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Food protein-induced allergic proctocolitis of infancy

Food protein-induced 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
Literature review current through: Nov 2022. | This topic last updated: Apr 22, 2022.

INTRODUCTION — Food protein-induced allergic proctocolitis (FPIAP; formerly known as allergic or eosinophilic proctocolitis or "protein intolerance") is a common problem in young infants. It often presents as rectal bleeding in an otherwise healthy young infant, although other infants may have significant irritability and diarrhea [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.

Other disorders of infancy characterized by non-IgE-mediated gastrointestinal inflammatory responses to food are food protein-induced 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 protein-induced enteropathy, in which the small bowel is affected. These disorders are discussed separately. (See "Food protein-induced enterocolitis syndrome (FPIES)".)

CLASSIFICATION AND TERMINOLOGY — Immunologic reactions to dietary proteins may be classified as IgE-mediated, non-IgE-mediated, 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].

IgE-mediated – The classical food allergy (food-induced 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 non-IgE-mediated components. These disorders are typically isolated to the gastrointestinal tract and/or skin (eg, eczema). They include:

Atopic dermatitis. (See "Role of allergy in atopic dermatitis (eczema)".)

Eosinophilic disease – Non-IgE mediated gastrointestinal diseases caused by eosinophilic infiltration of the mucosa, submucosa, or serosa. Dietary antigens play a major role in the eosinophilic inflammation in eosinophilic esophagitis and a minor role in eosinophilic gastroenteritis.

-Eosinophilic esophagitis (see "Clinical manifestations and diagnosis of eosinophilic esophagitis (EoE)")

-Eosinophilic gastroenteritis (see "Eosinophilic gastrointestinal diseases")

Non-IgE-mediated – Non-IgE-mediated reactions to food can affect any part of the gastrointestinal tract and include:

Food protein-induced allergic proctocolitis (FPIAP; involves the rectum and colon)

Food protein-induced enteropathy (involves the small intestine) (see "Food protein-induced enterocolitis syndrome (FPIES)", section on 'Allergic food protein-induced proctocolitis and enteropathy')

Food protein-induced enterocolitis syndrome (FPIES; involves the entire gastrointestinal tract) (see "Food protein-induced enterocolitis syndrome (FPIES)")

The previously used terms for these non-IgE-mediated disorders, "milk" (or "soy," etc) "sensitivity," "intolerance," or "protein intolerance," are no longer recommended. The new terminology helps to distinguish them from classical IgE-mediated food allergies (immediate hypersensitivity reactions). It also distinguishes them from food intolerances that do not involve immunologic mechanisms (eg, lactose intolerance).

EPIDEMIOLOGY — Food protein-induced allergic proctocolitis (FPIAP) is a common problem in young infants [4-6]. It generally occurs during the first few months of life and almost always resolves by one year of age [7,8]. The reported prevalence of this disorder varies widely and depends upon the case definition. One study reported a cumulative incidence of 17 percent among young infants in a general pediatric practice, using broad clinical criteria (occult blood in stool with no alternate explanation that resolves with milk elimination); approximately one-half of this cohort had grossly bloody stools [8]. Other studies that used narrower criteria estimated a population prevalence of 2 to 3 percent [9]. In separate studies that focused on infants with gross rectal bleeding, FPIAP was reported in 64 percent (using histologic criteria but no food challenge) [10] or 18 percent (using milk elimination and challenge) [11].

DIETARY TRIGGERS — Cow's milk is the most common trigger for food protein-induced 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 [12]. Reactions to other foods are also possible. As an example, in a prospective study of 240 exclusively breastfed infants who presented with blood-tinged stools, a specific food sensitivity was determined by sequential elimination of foods from the maternal diet [13,14]:

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 acid-based formula

FPIAP occurs in both breastfed and formula-fed infants, with no consistently reported predilection for either one of these groups [13,15-18]. 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 by one study's finding of perinuclear antineutrophil cytoplasmic (p-ANCA) antibodies in 24 of 25 infants with food protein-induced proctocolitis, compared with 0 of 18 controls [19].

CLINICAL PRESENTATION — Food protein-induced allergic proctocolitis (FPIAP) is diagnosed almost exclusively in young infants [15-18]. The disorder typically presents within a few months after birth, although symptoms occasionally begin as early as the first week of life [20]. It may present with any of the following symptoms [21]:

Frequent visible blood in normal or loose stools

Loose stools with mucus, with or without gross or occult blood

Constipation, usually with occult blood (uncommon presentation)

Each of these presentations is nonspecific but should raise the possibility of FPIAP if there are no other obvious causes of the symptom. Infants may be well-appearing and happy despite the gastrointestinal symptoms. Those who are well-appearing may have symptoms for weeks or months before they are formally diagnosed. A family history of atopic disease (IgE-mediated allergy, eczema, asthma, and allergic rhinitis) is somewhat more common among infants with FPIAP than in the general population [7]. (See 'Diagnosis' below.)

Warning signs that suggest a diagnosis other than food protein-induced proctocolitis include an infant with an unwell appearance or fever, poor weight gain, failure to thrive, severe diarrhea, forceful vomiting, and/or abdominal distension. In particular, in contrast with FPIAP, infants with food protein-induced enterocolitis syndrome (FPIES) typically present with severe symptoms (vomiting causing dehydration, abdominal distension, hypothermia, or voluminous watery diarrhea) beginning within hours after the ingestion of the offending antigen. Infants with severe rectal bleeding, especially those who develop a significant anemia, should also be evaluated for other etiologies of hematochezia. (See "Food protein-induced enterocolitis syndrome (FPIES)", section on 'Allergic food protein-induced proctocolitis and enteropathy' and 'Differential diagnosis' below and "Lower gastrointestinal bleeding in children: Causes and diagnostic approach".)

Cases of FPIAP presenting after infancy have been described, but these appear to be rare and may represent a different disorder [22].

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 protein-induced allergic proctocolitis (FPIAP), which can then quickly be followed by treatment with dietary restriction.

History – Generally, the presenting symptoms are any combination of rectal bleeding, increased streaks of mucus in the stool, and/or an increase in stool output (compared with the infant's previous stool appearance and patterns). 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.

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 milk-based formula, soy-based formula, or one of several formulas with extensively hydrolyzed proteins [sometimes called "hypoallergenic"]) (table 2), as well as the history of formula changes, duration of the trial, and symptomatic responses.

Physical examination – Infants with FPIAP are often remarkably well appearing but can be ill appearing. When visible bleeding is present, the physical examination should include a careful inspection of the anus for fissures. The clinician should examine one or more stools directly. Typical stools in proctocolitis are soft or loose, with blood specks or streaks distributed within the stool, with or without mucus. By contrast, stools that are hard or firm with blood streaks on the outside are more typical of other problems such as anal fissures.

If diarrhea is a presenting symptom, especially with mucus streaks and without visible bleeding, or if there is any question that the report of visible blood is inaccurate, testing the stool for occult blood will help to confirm the presence of bleeding, which often indicates an active colitis. An active colitis due to FPIAP may take several weeks to resolve after appropriate treatment is instituted. Serial testing of stools for occult blood is not necessary or useful unless there are ongoing concerns for anemia, which is uncommon in infants with FPIAP [21,23,24].

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 is not necessary in well-appearing infants with typical symptoms of proctocolitis. However, microscopic examination of the stool and a complete blood count with differential may be useful when the diagnosis is unclear, although the findings are nonspecific. Findings consistent with FPIAP include the presence of polymorphonuclear leukocytes, typically eosinophils, in the stool; the complete blood count sometimes reveals a peripheral eosinophilia or mild anemia if the infant's bleeding has been chronic.

Fecal calprotectin, a neutrophil-derived 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 [25]. 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 [26]. 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

Allergy testing — Skin prick testing and in vitro immunoassays for IgE antibodies to foods are not recommended for isolated symptoms of proctocolitis [21]. These tests evaluate for the presence of food-specific IgE and will be inconclusive in non-IgE gastrointestinal disorders. Such testing may be considered if there are factors suggestive of IgE-mediated allergy, such as rashes, hives, vomiting, or acute reactions. Similar to other non-IgE-mediated eosinophilic gastrointestinal disorders (eosinophilic esophagitis and eosinophilic gastroenteritis), FPIAP is associated with an increased risk for IgE-mediated food allergies [27]. IgE-mediated food allergy and the best use of these IgE-mediated tests are discussed elsewhere. (See "Clinical manifestations of food allergy: An overview" and "Diagnostic evaluation of IgE-mediated food allergy".)

In infants who also have additional significant atopic features such as moderate or severe eczema, consultation with an allergist may be useful. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis" and "Management of severe atopic dermatitis (eczema) in children".)

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 mucus-streaked stools but without grossly visible bleeding, or severe rectal bleeding or anemia despite a trial of cow's milk elimination diet [10]. 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 [11,13,28]. 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 [28,29]. Lymphoid nodular hyperplasia is frequently observed in these infants, but it is unclear whether this finding is associated with food protein-induced disease (see "Lower gastrointestinal bleeding in children: Causes and diagnostic approach", section on 'Lymphonodular hyperplasia'). Features that are not typical for food protein-induced 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 'Very early-onset inflammatory bowel disease'.)

DIAGNOSIS — Food protein-induced allergic proctocolitis (FPIAP) is almost always a clinical diagnosis, based upon typical presenting symptoms that resolve upon withdrawal of the presumed food antigen. Although the most accurate diagnosis of FPIAP would include either a sigmoidoscopy with biopsy demonstrating an allergic colitis or a food challenge (withdrawal of the offending antigen[s] and resolution of symptoms, followed by the reintroduction of the antigen[s] with a recurrence of symptoms), these diagnostic tools are not utilized by the majority of clinicians, due to the benign course of this disorder. (See 'Reintroduction' below.)

Patients with atypical features at presentation, those in whom the diagnosis is uncertain, or those who do not respond to a careful and consistent elimination of the suspected food should undergo further evaluation, guided by the infant's symptoms. (See 'Further evaluation for selected patients' above and 'Differential diagnosis' below.)

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.)

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 sudden-onset, 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's diverticulum – Meckel's 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 with the diverticulum as a lead point, and, in only one case, as large-volume painless rectal bleeding [30]. (See "Meckel's diverticulum".)

Food protein-induced 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 protein-induced proctocolitis and enteropathy. The clinical characteristics, diagnosis, and management of FPIES are discussed in detail in a separate topic review. (See "Food protein-induced enterocolitis syndrome (FPIES)".)

Food protein-induced enteropathy – This non-IgE-mediated 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. Endoscopy with biopsy of the proximal small intestine will confirm villus injury. (See "Food protein-induced enterocolitis syndrome (FPIES)", section on 'Allergic food protein-induced 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 gastrointestinal diseases".)

Necrotizing enterocolitis (NEC) – Approximately 90 percent of infants with NEC are born prematurely. Term infants who develop NEC typically have a preexisting illness. Seventy-five 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 genetically-based immunologic mechanism. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Very early-onset inflammatory bowel disease'.)

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 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. IgE-mediated 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 protein-induced allergic proctocolitis (FPIAP) is suspected clinically, the offending food(s) need to be removed from the infant's diet [3,9]. In general, the following approaches are suggested:

Exclusively breastfed infants — Continued breastfeeding should be encouraged if the mother is willing to completely eliminate the suspected food from her diet.

Cow's milk should be eliminated first, unless there is good evidence implicating another 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 cross-reactivity between these antigens. For infants with severe symptoms, it may be helpful to accelerate the dietary elimination by using an amino acid-based 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 [31]. 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 [32]. 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 [33]. A referral to a nutritionist can be helpful to provide further information to the mother and 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 symptoms typically clear within one to two weeks. When visible bleeding is present (indicating an active colitis), it may take longer for the bleeding to resolve. Testing of stools for occult blood is not generally necessary in this setting and may confuse the situation, because microscopic blood or polymorphonuclear leukocytes in the stool may persist for many weeks.

The majority of breastfed infants with food protein-induced proctocolitis respond to elimination of cow's milk from the mother's diet; only a few require elimination of multiple proteins [13]. If the infant's symptoms fail to resolve, 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 [18].

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) [13]. If the bleeding is minor, self-limited, 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 low-grade or intermittent symptoms despite reasonable maternal dietary restrictions. For this group, optimal management has not been established and should be considered on a case-by-case basis after discussion of the options and treatment burden with the parent(s). The options are:

Switch from breastfeeding to a hydrolyzed or amino acid-based 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 [34]. All of the infants became asymptomatic by six months of age, and only one had a mild anemia.

Formula-supplemented or formula-fed infants — For formula-fed infants, cow's milk- or soy-based 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 [35]; earlier reports suggested the proportion might be as high as 40 percent [13,36,37]. However, soy formula may be considered if an extensively hydrolyzed infant formula is not available or not affordable for the family [38].

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 soy-induced proctocolitis do not respond to feeding with an extensively hydrolyzed cow's milk formula and continue to bleed [36]. These infants should be given an amino acid-based ("elemental") formula (table 2) [39]. Very limited evidence suggests that probiotic supplement (eg, Lactobacillus rhamnosus GG) may promote recovery or acquisition of tolerance [40,41]. 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 traditional approach is to reintroduce the protein at approximately one year of age. This approach is successful in the vast majority of infants.

In some circumstances, a few clinicians begin to reintroduce limited quantities of the offending protein well before one year of age and, occasionally, as early as six months of age [13]. This approach has not been evaluated clinically and is not widely used in pediatric gastroenterology practice. However, if food is reintroduced by the family (inadvertently or not) and the infant remains asymptomatic, it is reasonable to continue with the unrestricted diet. For infants with atopic symptoms or other risk factors for IgE-mediated disease, the timing and approach to reintroduction involve other considerations and referral to an allergist may be useful. (See "Food allergy in children: Prevalence, natural history, and monitoring for resolution".)

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 acid-based formula may be switched to one containing extensively hydrolyzed protein (table 2) for one to two months before trying a formula with a milk-based 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 IgE-mediated reaction to the offending antigen.

Those infants who presented originally with severe diarrhea and/or vomiting and dehydration likely have food protein-induced enterocolitis syndrome (FPIES) or IgE-mediated food allergy, rather than FPIAP. For such infants, the food challenge should be performed in a hospital-based setting or day medicine unit because they have a significant risk of having a severe or anaphylactic reaction that requires emergency care. (See "Food protein-induced enterocolitis syndrome (FPIES)".)

Advancement – The author's personal approach for infants with cow's milk FPIAP is as follows:

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.

Formula-fed 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 milk-based 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. This strategy may not appear immediately successful 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 [42]. Therefore, we do not suggest avoidance of cow's milk protein for the sibling unless they display 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 milk-based formula, but there is little evidence to support this practice.

PROGNOSIS — The prognosis of food protein-induced allergic proctocolitis (FPIAP) is excellent. Nearly all infants will be able to tolerate cow's milk and soy products by one year of age [13,18,43]. 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 age four years was 4.39 (95% CI 1.03-18.68) and occurred in those with more severe FPIAP manifestations, including iron deficiency anemia, longer duration of hematochezia, and younger age at presentation [44].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gastrointestinal bleeding in children".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Bloody stools (The Basics)")

Beyond the Basics topic (see "Patient education: Blood in bowel movements (rectal bleeding) in babies and children (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Classification and terminology – Food protein-induced 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 protein-induced enteropathy involves similar mechanisms, except that the small bowel is affected. The previously used terms for these non-IgE-mediated disorders, "milk" (or "soy," etc) "protein intolerance" or "sensitivity," are no longer recommended. (See 'Classification and terminology' above.)

Clinical presentation and triggers – FPIAP typically presents with hematochezia or persistent mucus-streaked diarrhea in an infant who is often otherwise healthy. 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.)

Evaluation and diagnosis

Patients with typical features – For most patients, FPIAP is a clinical diagnosis, based upon typical presenting symptoms. When bleeding is present, other causes of hematochezia should be excluded 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 of FPIAP is presumptively confirmed if the symptoms resolve after withdrawal of the presumed food antigen.

Patients with atypical features – Patients with atypical features at presentation, those in whom the diagnosis is uncertain, or those who do not respond to a careful and consistent elimination of the suspected food should undergo further evaluation. This may include a sigmoidoscopy with biopsy or a retrial of the allergen in the weeks following resolution to observe for recurrence. These diagnostic tools may provide a more definitive diagnosis but are not commonly used. (See 'General evaluation for all patients' above and 'Diagnosis' above.)

Management – Treatment of FPIAP is empiric, consisting of complete elimination of cow's milk (and/or other suspected antigens) from the diet. For breastfed infants, this can be accomplished by eliminating all milk protein from the mother's diet. For formula-fed infants, an extensively hydrolyzed formula is used (table 2). Only a few infants require elimination of multiple dietary proteins or an amino acid-based formula. The disorder resolves by one year of age in almost all infants. (See 'Management' above.)

Differential diagnosis – The differential diagnosis includes anal fissures and several other causes of rectal bleeding in infants. Other non-IgE-mediated responses to food are food protein-induced enterocolitis syndrome (FPIES) and food protein-induced enteropathy/eosinophilic gastroenteritis, both of which typically involve the small intestine and stomach. 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 protein-induced enterocolitis syndrome (FPIES)".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Alan Lake, MD, who contributed to an earlier version of this topic review.

  1. Nowak-Węgrzyn A. Food protein-induced enterocolitis syndrome and allergic proctocolitis. Allergy Asthma Proc 2015; 36:172.
  2. Nowak-Węgrzyn A, Katz Y, Mehr SS, Koletzko S. Non-IgE-mediated gastrointestinal food allergy. J Allergy Clin Immunol 2015; 135:1114.
  3. NIAID-Sponsored Expert Panel, Boyce JA, Assa'ad A, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol 2010; 126:S1.
  4. Willetts IE, Dalzell M, Puntis JW, Stringer MD. Cow's milk enteropathy: surgical pitfalls. J Pediatr Surg 1999; 34:1486.
  5. Moon A, Kleinman RE. Allergic gastroenteropathy in children. Ann Allergy Asthma Immunol 1995; 74:5.
  6. Odze RD, Wershil BK, Leichtner AM, Antonioli DA. Allergic colitis in infants. J Pediatr 1995; 126:163.
  7. Odze RD, Bines J, Leichtner AM, et al. Allergic proctocolitis in infants: a prospective clinicopathologic biopsy study. Hum Pathol 1993; 24:668.
  8. Martin VM, Virkud YV, Seay H, et al. Prospective Assessment of Pediatrician-Diagnosed Food Protein-Induced Allergic Proctocolitis by Gross or Occult Blood. J Allergy Clin Immunol Pract 2020; 8:1692.
  9. Koletzko S, Niggemann B, Arato A, et al. Diagnostic approach and management of cow's-milk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines. J Pediatr Gastroenterol Nutr 2012; 55:221.
  10. Xanthakos SA, Schwimmer JB, Melin-Aldana H, et al. Prevalence and outcome of allergic colitis in healthy infants with rectal bleeding: a prospective cohort study. J Pediatr Gastroenterol Nutr 2005; 41:16.
  11. Arvola T, Ruuska T, Keränen J, et al. Rectal bleeding in infancy: clinical, allergological, and microbiological examination. Pediatrics 2006; 117:e760.
  12. Kaya A, Toyran M, Civelek E, et al. Characteristics and Prognosis of Allergic Proctocolitis in Infants. J Pediatr Gastroenterol Nutr 2015; 61:69.
  13. Lake AM. Food-induced eosinophilic proctocolitis. J Pediatr Gastroenterol Nutr 2000; 30 Suppl:S58.
  14. Based on Lake J Pediatr Gastroenterol Nutr 2000, updated by the author with additional unpublished data in 2015.
  15. Patenaude Y, Bernard C, Schreiber R, Sinsky AB. Cow's-milk-induced allergic colitis in an exclusively breast-fed infant: diagnosed with ultrasound. Pediatr Radiol 2000; 30:379.
  16. Anveden-Hertzberg L, Finkel Y, Sandstedt B, Karpe B. Proctocolitis in exclusively breast-fed infants. Eur J Pediatr 1996; 155:464.
  17. Pittschieler K. Cow's milk protein-induced colitis in the breast-fed infant. J Pediatr Gastroenterol Nutr 1990; 10:548.
  18. Lake AM, Whitington PF, Hamilton SR. Dietary protein-induced colitis in breast-fed infants. J Pediatr 1982; 101:906.
  19. Sekerkova A, Fuchs M, Cecrdlova E, et al. High Prevalence of Neutrophil Cytoplasmic Autoantibodies in Infants with Food Protein-Induced Proctitis/Proctocolitis: Autoimmunity Involvement? J Immunol Res 2015; 2015:902863.
  20. Wilson NW, Self TW, Hamburger RN. Severe cow's milk induced colitis in an exclusively breast-fed neonate. Case report and clinical review of cow's milk allergy. Clin Pediatr (Phila) 1990; 29:77.
  21. Meyer R, Chebar Lozinsky A, Fleischer DM, et al. Diagnosis and management of Non-IgE gastrointestinal allergies in breastfed infants-An EAACI Position Paper. Allergy 2020; 75:14.
  22. Ravelli A, Villanacci V, Chiappa S, et al. Dietary protein-induced proctocolitis in childhood. Am J Gastroenterol 2008; 103:2605.
  23. Concha S, Cabalín C, Iturriaga C, et al. [Diagnostic validity of fecal occult blood test in infants with food protein-induced allergic proctocolitis]. Rev Chil Pediatr 2018; 89:630.
  24. Rady HI, Samir H, Tomerak R, Gaafar M. Occult blood in stool in exclusively formula fed infants versus exclusively breast fed infants in the first six months of life. Egypt Pediatr Assoc Gazette 2014; 62:8.
  25. Beşer OF, Sancak S, Erkan T, et al. Can Fecal Calprotectin Level Be Used as a Markers of Inflammation in the Diagnosis and Follow-Up of Cow's Milk Protein Allergy? Allergy Asthma Immunol Res 2014; 6:33.
  26. Lee YM, Min CY, Choi YJ, Jeong SJ. Delivery and feeding mode affects fecal calprotectin levels in infants <7months old. Early Hum Dev 2017; 108:45.
  27. Martin VM, Virkud YV, Phadke NA, et al. Increased IgE-Mediated Food Allergy With Food Protein-Induced Allergic Proctocolitis. Pediatrics 2020; 146.
  28. Winter HS, Antonioli DA, Fukagawa N, et al. Allergy-related proctocolitis in infants: diagnostic usefulness of rectal biopsy. Mod Pathol 1990; 3:5.
  29. Goldman H, Proujansky R. Allergic proctitis and gastroenteritis in children. Clinical and mucosal biopsy features in 53 cases. Am J Surg Pathol 1986; 10:75.
  30. Sinha CK, Fishman J, Clarke SA. Neonatal Meckel's diverticulum: spectrum of presentation. Pediatr Emerg Care 2009; 25:348.
  31. United States Food Allergen Labeling and Consumer Protection Act of 2004.
  32. Fiocchi A, Restani P, Leo G, et al. Clinical tolerance to lactose in children with cow's milk allergy. Pediatrics 2003; 112:359.
  33. Sicherer SH. Food allergy: when and how to perform oral food challenges. Pediatr Allergy Immunol 1999; 10:226.
  34. Personal communication from Alan Lake, MD.
  35. Vandenplas Y. Prevention and Management of Cow's Milk Allergy in Non-Exclusively Breastfed Infants. Nutrients 2017; 9.
  36. American Academy of Pediatrics. Committee on Nutrition. Hypoallergenic infant formulas. Pediatrics 2000; 106:346.
  37. Lucarelli S, Di Nardo G, Lastrucci G, et al. Allergic proctocolitis refractory to maternal hypoallergenic diet in exclusively breast-fed infants: a clinical observation. BMC Gastroenterol 2011; 11:82.
  38. Vandenplas Y, AlFrayh AS, AlMutairi B, et al. Physician practice in food allergy prevention in the Middle East and North Africa. BMC Pediatr 2017; 17:118.
  39. Vanderhoof JA, Murray ND, Kaufman SS, et al. Intolerance to protein hydrolysate infant formulas: an underrecognized cause of gastrointestinal symptoms in infants. J Pediatr 1997; 131:741.
  40. Baldassarre ME, Laforgia N, Fanelli M, et al. Lactobacillus GG improves recovery in infants with blood in the stools and presumptive allergic colitis compared with extensively hydrolyzed formula alone. J Pediatr 2010; 156:397.
  41. Qamer S, Deshmukh M, Patole S. Probiotics for cow's milk protein allergy: a systematic review of randomized controlled trials. Eur J Pediatr 2019; 178:1139.
  42. Lake A. Infantile proctocolitis: are we empirically too casual? J Pediatr Gastroenterol Nutr 2005; 41:14.
  43. Lazare FB, Brand DA, Marciano TA, Daum F. Rapid resolution of milk protein intolerance in infancy. J Pediatr Gastroenterol Nutr 2014; 59:215.
  44. Di Nardo G, Cremon C, Frediani S, et al. Allergic Proctocolitis Is a Risk Factor for Functional Gastrointestinal Disorders in Children. J Pediatr 2018; 195:128.
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