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Food Protein-Induced Allergic Proctocolitis of Infancy - UpToDate
Food Protein-Induced Allergic Proctocolitis of Infancy - UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2019 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
Food proteininduced allergic proctocolitis of infancy
Author: Chris A Liacouras, MD
Section Editors: Scott H Sicherer, MD, FAAAAI, B UK Li, MD
Deputy Editor: Alison G Hoppin, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2019. | This topic last updated: Sep 11, 2018.
INTRODUCTION
Food proteininduced allergic proctocolitis (FPIAP, formerly known as allergic or eosinophilic
proctocolitis, or "protein intolerance") is a common cause of rectal bleeding in an otherwise healthy
young infant [1]. This disease usually begins within the first weeks of life, and in most cases resolves
by late infancy. It is characterized by inflammation of the distal colon in response to one or more food
proteins through a mechanism that does not involve immunoglobulin E (IgE). Cow's milk and soy
protein are the most common triggers. An association of symptoms to food protein antigens requires
demonstration of objective improvement following withdrawal of the suspected food antigen and, in
some cases, recurrence following a subsequent oral challenge. This disorder will be discussed in this
topic review.
Other disorders of infancy characterized by nonIgEmediated gastrointestinal inflammatory
responses to food are food proteininduced enterocolitis syndrome (FPIES), in which a large portion
of the entire gastrointestinal tract is affected and the clinical manifestations are much more severe
than FPIAP [2], and food proteininduced enteropathy, in which the small bowel is affected. These
disorders are discussed separately. (See "Food proteininduced enterocolitis syndrome (FPIES)".)
CLASSIFICATION AND TERMINOLOGY
Immunologic reactions to dietary proteins may be classified as IgEmediated, nonIgEmediated, or
mixed (table 1). Guidelines from a panel of experts in allergy and immunology published in 2010
clarified the clinical distinctions and pathophysiologic processes implicated in each of these disorders
and established the classification and terminology used in this topic review [3].
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IgEmediated – The classical food allergy (foodinduced anaphylaxis) is mediated by IgE
antibodies to food proteins with mast cell activation, and is also termed immediate
hypersensitivity. These reactions are rapid in onset, typically beginning within minutes to two
hours from the time of ingestion. Signs and symptoms can involve the skin, respiratory and
gastrointestinal tracts, and cardiovascular system, in isolation or combination. This type of
reaction is discussed in separate topic reviews. (See "Clinical manifestations of food allergy: An
overview" and "Food allergy in children: Prevalence, natural history, and monitoring for
resolution".)
Mixed – Some food allergy disorders can have both IgE and nonIgEmediated components.
These disorders are typically isolated to the gastrointestinal tract and/or skin. They include:
• Atopic dermatitis (see "Role of allergy in atopic dermatitis (eczema)")
• Eosinophilic esophagitis (see "Clinical manifestations and diagnosis of eosinophilic
esophagitis")
• Eosinophilic gastroenteritis (see "Eosinophilic gastroenteritis")
NonIgEmediated – NonIgEmediated reactions to food can affect any part of the
gastrointestinal tract, and include:
• Food proteininduced allergic proctocolitis (FPIAP; involves the rectum and colon); discussed
in this topic review
• Food proteininduced enteropathy (involves the small intestine) (see "Food proteininduced
enterocolitis syndrome (FPIES)", section on 'Allergic food proteininduced proctocolitis and
enteropathy')
• Food proteininduced enterocolitis syndrome (FPIES; involves the entire gastrointestinal
tract) (see "Food proteininduced enterocolitis syndrome (FPIES)")
The previously used terms for these nonIgEmediated disorders, "milk (or "soy," etc)sensitivity,"
"intolerance," or "protein intolerance," are no longer recommended. The new terminology helps
to distinguish them from classical IgEmediated food allergies (immediate hypersensitivity
reactions). It also distinguishes them from food intolerances that do not involve immunologic
mechanisms (eg, lactose intolerance).
EPIDEMIOLOGY
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Food proteininduced allergic proctocolitis (FPIAP) is a common cause of rectal bleeding in breastfed
or formulafed infants, sometimes with loose stools or diarrhea [46]. The overall prevalence of this
disorder in the general population is not well established. The population prevalence in infants is
approximately 1 to 2 percent; the prevalence among infants with rectal bleeding ranges from 18 to 64
percent in different reports; some of the variation in these estimates may be related to specific infant
populations, as well as different definitions used. In a large prospective populationbased study from
Israel, the prevalence of rectal bleeding attributed to cow's milk protein was 1.6 per 1000 infants [7]. In
contrast, a United Statesbased study performed a prospective cohort study of infants with rectal
bleeding, demonstrating that 14 of 22 (64 percent) were diagnosed with FPIAP, based on biopsy
findings from flexible sigmoidoscopy [8]. Five (23 percent) had normal biopsies, and three (14
percent) had nonspecific colitis. Finally, a Finnish study confirmed food proteininduced proctocolitis in
only 18 percent of infants presenting with rectal bleeding, when milk elimination and challenge was
used to make the diagnosis [9]. This study raises the possibility that many infants presenting with
rectal bleeding may have a benign and selflimited cause other than FPIAP.
DIETARY TRIGGERS
Cow's milk is the most common trigger for food proteininduced allergic proctocolitis (FPIAP) in most
series; the infant may be exposed to the protein through breast milk or infant formula. In one study
from Turkey, cow's milk was the offending antigen in all 60 patients diagnosed with FPIAP [10].
Reactions to other foods are also possible. As an example, in a prospective study of 240 exclusively
breastfed infants who presented with bloodtinged stools, a specific food sensitivity was determined
by sequential elimination of foods from the maternal diet [11,12]:
Cow's milk – 76 percent
Egg – 16 percent
Soy – 6 percent
Corn – 2 percent (all in infants with multiple protein allergies)
Multiple (two of the above) – 8 percent
No response to maternal dietary restriction – 8 percent; these infants improved after weaning to
an extensively hydrolyzed or amino acidbased formula
At least onehalf of infants with FPIAP are breastfed; it is somewhat less common in infants fed with
cow's milkbased or soy proteinbased formulas [11,1316]. It is unclear why an orally ingested protein
induces an inflammatory response that is limited to the rectum and distal sigmoid colon. One
hypothesis is that the offending protein is bound to antibodies in the breast milk until colonic bacterial
enzymes cleave or release the antigen. The possibility of an autoimmune mechanism has been raised
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by one study's finding of perinuclear antineutrophil cytoplasmic (pANCA) antibodies in 24 out of 25 of
infants with food proteininduced proctocolitis, compared with 0 out of 18 controls [17].
CLINICAL PRESENTATION
Food proteininduced allergic proctocolitis (FPIAP) is diagnosed almost exclusively in young infants
[1316]. The disorder typically presents within a few months after birth, although symptoms
occasionally begin as early as the first week of life [18]. The stool patterns vary from multiple daily
stools with visible blood, to mucusstreaked stools that are Hemoccult positive, to infrequent stools
with occasional bleeding. Rarely, constipation may be a presenting symptom. A minority of infants
have associated eczema, and a family history of atopic disease is somewhat more common than in
the general population [19]. While some infants are fussy and irritable, the majority of affected infants
are generally healthy appearing and happy. Because of this, many infants have symptoms for weeks
or months before they are formally diagnosed. (See 'Diagnosis' below.)
Warning signs that suggest a diagnosis other than food proteininduced proctocolitis include unwell
appearance or fever, poor weight gain, failure to thrive, frank diarrhea, forceful vomiting, and/or
abdominal distension. In particular, in contrast with FPIAP, infants with food proteininduced
enterocolitis syndrome (FPIES) typically present with severe symptoms, such as severe vomiting;
pain; fever; or voluminous, watery diarrhea, beginning within hours after the ingestion of the offending
antigen. (See "Food proteininduced enterocolitis syndrome (FPIES)", section on 'Allergic food
proteininduced proctocolitis and enteropathy' and 'Differential diagnosis' below.)
Cases of FPIAP presenting after infancy have been described, but these appear to be rare and may
represent a different disorder [20].
EVALUATION
General evaluation for all patients — For most patients, a focused history and physical examination
is sufficient to establish a presumptive clinical diagnosis of food proteininduced allergic proctocolitis
(FPIAP), which can then quickly be followed by treatment with dietary restriction.
History – Generally, the presenting symptom is a combination of rectal bleeding, streaks of
mucus in the stool, or an increase in stool output. If bleeding is not apparent, hemoccult testing of
the stool should be performed. The history should also evaluate for symptoms that are not typical
for FPIAP, including irritability, pain, feeding intolerance, vomiting, and weight loss or failure to
thrive.
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The infant's diet should be reviewed in detail. If the infant is breastfed, the history should evaluate
the mother's diet, including her intake of cow's milk or other dairy products (even small amounts),
soy, eggs, and corn. If the infant is fed formula, the history should document the type of formula
(ie, standard cow's milkbased formula, soybased formula, or one of several formulas with
extensively hydrolyzed proteins [which are sometimes called "hypoallergenic"]) (table 2), as well
as the history of formula changes, the duration of the trial, and symptomatic responses.
Physical examination – The physical examination should include a careful inspection of the
anus for fissures. The clinician should examine one or more stools directly and perform
Hemoccult testing to confirm the presence of blood. If possible, the stools should be tested when
fresh. Typical stools in proctocolitis are soft or loose, with blood specks or streaks distributed
within the stool, with or without mucous. By contrast, stools that are hard or firm with blood
streaks on the outside are more typical of other problems such as anal fissures.
To evaluate the infant's nutritional status, the general physical examination also should include
measurement of weight and height, and tracking of these parameters on a growth chart. (See
"Normal growth patterns in infants and prepubertal children", section on 'Evaluation of growth'.)
Laboratory testing – Laboratory testing (other than stool hemoccult testing) is not necessary in
wellappearing infants with typical symptoms of proctocolitis. However, microscopic examination
of the stool and a complete blood count (CBC) with differential may be useful when the diagnosis
is unclear, although the findings may be nonspecific. Findings consistent with FPIAP include the
presence of polymorphonuclear leukocytes, typically eosinophils, in the stool; the CBC
sometimes reveals a peripheral eosinophilia or mild anemia if the infant's bleeding has been
chronic.
Fecal calprotectin, a neutrophilderived protein that serves as a marker of intestinal inflammation,
may be elevated in infants with FPIAP, but its clinical utility has not been established. In one
study of 32 infants with FPIAP due to cow's milk, the mean fecal calprotectin value at
presentation was 516±311 mcg/g, compared with 296±94 mcg/g in a control group [21]. After
implementing a cow's milk elimination diet, the mean fecal calprotectin value fell to 254±169
mcg/g. However, the utility of this test for diagnosis is limited by the considerable overlap
between fecal calprotectin values in infants with FPIAP compared with controls, in part because
fecal calprotectin levels are generally higher in infants less than seven months of age than in
older individuals [22]. The test is not indicated in most cases of suspected FPIAP; however, it
may be considered in individual patients who have not responded to dietary changes.
Further evaluation for selected patients
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Allergy testing — Skin prick testing and in vitro immunoassays for IgE antibodies to foods are not
recommended for isolated symptoms of proctocolitis. These tests evaluate for the presence of food
specific IgE and will likely be inconclusive in nonIgE gastrointestinal disorders. Such testing may be
considered if there are factors suggestive of IgEmediated allergy, such as rashes, hives, vomiting, or
acute reactions. IgEmediated food allergy and the best use of these IgEmediated tests are
presented elsewhere. (See "Clinical manifestations of food allergy: An overview" and "Diagnostic
evaluation of food allergy".)
Endoscopy — Flexible sigmoidoscopic or colonoscopic evaluation with biopsy is a useful tool for
further evaluation of selected patients. This test is usually reserved for patients with unusual or
atypical symptoms, such as constipation, diarrhea with mucusstreaked stools but without grossly
visible bleeding, or severe rectal bleeding or anemia despite a trial of cow's milk elimination diet [8].
The results also may be useful to families who desire a definitive diagnosis before making treatment
decisions because they are concerned about the burden of treatment (breastfeeding with maternal
dietary restrictions or changing to formula feeding).
If flexible sigmoidoscopy/colonoscopy is performed in a patient with FPIAP, gross findings include a
mild colitis with patchy erythema, and edematous mucosa with loss of vascularity [9,11,23]. These
mucosal changes are usually confined to the distal colon, although they occasionally extend
proximally. Biopsies typically reveal high numbers of eosinophils (including eosinophilic abscesses) in
the lamina propria and muscularis mucosa [23,24]. Lymphoid nodular hyperplasia is frequently
observed in these infants, but it is unclear whether this finding is associated with food proteininduced
disease (see "Lower gastrointestinal bleeding in children: Causes and diagnostic approach", section
on 'Lymphonodular hyperplasia'). Features that are not typical for food proteininduced proctocolitis
include cryptitis, neutrophilic crypt abscesses, glandular distortion, and Paneth cell metaplasia; such
findings suggest an alternate diagnosis, such as early onset inflammatory bowel disease (IBD). (See
"Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Early
onset IBD'.)
DIAGNOSIS
Food proteininduced allergic proctocolitis (FPIAP) is almost always a clinical diagnosis. The condition
is suspected in an otherwise healthy newborn or young infant presenting with persistent diarrhea and
rectal bleeding. The diagnosis is confirmed after resolution of symptoms upon withdrawal of the
presumed food antigen. Of note, there is some variability in this clinical diagnosis, and it is possible
that some infants diagnosed with FPIAP could instead have a benign and selflimited cause of their
rectal bleeding, such as an undetected anal fissure. In cases where uncertainty exists, either a short
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period of observation (days to a few weeks) or a food challenge (restriction and reintroduction) could
be used to distinguish these infants; however, this approach is not commonly practiced.
The evaluation and empiric elimination diet can be instituted by the primary care provider and is also
widely practiced by pediatric gastroenterologists. The approach to the elimination diet is described
below. (See 'General evaluation for all patients' above and 'Management' below.)
Patients with atypical features at presentation, or those who do not respond to a careful and
consistent elimination of the suspected food, should undergo a more extensive evaluation. This may
include flexible sigmoidoscopy or colonoscopy for infants with persistent rectal bleeding, allergy
testing for those with foodinduced vomiting or other features of IgEmediated disease (see 'Further
evaluation for selected patients' above), or other testing guided by the infant's symptoms. (See
'Differential diagnosis' below.)
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of bloody stools in an infant includes the following:
Anal fissure – Anorectal fissures are the most common cause of rectal bleeding in patients
younger than one year. They are diagnosed easily by spreading the perineal skin to evert the
anal canal. This problem is quickly remedied by treating constipation. (See "Lower
gastrointestinal bleeding in children: Causes and diagnostic approach", section on 'Anal
fissures'.)
Intussusception – Patients with intussusception typically develop episodes of suddenonset
severe, crampy, progressive abdominal pain, accompanied by inconsolable crying and drawing
up of the legs toward the abdomen. As symptoms progress, increasing lethargy may develop. It
is most common in infants and children between 6 and 36 months of age, and uncommon prior to
three months of age. (See "Intussusception in children".)
Enteric infection – A number of pathogens can cause lower gastrointestinal bleeding in infants
and children, including typical bacterial enteric pathogens and occasionally rotavirus. Infection
should be considered in infants presenting with rectal bleeding accompanied by fever, abdominal
pain, and tenesmus, particularly if there is a history of exposure to contacts with similar
symptoms. (See "Lower gastrointestinal bleeding in children: Causes and diagnostic approach",
section on 'Infectious colitis'.)
Meckel diverticulum – Meckel diverticulum typically presents as painless rectal bleeding in an
otherwise healthy child. Symptomatic presentation in young infants (less than six months of age)
is rare. Case reports in this age group describe it presenting as a perforation, intussusception
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with the diverticulum as a lead point, and in only one case as largevolume painless rectal
bleeding [25]. (See "Meckel's diverticulum".)
Food proteininduced enterocolitis syndrome (FPIES) – For infants with gastrointestinal
symptoms triggered by exposure to specific foods (typically cow's milk or soy), the differential
diagnosis includes FPIES. FPIES may have acute or chronic symptoms and may include
vomiting, diarrhea (with or without blood), and weight loss (table 3). Infants with FPIES are
generally sicker than those with food proteininduced proctocolitis and enteropathy. The clinical
characteristics, diagnosis, and management of FPIES are discussed in detail in a separate topic
review. (See "Food proteininduced enterocolitis syndrome (FPIES)".)
Food proteininduced enteropathy – This nonIgEmediated inflammatory response to food
causes small bowel injury, leading to malabsorption, intermittent vomiting, diarrhea, failure to
thrive, and rarely, bloody stools. The diagnosis is suspected based upon the clinical features and
should be confirmed by endoscopy with biopsy of the proximal small intestine to confirm villus
injury. (See "Food proteininduced enterocolitis syndrome (FPIES)", section on 'Allergic food
proteininduced proctocolitis and enteropathy'.)
Eosinophilic gastroenteritis – Eosinophilic gastroenteritis is a chronic immunologic
gastrointestinal disorder that causes tissue eosinophilia in any or all of the intestinal mucosa,
muscularis, or serosal layer of the gastrointestinal tract. The inflammation may cause vomiting,
abdominal pain, diarrhea, gastrointestinal bleeding (hematemesis or hematochezia), anemia,
hypoalbuminemia, ascites, or failure to thrive. (See "Eosinophilic gastroenteritis".)
Necrotizing enterocolitis (NEC) – Approximately 90 percent of infants with NEC are born
prematurely. Term infants who develop NEC typically have a preexisting illness. Overall, 75
percent of cases present within the first month of life. (See "Neonatal necrotizing enterocolitis:
Clinical features and diagnosis".)
Early onset inflammatory bowel disease (IBD) – Early onset IBD, or IBD of infancy, is a rare
cause of rectal bleeding and diarrhea in infants, likely caused by an unknown geneticallybased
immunologic mechanism. (See "Clinical presentation and diagnosis of inflammatory bowel
disease in children", section on 'Early onset IBD'.)
Other causes of bloody stools in infants include swallowed maternal blood, intestinal duplication
cysts, vascular malformations, and lymphonodular hyperplasia. Infants with Hirschsprung disease
with enterocolitis, or malrotation with volvulus, can have bloody stools as well as marked
abdominal distention, vomiting, and/or other symptoms of obstruction. (See "Lower
gastrointestinal bleeding in children: Causes and diagnostic approach", section on 'Neonatal
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period' and "Lower gastrointestinal bleeding in children: Causes and diagnostic approach",
section on 'Infants and toddlers'.)
In infants presenting with vomiting, with or without diarrhea, the differential diagnosis includes IgE
mediated food allergy. IgEmediated food allergies are characterized by rash, hives, difficulty
breathing, vomiting, diarrhea, and abdominal pain; these symptoms usually develop rapidly after
ingestion of the antigenic food, typically within minutes. Bloody stool is not a typical feature of IgE
mediated disease. (See "Clinical manifestations of food allergy: An overview".)
MANAGEMENT
If food proteininduced allergic proctocolitis (FPIAP) is suspected clinically, then the following
interventions are suggested:
Exclusively breastfed infants — Continued breastfeeding should be encouraged if the mother is
willing to eliminate completely the suspected food from her diet.
Cow's milk should be eliminated first, unless there is good evidence implicating some other specific
food. All dairy products should be completely eliminated from the mother's diet, including butter. All
other mammalian milks (eg, from goats, sheep, or camels) should also be eliminated because of
crossreactivity between these antigens. For infants with severe symptoms, it may be helpful to
accelerate the dietary elimination by using an amino acidbased formula rather than breast milk for
three to five days, while the mother pumps and discards her breast milk (to wash out the antigens
from the mother's body) to maintain lactation.
Successful elimination of foods requires careful reading of labels on everything that is ingested, not
just foods in which the ingredient is anticipated to be present. In the United States, nutritional labels
on food packages are required to identify eight specified food allergen sources (milk, eggs, fish,
crustacean shellfish, tree nuts, peanuts, wheat, and soybeans) [26]. Cow's milk proteins also may be
listed as "casein" or "whey" on some processed food labels. Foods that contain lactose as an
ingredient are usually safe to consume provided that they do not contain other components of cow's
milk [27]. In addition, "substitute" foods that are intended to remove fats or other components of a
food may not remove the allergenic proteins. As an example, some egg substitutes (which are lower
in cholesterol) still contain egg white proteins [28]. A referral to a nutritionist can be helpful to provide
further information to the mother, and to ensure that her diet includes sufficient calories, calcium, and
other nutrients after eliminating the suspected food antigens.
With complete elimination of the offending protein from the mother's diet, clinical bleeding typically
clears within one to two weeks. Testing of stools for occult blood is not generally necessary in this
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setting and may confuse the situation because microscopic blood or polymorphonuclear leukocytes in
the stool may persist for several weeks.
The majority of breastfed infants with food proteininduced proctocolitis respond to elimination of
cow's milk from the mother's diet; only a few require elimination of multiple proteins [11]. If the infant's
symptoms fail to resolve, then the first step is to review the mother's diet carefully to make sure that
all sources of cow's milk protein have been completely eliminated. If cow's milk was completely
eliminated for at least two weeks and the infant remains symptomatic, then soy, followed by egg,
should also be removed from the mother's diet [16].
Occasional recurrence of bleeding is common in breastfed infants, probably because of inadvertent
maternal intake of small amounts of the triggering protein (eg, in food eaten at restaurants) [11]. If the
bleeding is minor, selflimited, and infrequent, it is reasonable to take no action other than ongoing
vigilance to maintain the current level of dietary restriction.
Some infants continue to have lowgrade or intermittent symptoms despite reasonable dietary
restrictions to the mother. For this group, optimal management has not been established and should
be considered on a casebycase basis after discussion of the options and treatment burden with the
parents. The options are:
Switch from breastfeeding to a hydrolyzed or amino acidbased formula. This option may be
appropriate for mothers who find the dietary restrictions to be very burdensome, or those who
were considering stopping breastfeeding for other reasons, such as returning to work.
Continue breastfeeding despite ongoing symptoms. This treatment is controversial but may be
appropriate for infants with mild symptoms if the mother is committed to breastfeeding despite the
need for dietary restrictions. The risks to the infant are not well defined but are probably low. In
an unpublished report from a large pediatric gastroenterology practice, there were 27 mothers
who chose to continue restricting only cow's milk although their infants had only a partial
response to this intervention [29]. All of the infants became asymptomatic by six months of age,
and only one had a mild anemia.
Formulasupplemented or formulafed infants — For formulafed infants, cow's milk or soybased
formulas should be replaced with an extensively hydrolyzed formula (table 2). Changing to a soy
based formula is not generally recommended because a significant percentage of children who are
sensitive to cow's milk are also sensitive to soy protein. This combined sensitivity probably occurs in
at least 15 percent of infants [30]; earlier reports suggested the proportion might be as high as 40
percent [11,31,32]. However, soy formula may be considered if an extensively hydrolyzed infant
formula is not available or not affordable for the family [33].
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Of note, many infants will develop a change in stool color and consistency (looser stools) when fed an
extensively hydrolyzed formula; this does not indicate ongoing colitis.
Approximately 5 percent of infants with cow's milk or soyinduced proctocolitis do not respond to
feeding with an extensively hydrolyzed cow's milk formula and continue to bleed [31]. These infants
should be given an amino acidbased ("elemental") formula (table 2) [34]. One study suggests that
infants on an extensively hydrolyzed formula recover more rapidly when the formula is supplemented
with the probiotic Lactobacillus GG [35]. Referral to a pediatric gastroenterologist is recommended if
the infant fails to improve or the diagnosis is not clear.
Reintroduction
Timing – For infants who become asymptomatic after elimination of cow's milk (or other
suspected antigenic protein), the standard approach is to reintroduce the protein at one year of
age, and this is usually successful. In some circumstances, it may be possible to successfully
reintroduce the offending protein into the diet as early as six months of age. In one expert's
experience, approximately 50 percent of breastfed infants will tolerate the ingestion of the
offending protein by six months of age, and 95 percent will tolerate its resumption by nine months
of age [12]. However, no published studies have confirmed these reports. Since some studies
suggest that infants with rectal bleeding may have a benign and selflimited cause other than
FPIAP [9], it is possible that early reintroduction of the restricted protein is appropriate for infants
who presented with mild uncertain symptoms and had no signs of atopic disease.
Setting – For infants who presented with typical symptoms of bloody stools and were
successfully treated with a hydrolyzed formula, reintroduction of standard cow's milk or soy
based formula can be done at home. For infants who are breastfeeding, similar parameters can
be used to guide reintroduction of these proteins to the mother's diet. Patients receiving an amino
acidbased formula may be switched to one containing extensively hydrolyzed protein (table 2)
for one to two months before trying a formula with a milkbased protein. Some clinicians prefer to
observe the first reintroduction in their office as a precaution against the rare possibility that the
infant also has an IgEmediated reaction to the offending antigen.
Those infants who presented originally with severe diarrhea and/or vomiting and dehydration
likely have food proteininduced enterocolitis syndrome (FPIES) or IgEmediated food allergy,
rather than FPIAP. For such infants, the food challenge should be performed in a hospitalbased
setting or day medicine unit because they have a significant risk of having an emergent or
anaphylactic reaction on food challenge.
Advancement – The author's personal approach for infants with cow's milk FPIAP is as follows:
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• Breastfed infants – Mother adds 1 ounce (30 mL) of cow's milk (or dairy equivalent) to her
diet and increases her diet by 1 ounce each day for five days.
• Formulafed infants or infants no longer breastfeeding – One ounce (30 mL) of cow's
milk (or dairy equivalent) is added to 6 to 8 ounces of the infant's current formula or pumped
breast milk, and is increased by 1 ounce every two to three days until the infant is drinking a
full bottle or cup of milk.
This stepwise introduction is continued as tolerated until the full feed consists of the standard
cow's milkbased formula or unmodified cow's milk. During this time, the infant is observed for
any clinical changes including the development of bloody stools, diarrhea, vomiting, and
irritability. The success of this strategy may not be immediately apparent since it may take up to
one to two weeks for the hematochezia or other clinical symptoms to recur after the
reintroduction of the protein. For infants who present with either mild symptoms or for those who
rapidly improved (and remained improved) after dietary restriction, a more rapid reintroduction of
the restricted dietary antigen can be attempted.
The reintroduction of cow's milk is generally effective. If it fails, one option is to attempt
introducing "cooked" or "baked" milk products to the infant's diet. This approach may allow for
some dairy products in the diet of an infant whose diet is otherwise limited.
Recurrence – If hematochezia or other symptoms of proctocolitis recur, then we resume the diet
restriction for an additional six months before attempting another food reintroduction.
Management of younger siblings — There are no published data describing the risk of FPIAP in
siblings of an affected infant, but clinical experience suggests that the risk is low [36]. Therefore, we
do not suggest avoidance of cow's milk protein for the sibling unless he or she displays symptoms
suggestive of protein intolerance. In particular, mothers should not decline breastfeeding because of
these concerns. If the mother chooses to breastfeed, there is no need for dietary restriction if the
infant is asymptomatic. For infants who are fed formula, some families choose to use a partially or
extensively hydrolyzed formula rather than a cow's milkbased formula, but there is little evidence to
support this practice.
PROGNOSIS
The prognosis of food proteininduced allergic proctocolitis (FPIAP) is excellent. Nearly all infants will
be able to tolerate cow's milk and soy products by one year of age [11,16,37]. Progression to
persistent food allergy or chronic colitis including inflammatory bowel disease (IBD) is extremely rare.
One study indicates the odds ratio for developing a subsequent functional gastrointestinal disorder by
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age four years was 4.39 (95% CI 1.0318.68) and occurred in those with more severe FPIAP
manifestations, including iron deficiency anemia, longer duration of hematochezia, and younger age
at presentation [38].
SOCIETY GUIDELINE LINKS
Links to society and governmentsponsored guidelines from selected countries and regions around
the world are provided separately. (See "Society guideline links: Gastrointestinal bleeding in
children".)
SUMMARY AND RECOMMENDATIONS
Food proteininduced allergic proctocolitis (FPIAP) is characterized by inflammation of the distal
colon in response to specific food proteins, through a mechanism that does not involve
immunoglobulin E (IgE) (table 1). Food proteininduced enteropathy involves similar
mechanisms, except that the small bowel is affected. The previouslyused terms for these non
IgEmediated disorders, "milk (or "soy," etc) protein intolerance," or "sensitivity" are no longer
recommended. (See 'Classification and terminology' above.)
FPIAP typically is characterized by hematochezia in an otherwise healthy infant. It is commonly
triggered by proteins from cow's milk, and occasionally soy or other food proteins, which are
ingested through breast milk or standard infant formulas. (See 'Dietary triggers' above and
'Clinical presentation' above.)
FPIAP is a clinical diagnosis. The condition is suspected in healthyappearing infants presenting
with lower gastrointestinal bleeding, after eliminating other causes of hematochezia through a
focused history and physical examination. In particular, the examination should include a careful
inspection of the anus for fissures, which are also a common cause of isolated rectal bleeding.
The diagnosis is confirmed after resolution of symptoms upon withdrawal of the presumed food
antigen. (See 'General evaluation for all patients' above and 'Diagnosis' above.)
Treatment of FPIAP is empiric, consisting of complete elimination of cow's milk (or other
suspected antigen) from the diet. For breastfed infants, this can be accomplished by eliminating
all milk protein from the mother's diet. For formulafed infants, an extensively hydrolyzed formula
is used (table 2). Only a few infants require elimination of multiple proteins or an amino acid
based formula. The disorder resolves by one year of age in almost all infants. (See 'Management'
above.)
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Food proteininduced enterocolitis syndrome (FPIES) and food proteininduced
enteropathy/eosinophilic gastroenteritis, while also nonIgEmediated responses to food, typically
involve the small intestine and stomach. In contrast with FPIAP, FPIES manifests as profuse,
repetitive vomiting, often with diarrhea, leading to dehydration and lethargy in the acute setting
(often requiring rehydration), or weight loss and failure to thrive in a chronic form. (See
'Differential diagnosis' above and "Food proteininduced enterocolitis syndrome (FPIES)".)
ACKNOWLEDGMENT
The editorial staff at UpToDate would like to acknowledge Alan Lake, MD, who contributed to an
earlier version of this topic review.
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