allergy. 200459:1272-76.
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.
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.
Immune Mediated
• IgA
• IgE
– Class 1
– Class 2
• Eosinophil
• Mixed
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
Eosinophilic Esophagitis - Presentation
• Symptoms tend to vary
depending on age;
• Infants
– Failure to thrive
– Irritability
– Food refusal
• Young children
–
–
–
–
vomiting
Regurgitation
Epigastric pain
Abdominal Pain
• Older children and adults
–
–
–
–
Dysphagia > 90%
Heartburn
Chest Pain
Food Impaction > 60%
• Easy to see why
symptoms often
attributed to reflux
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
Uncommon
Eosinophilic Esophagitis - Diagnosis
• EE is a histo-clinical diagnosis
– Made by endoscopy and biopsy
Concentric rings
Linear furrows
Mucosal laceration
Eosinophilic Esophagitis - Diagnosis
• Diagnostic criteria based on consensus
recommendations:
1. Clinical symptoms of esophageal dysfunction
2. Greater than 15 eosinophils per hpf
•
•
< 10 eosinophils often seen in reflux
Unlike other GI tissues, normal esophagus is devoid
of eosinophils.
3. No improvement with high-dose PPI or normal
pH probe.
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.
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.
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 back
– Removed 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.
Eosinophilic Esophagitis – Role of Food
Allergy
Most common foods positive in skin tests
(66% of patients react to 1 or more foods)
Most common foods positive on
atopy patch tests
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Cow’s milk
Egg
Peanut
Almonds
Soy
Rice
Beans
Pea
Mustard
Beef
Carrot
Cow’s milk
Egg
Beef
Lamb
Veal
Chicken
Oat
Rye
Rice
Corn
Wheat
Soy
Potato
Peas
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 improvement
• Avoidance 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 liberalized
Eosinophilic Esophagitis – Treatment
Swallow 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 loss
Eosinophilic Esophagitis – Treatment
Swallowed 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.
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 common
Immune Mediated
• IgA
• IgE
– Class 1
– Class 2
• Eosinophil
• Mixed
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 weeks
Mixed Cell mediated Food Allergy
• Allergic 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.
Non-Immune Mediated
•
•
•
•
•
Pharmacologic
Gastrointestinal
Toxins
Sensitivity to Additives
Intolerance
– Lactose
– Gluten
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 sorbitol
Non-Immune mediated
•
•
•
•
•
Pharmacologic
Gastrointestinal
Toxins
Sensitivity to Additives
Intolerance
– Lactose
– Gluten
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.
Non-Immune Mediated
•
•
•
•
•
Pharmacologic
Gastrointestinal
Toxins
Sensitivity to Additives
Intolerance
– Lactose
– Gluten
Sulfite Sensitivity
• Sulfites 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.
Non-Immune Mediated
•
•
•
•
•
Pharmacologic
Gastrointestinal
Toxins
Sensitivity to Additives
Intolerance
– Lactose
– Gluten
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 including
•
•
•
•
Loose 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.
Lactose Intolerance
• When 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 testing
– Between 56 – 69% of patients exhibited sensitization to cow’s
milk proteins.
Lactose Intolerance Diagnosis
• Lactose 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.
Lactose Intolerance Diagnosis
• Lactose 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.
Lactose Intolerance
• Diagnosis Difficulties
– Self 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.
Lactose Intolerance
• Dose 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 lactose
• Solid phase (casein) as found in cheese has less lactose due
to removal of whey
Lactose Intolerance
• Treatment
– Lactase supplements
– Lactose free or reduced milk products
– Probiotics – uncertain
Non-Immune Mediated
•
•
•
•
•
Pharmacologic
Gastrointestinal
Toxins
Sensitivity to Additives
Intolerance
– Lactose
– Gluten
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.
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
Schizophrenia
Non Celiac Gluten Sensitivity
• Pathophysiology 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 challenge
• Unknowns:
– Is minimum amount tolerated?
– Can it reverse after period of avoidance?
– Long-term complications if gluten consumed?
• Thus diagnosis is controversial!
NCGS and IBS
• Many 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.
NCGS
• Objective: 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.
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.
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.
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.
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.)
IgG4 testing
• 50 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.
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.
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).
Food Related
Adverse
Reaction
NonImmunologic
Immunologic
IgA
Celiac Disease
IgE
Eosinophil
Mixed
Intolerance
Class 1
Eosinophilic
Esophagitis
FPIES
Lactose
Class 2 (OAS)
Eosinophilic
Gastroenteritis
Proctocolitis
Gluten
Atopic
Dermatitis
Heiner
Syndrome
Contact
Dermatitis
Pharmacologic
Caffeine
Toxin
Additive
Sensitivity
Gastrointestinal
Bacteria
Sulfite
Sorbitol
Scombroid
MSG
Caffeine
Parasites
Juices
Bibliography
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
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. Curr Opin Allergy Clin
Immunol. 2009;9:364-370.
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.
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.
Bonilla FA. Adaptive Immunity. J Allergy Clin Immunol. 2010;125:533-40.
Romagnani S. The role of lymphocytes in allergic disease. J Allergy Clin Immunol. 2000;105:399-408.
Jones SM, et al. Clinical efficacy and immune regulation with peanut oral immunotherapy. J Allergy Clin Immunol.
2009;124:292-300.
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.
Burks AW, et al. Oral immunotherapy for treatment of egg allergy in children. NEJM. 2012;367:233-43.
Bucher X, et al. Effect pf tree pollen specific, subcutaneous immunotherapy on the oral allergy syndrome to apple
and hazelnut. Allergy. 200459:1272-76.
Kopac P, et al. Continuous apple consumption induces oral tolerance in birch-pollen-associated apple allergy.
Allergy. 2012:67:280-85.
Aceves SS, et al. Oral viscous budesonide: A potential new therapy for eosinophilic esophagitis in children. Am J of
Gastroenterology 2007;102:2271-279.
Kaukinen K, et al. Intolerance to cereals is not specific for coeliac disease. Scand J Gastroenterol. 2000. 35:942946.
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.
Atkinson W, et al. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled
trial. Gut. 2004;53:1459-1464.
Kruszewski, 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.
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.

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