++
Allergic and eosinophilic disorders of the gastrointestinal (GI)
tract have in common an infiltrate of eosinophils into the wall
of the GI tract—sometimes located in the lamina propria
only, sometimes in the muscularis propria, sometimes in both. The
associated disorders are highly variable in severity of symptoms
and endoscopic and histologic manifestations (Table
411-1). Different parts of the GI tract may be involved separately
or together (eg, eosinophilic esophagitis is almost always a stand-alone
disorder; eosinophilic gastritis may occur on its own, or, more
commonly as a gastroenteritis; eosinophilic colitis may occur alone, or in combination with small bowel
involvement, ie, enterocolitis). Complicating this is the fact that
eosinophils are found in the GI tract in a number of other disorders,
not considered to be primarily allergic in origin. These include
disease induced by parasitic, bacterial, and viral pathogens as
well as certain systemic diseases such as vasculitis. The general
principles, diagnostic approach, and management of food allergy
is discussed in detail in Chapter 194.
++
Adverse reactions to foods have now been subclassified by the
American Academy of Allergy and Immunology into three categories: food
anaphylaxis, food hypersensitivity, and food
intolerance. Anaphylaxis and hypersensitivity involve allergic
mechanisms, whereas intolerance is a reproducible nonallergic response.
Allergic food reactions may be broadly divided into IgE–mediated
(eg, anaphylaxis) and non-IgE–mediated ones (eg, celiac),
or combinations (eg, eosinophilic esophagitis). Food anaphylaxis is
an IgE-mediated reaction of rapid onset (within minutes) and includes
classic anaphylaxis and oral allergy syndrome. Food hypersensitivity includes
immunologic reactions that are typically delayed, cell-mediated
with or without IgE antibody involvement, and include eosinophilic
esophagitis, food protein-induced enterocolitis syndrome, food protein-induced
proctocolitis, and celiac disease. Food intolerance represents
an abnormal, nonallergic physiologic response including idiosyncratic
(monosodium glutamate), metabolic (galatosemia), digestive (lactase
deficiency), pharmacologic (caffeine), toxic (Bacillus cereus),
organ-based (irritable bowel syndrome), and behavioral (food texture
aversion) reactions.
++
The incidence of food allergies is on the rise and affects 2% to
7.5% of children in the first 3 years of life.1,2,3 During
the first year of life, cow milk proteins are the main food antigens
involved in GI allergic reactions with an incidence ranging from
0.3% to 7.5%.4 The incidence and prevalence
of specific gastrointestinal presentations of food allergy or eosinophilic
gastroenteropathies are unknown. Eosinophilic disorders of the intestine
appear to be more frequent in children with other immunologic disorders
or those receiving immunosuppression.5,6
++
Allergic gastrointestinal disorders can be divided into those
that are IgE mediated and those that are not. Under normal
circumstances, the intestinal mucosa acts as a critical barrier
to potential injurious agents including pathogens, toxins, and foreign
antigens (eg, foods). Both nonimmunologic and immunologic defense
mechanisms are less developed in infancy. Nonimmunologic factors
include decreased gastric acidity (to enhance gastric pepsin activity),
decreased activity of intestinal proteolytic enzymes, and greater
permeability of the intestinal barrier which contribute to incomplete
digestion of proteins into nonantigenic peptides. Commensal flora
or probiotic bacteria help prevent overgrowth of pathogenic organisms
by inhibiting attachment of pathogenic organisms to mucous glycoproteins.
Undigested cow milk or food protein macromolecules can then cross
the intestinal epithelium to stimulate lamina propria lymphocytes
cells to release proinflammatory cytokines (eg, tumor necrosis factor-α),
as well as decrease secretion of both transforming growth factor-β,
an anti-inflammatory cytokine that induces T cell suppression, and
protective IgA. Among the 20 protein fractions in cow milk, whey
protein β-lactoglobulin is considered to be the
most antigenic. Soy protein is also a common antigen, and 15% to
30% of cow-milk–sensitive infants will react to
soy. Solid food proteins become prime antigens once introduced to
the diet. Foods commonly associated with GI allergic reactions include
egg white, tree nuts (peanuts), wheat, rice, potato, seafood, and
various meats (eg, chicken, beef, pork). Cow milk or soy protein
allergy tends to be transient during the first year or two of life
and outgrown with intestinal maturation. In contrast, tree nut allergy
is lifelong and more often life threatening. Intestinal maturation
in the first year of life may explain why cow milk sensitivity rarely
begins after 1 year, and why most outgrow their sensitivity by age
2 to 3 years.
++
Immaturity of the infant’s immunologic defenses plays
a key role in the development of food sensitivities. After birth,
IgA- and IgM-producing cells respond gradually to the point that
secretory IgA becomes the predominant mucosal surface Ig leaving
an early window of vulnerability during which T-cell reactivity
toward food antigens peaks. The optimal intestinal response is a
local secretory IgA response and concomitant T suppressor cell induced
reduction in IgG and IgE resulting in development of oral
tolerance. Oral tolerance may not develop because of failed
T-cell suppression, altered Th2 responses, and cytokine release
(IL-4, IL-5, IL-10, IL-13).
++
The etiology of other eosinophilic gastrointestinal disorders
is unclear, as are the relationships to specific food allergens,
which are often never identified. Some of these disorders may represent
primary immunoregulatory disorders, but a subset of the eosinophilic
gastroenteropathies are responsive to food elimination, and these
most likely will be due to cell-mediated or IgE-antibody-mediated
processes.7
+++
Clinical Phenotypes of
Allergic and Eosinophilic Gastrointestinal Disease
+++
Food Protein-Induced
Enterocolitis Syndrome
++
Food protein-induced enterocolitis syndrome (FPIES) is often
considered an anaphylactic-like or anaphylactoid reaction because
of its rapid onset, high acuity and upper gastrointestinal (GI)
symptoms of vomiting and diarrhea, and systemic manifestations of
pallor, hypotension, and shock.7,8 However, FPIES is a
non-IgE-mediated process that is associated with villous atrophy
and lymphocytic inflammation, as seen in celiac disease, rather
than the eosinophilic infiltration found in eosinophilic gastroenteritis.
Although the small intestine is the usual target of inflammation,
FPIES can be more extensive and cause gastritis, intestinal protein
loss (ie, protein-losing enteropathy), or colitis (ie, hematochezia).
++
FPIES presents in various patterns. An acute presentation with
vomiting and diarrhea within 1 to 3 hours of exposure progressing
to systemic pallor, lethargy, and hypotension is the most worrisome
because of the potential for shock resulting from an unobserved
challenge.9,10 This condition appears to be uncommon, with
only 14 cases being observed by 2 major food allergy centers over
a 5-year span.11 A second subacute presentation begins
less dramatically following ingestion of an allergen. This makes
it more difficult to pinpoint the relationship to specific foods.
There is less vomiting but more diarrhea with poor weight gain as
a result of loss of small intestinal surface epithelium (villous
atrophy) and resultant nutrient malabsorption. In more severe cases,
the infant may progress from failure to thrive to chronic acidemia
and methhemoglobinemia.12
++
FPIES usually begins in infants less than 1 year of age. Formula
protein hypersensitivity typically develops during the first month
of life. Food protein sensitivities typically develop shortly after
the introduction of solids.12 Because of its common use
as a formula thickener to treat gastroesophageal reflux, rice-induced
enterocolitis can begin before 6 months of age.7,8 Common
food allergens include egg white, wheat, rice, peanut, and fish,
often in combination. Less common food allergens include oat, barley,
sweet potato, squash, string beans, peas, chicken, and turkey.13 Symptoms
may be provoked by direct consumption of formula protein or indirectly
by antigens crossing through breast milk or via the intrauterine
route. Although GI symptoms usually predominate, affected infants
typically have other coexisting allergic symptoms, especially eczema.
Although symptoms of FPIES often subside by 2 to 3 years of age,
they can persist in 30% of the toddlers.
+++
Eosinophilic
Gastroenteritis
++
Eosinophilic gastroenteritis (EGE), also known as eosinophilic
gastroenteropathy, is a dense eosinophilic inflammation of the gastrointestinal
mucosa accompanied by peripheral blood eosinophilia in 75% of
those affected.14,15 The disease is relatively uncommon,
predominantly affecting boys and young adult men. Signs and symptoms
depend upon the depth of involvement, either to the superficial
mucosa alone or deeper. The mucosal involvement can induce abdominal
pain, vomiting, diarrhea, and growth failure and, in more severe
cases, also involve anasarca from protein-losing enteropathy and
iron-deficiency anemia.14,15 Deeper muscle infiltration
can lead to gastric outlet obstruction.16 Serosal involvement
may rarely lead to ascites.
++
EGE usually involves the mucosa of the stomach (ie, antrum),
small intestine, and occasionally extends to the colon.14 From
one third to three quarters of pediatric patients have a history
of atopic disease (eg, urticaria, eczema, asthma) or food allergy.
The majority have elevated peripheral eosinophil counts and positive food-specific
skin prick or radioallergosorbent (RAST) tests. The mucosal form
typically occurs in toddlers and responds to an elimination diet.17
++
EGE is categorized based on the depth of eosinophilic infiltration:
mucosal, muscular, and serosal forms, and the distribution of the
infiltrate in the gastrointestinal tract.18 Eosinophilic
infiltration of the muscle layers results in wall thickening and
gastric outlet obstruction or intestinal stenosis that can mimic
pyloric stenosis or Crohn stricture, respectively. Serosal involvement
is rare but can cause eosinophilic ascites, usually without significant
gastrointestinal symptoms. Extraintestinal eosinophilia can rarely
involve the other organs, including gallbladder, spleen, pancreas,
bladder, peritoneum, and pericardium, to induce polyserositis-like
pericardial effusions.19 Other rare presentations include
acute abdomen, colonic obstruction, and duodenal perforation from
ulcer.20,21
++
Although the cause remains unknown, the common presence of peripheral
eosinophilia suggests an allergic etiology and both IgE and non-IgE-mediated
mechanisms are thought to be involved.15 Although specific
foods have been implicated in some cases, in most cases food elimination
does not resolve the symptoms.17,22 Levels of IL-3, IL-5,
and granulocyte colony-stimulating factor are significantly increased.23 New
evidence suggests that an underlying immune dysregulation may be
a contributory factor.6
+++
Eosinophilic
Proctocolitis
++
Eosinophilic proctocolitis (EPC), also referred to as “allergic
colitis,” is the most prevalent and benign of all allergic
gastrointestinal disorders.14,24,25,26 EPC typically begins
at 4 to 12 weeks of age and is more frequent in boys than girls
by a 2:1 ratio. The typical presentation is one of painless hematochezia
mixed with mucus and occasional diarrhea, but the infants are otherwise
feeding and growing well.14,27 The stools contain flecks
of blood, insufficient in amount to cause anemia, unless untreated
for long periods. Among all infants presenting with hematochezia,
approximately two thirds will be expected to have biopsy-proven
eosinophilic proctocolitis.25 The approach to the infant
with hematochezia is discussed in Chapter 387.
The most common protein sensitivities are to either cow milk (via
direct consumption or transfer via breast milk) or soy proteins
in formula. In two thirds of breast-fed cases, cow milk is the offending protein,
and its elimination from the maternal diet is effective treatment
in over 80%.28,29,30
++
The mechanism of EPC remains unclear. The early window of susceptibility
of between 4 and 12 weeks coincides with a period of increased permeability
of the mucosal barrier and immaturity of mucosal immune. Elevated
levels of eosinophil cationic protein and platelet-activating factor
are found in EPE, but the underlying pathophysiology has not been
elucidated.31
+++
Cow Milk-Induced Gastroesophageal
Reflux
++
Gastroesophageal reflux is discussed in Chapter 394. Cow’s milk allergy may play an etiologic role
in some cases of patients with significant gastroesophageal reflux.32,33,34 These
patients have positive skin prick tests, increased nasal or peripheral
eosinophilia, and the presence of circulating anti-β-lactoglobulin
IgG. Elimination of cow milk improves symptoms that recur when cow
milk is reintroduced. The overlap of this entity and eosinophilic
esophagitis requires clarification.
+++
Cow Milk Protein-Induced Constipation
++
Cow milk hypersensitivity appears to induce chronic constipation
in some patients.35,36,37 These patients have findings
of a higher frequency of concomitant rhinitis, eczema, and bronchospasm,
and elevated IgE to cow milk antigens than those with constipation
from other causes. The mechanism by which cow milk proteins induce
altered colonic function is unclear.
+++
Cow Milk Protein-Induced Anemia
++
Occasionally, children present between the ages of 1 and 3 years
with profound microcytic anemia (hemoglobin 6–8 g), hypoalbuminemia,
and excess cow milk intake. Despite the evident pallor and edema
on examination, because of its insidious development of anemia and
hypoalbuminemia, the child does not develop orthostatic hypotension
or symptoms.38 Laboratory studies reveal a profound microcytic
anemia, a low serum albumin, and elevated fecal α1-antitrypsin
excretion indicating severe iron-deficiency anemia and protein-losing
enteropathy. However, stool guaiac test for blood is negative. The
dietary history usually reveals that this “milk” baby
is drinking in excess of 32 ounces of whole milk largely to the
exclusion of other iron-containing nutrient sources. Although full
exclusion of cow milk protein, intake of a regular diet, and supplementation with
iron is the usual therapeutic approach, one study demonstrates that
reduction in cow milk intake below 24 ounces per day rather than
total elimination may be sufficient.39 Although the mechanism
by which cow milk induces the anemia is unclear, the lack of documented
stool heme and threshold effect for milk intake suggests that it
more likely results from either iron deficiency or mucosal toxicity
rather than from hypersensitivity to cow milk protein.
++
A positive oral food challenge remains the definitive gold standard
test for food allergy.40 However, given the inherent risks
involved in those with severe symptoms, such testing may be avoided
if alternative nutrient sources are acceptable. If performed, it
is recommended that the challenge be carried out in hospital with
intravenous fluids and available epinephrine, diphenhydramine, and
methylprednisolone. The oral challenge includes progressively increasing
(by 2- to 5-fold) amounts of protein every 15 minutes beginning
with mg amounts of food protein as described above. Clinical symptoms
may be accompanied by a rise in peripheral and stool polymorphonuclear cells.12,41 The
challenge is terminated if clinical symptoms occur (vomiting, diarrhea,
hypotension, listlessness) or physiologic amounts (2 ounces of formula
or 15 g food) of protein have been ingested without symptoms.
++
Despite its acute presentation, FPIES is a non-IgE-mediated condition,
and skin prick and RAST testing are usually negative. Diagnosis
is based upon the typical history combined with typical endoscopic
findings that include inflammation and villous atrophy, often indistinguishable
from that of celiac disease.
++
Diagnosis of EGE is based upon the clinical presentation and
findings of endoscopic evaluation. Laboratory findings of eosinophilia,
increased serum IgE, hypoalbuminemia, and protein-losing enteropathy
(elevated stool α1-antitrypsin level)
are common. Diagnosis requires the demonstration of significant
tissue eosinophilia in submucosa (and muscularis mucosa) of the
gastric antral and duodenal specimens.42,43 In a few, a
lacy mucosal pattern called areae gastricae can
be visualized on a barium contrast study.44 The differential
diagnosis of gastroduodenal eosinophilia includes Crohn disease,
ulcerative colitis, parasitic infections, Ménétrier
disease, chronic granulomatous disease, collagen vascular disease, and
hypereosinophilic syndrome (ie, hyper-IgE syndrome).
++
The diagnosis of eosinophilic proctocolitis in infants, and other
cow milk allergic presentations, is made based upon the typical
symptom presentation and response to removal of the offending antigen.
If the child responds promptly to the dietary antigen elimination,
no testing is necessary. However if the symptoms persist beyond 4
weeks, a full evaluation should be undertaken. This includes a hemoglobin,
stool bacterial cultures, and flexible sigmoidoscopy. The visual
sigmoidoscopic findings typically show patchy erythema with friability
and edema (mucosal pallor) and occasional mucosal erosions or ulcerations,
but in some cases the mucosa may have lymphonodular hyperplasia
or may appear entirely normal.31 The histopathology reveals
eosinophils (⩾ 6/hpf) within the lamina propria and infiltrating
normal colonic glands.14,45 Stains for stool polymorphonuclear
cells and eosinophils may be positive, but their absence does not
exclude EPC. The differential diagnosis includes bacterial colitis,
anal fissure, and, much less commonly in infants, inflammatory bowel
disease. Most of the infants will outgrow this sensitivity and become
tolerant of the offending protein by the age of 1 year. The parents
can be reassured about the good prognosis. However, a formal challenge
in a physician’s office is recommended to exclude the possibility
of evolution to FPIES or anaphylaxis.
++
A time-limited, 2-week treatment trial of directed dietary elimination
may be an appropriate initial diagnostic test in food protein-induced
proctocolitis and cow milk–induced constipation.
++
Treatment of food allergy syndromes requires fastidious avoidance
of the offending food allergen(s). In cases associated with anaphylactic-type
reactions, a medical alert bracelet that identifies the allergen,
as well as provision and training in the use of an epinephrine injection for
initial home management of an acute anaphylactic reaction is appropriate.
For infants and young children with cow milk protein hypersensitivities,
the appropriate choice of a milk substitute should meet certain
essential criteria that include no or little cross-reactivity with
cow milk, lower allergenicity, and nutritional adequacy. Infant
formulas that meet those requirements include cow milk protein (eg, casein,
whey) hydrolysates (eg, ⩽ 6 amino acid peptides) and elemental (amino
acid) formulas.46,47 Soy protein formulas are not tolerated
in all cow milk–sensitive infants because soy protein allergy
coexists in 17% to 47%.46,47,48 The unpalatability
of protein hydrolysate and elemental formulas (requiring nasogastric
feedings) and the high costs may affect compliance. In infants with
mild symptoms, a hydrolyzed formula should be used for at least
1 month to allow adequate time for mucosal healing. Delayed-type
cow milk and soy protein hypersensitivity with predominantly GI
manifestations usually become less severe with increasing age. At
1 year, 2 years, and 3 years of age, 45% to 50%,
60% to 75%, and 85% to 90%,
respectively, of children become fully tolerant to cow milk protein,
with some 25% continuing to manifest severe IgE-mediated
type I reactions to milk.49,50 Reintroduction of cow milk
or soy protein in a previously highly sensitive child should be
performed under medical supervision because of the low but potential
risk of anaphylaxis.
++
Treatment options of children with eosinophilic gastroenteritis
include both dietary elimination of food antigens and anti-inflammatory medications
and mast cell stabilizers. As first-line therapy, exclusion of the
offending food antigen(s) either by an elemental diet or elimination
diet directed by results of allergy testing or by avoidance of highly
allergenic (eg, 6 food elimination) foods can be initiated.17,22 Different
from EE, the majority of children have a non-food-allergic form
that responds only to glucocorticoid therapy22 that is
associated with side effects, including cushingoid appearance, acne,
hirsuitism, impaired growth, and diminished bone density. Although
the steroid side effects can be reduced with alternate day or low
daily dosing, both can lead to impaired linear growth. Another alternative
is budesonide, a corticosteroid that, because of a first-pass liver
clearance, has few systemic side effects.51 A number of
other classes of medications have been tried with some success.
These include mast cell stabilizers cromolyn sodium52 or
ketotifen,53 selective leukotriene receptor antagonist,54 and
a Th2 suppressor suplatast tosilate.53,55 EGE appears to
be a long-standing disorder that is not outgrown with age. Recent
trials indicate that an anti–IL-5 antibody (mepolizumab)
may be highly effective in patients with steroid-resistant disease.56
++
Exclusive breastfeeding during the first 6 to 12 months of life
has been reported to either prevent or delay the onset of allergic
gastrointestinal disease in some studies, but others have not shown similar
results. There is limited evidence that feeding with a hydrolysed
formula compared to a cow milk formula reduces infant and childhood allergy
and infant cow milk enterocolitis.57 Thus, the role of
exclusive breastfeeding in preventing food allergy remains somewhat
controversial.58 The American Academy of Pediatrics recommends
delaying introduction of solids to beyond 6 months of age. For those
at high risk for developing food hypersensitivities, based on family
history, the American Academy of Allergy, Asthma and Immunology
(AAAAI) and the American College of Allergy, Asthma and Immunology
(ACAAI) further recommend delaying introduction of cow milk to 1 year,
soy, egg white, and wheat until 2 years, and tree nuts and fish
until age 3.59 No maternal dietary restrictions during
pregnancy are necessary with the possible exception of excluding
peanuts.59