Non-IgE-Mediated Gastrointestinal Food Allergies Explained; FPIAP, FPE and FPIES

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Non-immunoglobulin E-mediated gastrointestinal food allergies (or, non-IgE-mediated GI allergies) are dastardly conditions. They may not be life-threatening, but that doesn’t stop them from significantly affecting the quality of life of not only those who have them but their families, too. Because their symptoms have so much overlap with other conditions, they’re also difficult to diagnose. Luckily for the children who are affected, these types of allergies tend to have a limited shelf-life and are often outgrown before school age.

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What are non-IgE-mediated GI food allergies?

Non-IgE-mediated GI food allergies encompass a wide spectrum of disorders. Unlike classic food allergies, which involve just one type of mechanism—namely, the production of IgE antibodies to certain foods allergens which ultimately results in the release of substances like histamine—gastrointestinal food allergies encapsulate a number of conditions that are caused by different mechanisms but are unified in their ability to cause problems in the gastrointestinal tract.

Symptoms typically occur several hours after eating the offending food and are thought to be caused by the activation of the cell-mediated immune response. The most common symptoms are abdominal pain and diarrhoea, but symptoms associated with GI allergies are not necessarily limited to the gastrointestinal tract; about 2 in 5 sufferers will have eczema (atopic dermatitis) and about a third have asthma. Around two thirds will also suffer from frequent respiratory infections.

The exact mechanisms behind these types of allergic disorders are still unclear, but they seem to represent a continuum of disease in which the expression of symptoms and their severity depends on the affected segment of the GI tract, which is also where they get their names from.

The most common non-IgE gastrointestinal disorders are food protein–induced allergic proctocolitis (FPIAP), food protein–induced enteropathy (FPE), and food protein–induced enterocolitis syndrome (FPIES).

Food Protein-Induced Allergic Proctocolitis (FPIAP)

FIAP is also referred to as allergic proctocolitis, allergic eosinophilic proctocolitis, allergic dietary proctitis, dietary protein-induced proctitis/colitis/proctocolitis, food protein-induced proctocolitis, breast-milk-induced proctocolitis, eosinophilic proctitis, benign dietary protein proctitis and, more colloquially, ‘milk protein allergy’.

These names all become easier to decipher once you know what the different terms mean:

• Colitis is medical-speak for inflammation of the large intestine (colon)
• Proctitis is medical-speak for inflammation of the rectum and anus
• Proctocolitis is medical-speak for inflammation of the rectum and colon

Thus, food protein-induced allergic proctocolitis is an allergy to food proteins that causes inflammation in the large intestine and rectum. This leads to:

• blood in the poo, (stools) referred to in medical terms as hematochezia. The blood can be visible or hidden (occult).

Food protein-induced allergic proctocolitis is at the milder end of the spectrum of gastrointestinal allergies. It generally occurs in young infants who otherwise look and are perfectly healthy. It’s one of the most common manifestations of non–IgE-mediated food allergies in breastfed infants—unlike FPE or FPIES, a slight majority (around 60%) of FPIAP cases develop during exclusive breastfeeding.

Food protein-induced allergic proctocolitis can be caused by several foods, most commonly egg, milk and soy.

Although it’s generally thought of as a disease of infancy, often resolving within weeks, FPIAP has been reported in children as old at 14.

Food Protein-induced Enteropathy (FPE)

‘Enteropathy’ means any disease affecting the small intestine. Food protein-induced enteropathy (FPE) is a subset of protein-losing enteropathy (PLE). It can be a non-IgE-mediated or a mixed—i.e. IgE and non-lgE-mediated—form of food allergy and involves large quantities of blood (serum) proteins being lost from the gastrointestinal tract, which results in low blood albumin protein levels (hypoalbuminemia). Albumin is responsible for keeping fluid from leaking out of your blood vessels, so having low levels of blood albumin can make it harder for important substances to get around your body.

As food protein-induced enteropathy mainly affects the small intestine, it is associated with lower digestive symptoms and a failure to absorb food nutrients properly (malabsorption), which can be accompanied by poor growth, a so-called ‘failure to thrive’. The most common signs of FPE are:

• watery diarrhoea
• swelling (oedema)
• poor weight gain
• bloody stools

Food protein-induced enteropathy is considered an uncommon disorder. After a flurry of reports of FPE to milk which peaked in Finland in the 1960s, cases of FPE to milk are now rarely described.

Food protein-induced enteropathy can be caused by several foods, most commonly egg and milk.

A better-known and similar condition to FPE is coeliac disease, also known as gluten-sensitive enteropathy. Coeliac disease is an autoimmune disease caused by gluten that leads to erosion of the intestinal villi—the tiny tentacles that line the wall of your small intestine—leaving a virtually flat surface. Since the intestinal villi are responsible for absorbing food nutrients, losing them can result in nutritional deficiencies. Symptoms of coeliac disease are similar to those of FPE and include poor growth, diarrhoea, stomach aches, bloating and vomiting. As a result, coeliac disease is often one of the disorders that has to be eliminated on the way to a diagnosis of FPE.

Food Protein-Induced Enterocolitis Syndrome (FPIES)

‘Enterocolitis’ is medical-speak for inflammation of both the small intestine and large intestine (colon). Food protein-induced enterocolitis syndrome is a food allergy that can affect the whole gastrointestinal tract.

Food protein-induced enterocolitis syndrome is the most serious of the non-IgE-mediated gastrointestinal food allergies. Although considered a non-IgE-mediated disease, FPIES can also be a mixed allergy involving IgE antibodies. It’s actually a varied disorder with a wide spectrum of observable characteristics (phenotypes) although it is generally classified into 2 main phenotypes; acute and chronic.

Chronic FPIES is quite rare and happens when an infant is regularly exposed to a food that they are allergic to (e.g. infant formula). It’s associated with:

• persistent vomiting
• chronic diarrhoea

It can include a failure to thrive, making it clinically indistinguishable from FPE.

Although initial reports of FPIES described it occurring only in newborns and young infants, recent research has shown that it can also develop in adults.

Acute FPIES is the more common of the two categories and affects all age groups. It generally involves copious vomiting after eating trigger food that can be serious enough to cause hypovolemic shock (an emergency situation caused when severe fluid loss makes the heart unable to pump enough blood around the body, causing organs to stop working). The symptoms may differ per age group, the most common being:

• profuse vomiting (children more commonly than adults)
• stomach cramps (adults)

These can be accompanied by other signs, including:

• watery diarrhoea that develops 5–8 hours after eating
• pallor
• lethargy

Because the symptoms are so similar to a severe stomach bug, it’s commonly misdiagnosed as such.

Food protein-induced enterocolitis syndrome can be caused by any food, most commonly milk, grains, soy, egg, peanut, tree nuts and fish in children, and fish and shellfish in adults.

Side by side: age, foods, symptoms & prognosis

The signs and symptoms of gastrointestinal food allergies have considerable overlap, but there are differences which can help to distinguish one condition from another.

	FPIAP	FPE	FPIES
Who’s affected	Infants, children	Infants, children	Infants, children, adults
Age at onset	1 day–6 months (usually within first 4 weeks of life) Can also occur in older children	2–24 months Can also occur in older children	Formula: First weeks-months of life Solid foods: 4–7 months Can also occur in adults, with an average age at onset in the mid-30s
Culprit foods	Common: cow’s milk, egg, soy, corn Less common: wheat, chicken, fish, sesame	Common: cow’s milk, soy Less common: wheat, egg, rice, seafood	Common: cow’s milk, soy, grains, egg, seafood (for adults) Less common: meat, vegetables, fruits, nuts
Symptoms	Always: Blood-streaked stools Sometimes: Mucous in the stool Mild diarrhoea Painful gas in stomach or bowels (flatus) Anal chaffing	Always: Diarrhoea Failure to thrive (FTT) Sometimes: Intermittent vomiting Abdominal bloating or pain Lack of appetite Malabsorption (fat in stool/steatorrhea) Bloody/mucous-streaked stools (rarely)	Diagnostic criteria for FPIES include: Chronic Intermittent but progressive vomiting Diarrhoea Failure to thrive (sometimes) Metabolic acidosis (too much acid in your blood – happens rarely) Acute Profuse vomiting (1 to 4 hours after eating) Absence of classic, IgE-mediated allergic skin or respiratory symptoms AND 3 or more from: – A second (or more) episode of vomiting after eating the same suspect food – Repetitive vomiting episode 1 to 4 hours after eating a different food – Diarrhoea within 24 hours, usually 5 to 10 hours – Extreme lethargy – Marked pallor – Need for emergency department visit – Need for intravenous fluid support – Dehydration – Hypotension (low blood pressure, aka shock) – Hypothermia – Hypovolemia (not enough fluid circulating in your body) Typical symptoms seem to be different for adults: – Stomach pain and cramps – Diarrhoea – Vomiting – Weight loss
Prognosis	The vast majority of infants outgrow the allergy by the age of 1 to 3	The majority of children outgrow the allergy by the age of 2 to 3	The majority of children outgrow the allergy by the age of 3 to 5, but can be later if solid foods or IgE sensitisation are involved Adults who develop the disease tend to keep it

Diagnosing a non-IgE-mediated GI food allergy

Diagnosing a non-IgE-mediated gastrointestinal food allergy can be challenging (and is therefore often delayed) because of the wide variety of signs and symptoms which are very similar to those of other conditions such as bacterial, viral, and parasitic infections, IBS, autoimmune intestinal conditions and a whole host of other disorders.

A lack of confirmatory lab tests—the usual IgE-based allergy tests are, in most cases, useless—makes things even more difficult although some findings, even if non-diagnostic, can provide supporting evidence for a diagnosis.

Diagnosis of FPIAP, FPE and FPIES leans heavily on the patient’s history of symptoms—at what age did they start, what were they exactly, how long did they take to appear, how bad were they—to exclude other diseases. The disappearance of symptoms once the offending food is removed from the diet, and their reappearance when the food is reintroduced, is often considered good enough for a provisional diagnosis.

Diagnosing FPIAP

Food protein-induced allergic proctocolitis can be differentiated from the other GI allergies by the fact that symptoms are often limited to bloody stools (no vomiting or plentiful diarrhoea) in an otherwise healthy-looking infant.

It’s actually not uncommon for healthy infants to suffer from rectal bleeding and FPIAP as a cause is actually quite rare, so other, more common causes like infection, anal fissures and transient colitis are generally considered before a provisional diagnosis of FPIAP is made.

Laboratory tests can help to confirm a suspicion of FPIAP by, for example, registering mild iron deficiency (anaemia) or an increase of eosinophils (a type of white blood cell) in the blood. However, these abnormalities are pretty mild and lab tests are more likely to help rule out other causes.

Because FPIAP is generally quite a benign condition that occurs in otherwise healthy infants, some allergists advocate a ‘watch and wait’ approach; waiting for 2 to 4 weeks to see if the condition gets better by itself without eliminating any food from the diet.

If symptoms persist, it’s time for the elimination diet. Suspect foods—first milk, then maybe soy and/or egg—are taken out of the infant’s diet. If the diagnosis of FPIAP is correct, symptoms should disappear within 1 to 2 weeks. They often resolve within 72–96 hours.

If the symptoms do disappear, the food can be (briefly) reintroduced into the infant’s diet 1 to 2 months later, generally at home without any need for medical supervision. Any reactions or lack thereof can be documented with a symptom diary. If symptoms reappear, the diagnosis is unofficially confirmed. Theoretically, an oral food challenge (OFC) is necessary to properly confirm the diagnosis but, in practice, this isn’t done during the first months of life if the infant looks well. In fact, reintroducing the food within a few weeks to provisionally confirm the diagnosis is also rarely done in practice.

However, if infants are breastfed, guidelines call for the suspect food(s) to be eliminated from the mother’s diet and then re-introduced 2 to 4 weeks later to confirm or refute the diagnosis in order to make sure that the mother is not unnecessarily eliminating foods that would otherwise contribute important nutrients to her diet.

If symptoms are severe or abnormal (e.g. include severe bleeding, constipation or diarrhoea with mucus-streaked stools but no blood), other tests might have to be performed, such as a sigmoidoscopy (investigation of the large colon via the rectum) or a colonoscopy with biopsies, before a diagnosis can be made.

Diagnosing FPE

The symptoms predominantly associated with food protein–induced enteropathy are chronic diarrhoea, an infant who is small for their age (i.e. failing to thrive) and, quite often, sporadic vomiting.

Confirmatory lab test results may show low levels of iron (anaemia), low levels of albumin (hypoalbuminaemia) or low level of protein (hypoproteinaemia) in the blood.

An elimination diet should result in the disappearance of obvious symptoms within 1–4 weeks, often within a fortnight. Reintroducing the food(s) after 1 to 2 months should cause symptoms to reappear. The damage done to the intestine may take several months to heal, but it will get better.

An endoscopy and biopsy to check on the state of the small intestine is needed to make a definite diagnosis—unlike the other conditions mentioned on this page, this invasive test is unfortunately necessary to avoid misdiagnosis. If it is FPE, the intestine will have signs of inflammation, the small intestinal villi will show patches of erosion and the crypts of Lieberkühn (intestinal glands) will be elongated. These findings are similar to those seen in coeliac disease, but less severe.

Diagnosing FPIES

Chronic and acute FPIES are diagnosed using different methods.

Chronic FPIES looks a lot like FPE, with intermittent vomiting and/or diarrhoea and poor growth being the predominant signs. The only thing which helps to distinguish it from similar gastrointestinal diseases is an elimination diet. Taking the offending food out of the diet should result in the disappearance of the symptoms within 3 to 10 days. Reintroducing the food should be followed by the sudden onset of acute FPIES symptoms, i.e. severe vomiting.

Acute FPIES is characterised by projectile vomiting within 1 to 4 hours after eating and an absence of (skin or respiratory) symptoms that suggest an IgE-mediated reaction. Other symptoms such as diarrhoea (up to 10 hours later), dehydration and a sickly-looking appearance (pallor, lethargy) may also be present.

Atopy patch testing (APT) is also used on occasion, although it has mixed results, with the majority of studies not finding it particularly useful in helping to diagnose gastrointestinal allergies. However, it’s a safe and non-invasive test, and a positive reaction means that an allergy is quite likely, so there can still be some benefit to carrying it out.

Even though FPIES is classified as a non-IgE-mediated disorder, sometimes specific IgE antibodies for the offending foods can be detected. These cases of so-called ‘atypical FPIES’ can actually occur in up to 1 in 4 FPIES-sufferers. People with this type of FPIES can eventually develop IgE-mediated reactions to the food(s) and they are less likely to outgrow the condition.

Other lab tests might pick up signs of moderate anaemia, an increase in the number of white cells (leukocytosis and neutrophilia) or platelets (thrombocytosis) in the blood, too much acid in the blood (metabolic acidosis) and/or too much methaemoglobin in the blood (methemoglobinemia).

A diagnosis of acute FPIES is considered definite if re-exposure to the offending food produces the same symptoms. Although an oral food challenge is the gold standard for diagnosing FPIES, if someone has already experienced 2 or more episodes of the same type of symptoms within 2 to 4 hours of being exposed to the same food(s), an OFC is not strictly necessary. Some doctors may even consider an OFC unnecessary when an infant experiences typical signs like profuse vomiting, lethargy, pallor and floppiness after eating, for example, rice for the first time and then completely recovers within a few hours.

Unlike FPIAP and FPE, any food challenge for FPIES should take place under medical supervision because of the potential for serious reactions which could need medical support like intravenous hydration.

Managing a non-IgE-mediated GI food allergy

Currently, the only way to manage a non-IgE-mediated food allergy is to remove the offending food(s) from the diet and to treat the symptoms. In the case of breastfeeding infants, this may mean removing the food(s) from the mother’s diet, but this should only be done if symptoms appear while breastfeeding.

There are 2 different approaches that can be taken when it comes to eliminating foods, depending on how serious the symptoms are:

• the bottom-up approach, which is used in most cases and involves limiting only the foods known to cause reactions. In the case of infants, cow’s milk is the most frequent trigger and the doctor may recommend an extensively hydrolysed formula (in which casein, the major milk allergen, is broken down into smaller pieces) or even an amino acid-based formula (which just contains amino acids—the building blocks of proteins—and no intact proteins) when symptoms are persistent
• the top-down approach, which can be used in cases of FPIES with severe symptoms—such as dehydration or poor growth—and involves initially limiting a wide variety of foods that might trigger a reaction and then reintroducing individual foods one by one while carefully monitoring for a recurrence of symptoms. With this type of approach, counselling with a nutritionist is recommended because of the high risk for nutritional deficiencies

In cases of FPIES, the introduction of new foods that are considered high risk may be delayed, and the introduction of closely related and potentially cross-reactive foods from the same food group, like nuts or fish, is best done under a physician’s supervision.

Patients and parents of young children with non-IgE-mediated gastrointestinal food allergies should be provided with a post-diagnosis plan that provides support to avoid nutritional deficiencies and balances food avoidance with new food introduction. In more complex cases which require the avoidance of multiple foods, regular medical and psychological support should be made available.

In cases of acute FPIES, patients or parents should also get an emergency treatment plan on how to deal with reactions.

Unlike IgE-mediated allergies, because gastrointestinal allergies are generally not life-threatening, there’s no need to avoid food products with precautionary labels (such as ‘may contain’), and no need to carry an epinephrine auto-injector in case of accidental exposure.

Reintroducing foods

Periodic food challenges should be carried out to see whether infants and small children have developed tolerance to their food triggers.

According to current guidelines, when it comes to FPIAP and FPE, food can gradually be reintroduced in the infant’s diet (or the mother’s, in the case of breastfed infants) after the age of 1 or, in mild cases, after the food has been eliminated for six months. This can normally be done at home, although when it comes to children who have had more severe reactions, like blood stained diarrhoea, or those who have had positive IgE skin of blood tests to specific foods, reintroduction should be done under the supervision of a physician or dietitian.

FPE may also require a biopsy to check on the state of the small intestine.

When it comes to FPIES, an oral food challenge should be performed between the age of 1 and 2 and be supervised by a physician in an environment that has the equipment necessary to deal with a serious reaction.

Associated problems

Children with non-IgE-mediated gastrointestinal food allergies are more likely to have to deal with feeding problems and/or nutritional deficiencies than children with other types of food allergies.

Feeding difficulties

The symptoms of non–IgE-mediated GI allergies often lead to feeding difficulties. Chronic stomach or rectal pain, constipation or bloating understandably makes a person less interested in eating, and the violent vomiting seen in acute FPIES can be traumatic for both the parents and the child.

Research shows that parents of children with non-IgE-mediated allergies are more anxious and have a worse quality of life than parents of children with arguably more dangerous conditions like sickle cell disease and intestinal failure. Their anxiety can impact on their child’s feeding habits; as children learn to eat by watching their parents, they can become very selective in their intake when they see their parents carefully selecting allergen-free products and being reluctant to introduce new foods because of the fear of an allergic reaction.

Feeding skills also develop early, and the restricted dietary therapies implemented for many non–IgE-mediated diseases during this critical phase of developmental can affect a young child’s willingness to eat and explore new foods which, in turn, affects their development of oral-motor skills and sensory perception of food.

Signs that a child is developing feeding problems include:

• Crying or refusing to come to the table after having previously been well-behaved
• Exhibiting fear or anxiety around new foods
• Having a list of preferred foods that becomes shorter and shorter
• Only wanting to eat certain brands
• Needing food to be prepared in a certain way
• Exhibiting poor growth or lack of weight gain (infants and toddlers)

General guidelines for dealing with feeding difficulties recommend:

• Aiming for meals at 3–4 hours intervals with no snacking in between to maximize appetite
• Limiting mealtime duration to 20 to 30 minutes
• Keeping mealtimes as pleasant and relaxed as possible
• Avoiding distractions or noise (screens, phones, toys and books)
• Serving age-appropriate foods in relatively small portions
• Encouraging self-feeding (toddlers should have their own spoon), mess and food exploration
• Introducing new foods one at a time and re-offering foods that have been refused up to 15 times

Behavioural scientists have come up with several approaches to deal with children who refuse their food. The most popular among these is the food chaining method, a systematic approach popularised by the book ‘Food Chaining: The Proven 6 Step Plan To Stop Picky Eating, Solve Feeding Problems, and Expand Your Child’s Diet.‘

This approach involves ‘chaining’ from one food that a child currently enjoys to a new food by changing 1 aspect of the preferred food—texture, colour, flavour, shape or temperature—at a time. For example, if your child likes chips (or ‘fries’ if you’re American, so beige and crispy things), you could ‘chain’ to chicken nuggets (also beige and crispy but a different shape) or to fish sticks (also crispy but a slightly different colour), and then you could add mayo or cheese sauce (a different texture) to the meal. Your child is now eating a wider range of foods that were introduced slowly in a non-threatening manner. That said, the foods in this standard example are not what you would call healthy picks, so trying to shoe-horn in some carrot sticks in the shape of potato chips might be an even better idea.

Nutritional deficiencies

Non-IgE-mediated food allergies can lead to nutritional deficiencies because of the underlying disease itself—for example, chronic inflammation can lead to the intestine being unable to properly absorb food nutrients—and/or the feeding difficulties and restricted diet associated with the disease.

The most common foods involved in non-IgE-mediated GI allergies are cow’s milk, egg, soy and wheat and many of these foods contribute significantly to the intake of macro- and micronutrients essential for normal growth and development during early childhood.

As such, research has highlighted an increased risk of faltering growth in young children with food allergies, especially in those who are allergic to milk or have multiple food allergies, even when their nutrient intake is the same. These children are more likely to be shorter for their age than underweight, although underweight—and overweight—are both problems associated with malnourished children.

Although all children with food allergies are at risk of poor growth, children with non-IgE-mediated and mixed allergies seem to be at greater risk than those with IgE-mediated allergies.

An analysis of the diet diaries of 110 British children with non-IgE-mediated allergies found that children whose diets were not supplemented were at risk of not getting in enough vitamin D, zinc, calcium and selenium, and that many of those who did receive supplements either did not get enough or got too much of certain nutrients.

An analysis of the medical records of 92 children with non-IgE-mediated gastrointestinal food allergy seen at Great Ormond Street Hospital in London between January 2002 and September 2015 revealed that a quarter of them were not getting in enough vitamin D. Risk factors for vitamin D deficiency included being a girl and being older (around 12 and a half years old). About 1 in 5 also had vitamin A, selenium, copper and zinc deficiencies.

Growing children are at particularly high risk of suffering the long-term effects of malnutrition when put on an inadequate diet, especially those who are allergic to milk. Proper nutritional guidance is crucial.

A trained dietitian or nutritionist can develop a personalised diet to avoid unnecessary dietary restrictions and ensure normal growth and development for age and gender, including:

• provide clear guidance about which foods to avoid (including which foods to avoid because of hidden allergens. For example, a drink that is advertised as being for ‘people who cannot drink milk’ can actually be milk with added lactase enzyme, which is suitable for people with a lactose intolerance but still contains milk protein)
• provide a list of substitute foods
• provide help in reading ingredients labels
• ensure that the diet contains the right amount of nutrients and provide guidance about which supplements to take in case of unavoidable nutrient deficits
• provide guidance on when to introduce complementary foods, which will help to promote oral feeding skills and increase nutritional intake
• help with the earlier introduction of allergens such as peanut and cooked egg
• provide guidance in cases of allergy-related eating disorders

Food-allergic children who(se parents) receive dietary advice and who are regularly monitored have a much better chance of getting in all the nutrients they need and are more likely to achieve the expected rate of growth for their age, although a significant number of those with non-IgE-mediated GI allergies will still be somewhat short for their age.

The bottom line

Non-IgE-mediated gastrointestinal food allergies affect people of all ages, from day-old infants with FPIAP to 68-year-olds with FPIES, and they negatively impact the quality of life of those who have them and those who live with the people who have them.

That said, they predominantly affect young children, both in terms of prevalence and associated issues, with around 1 in 10 experiencing growth problems, which is why experts recommend that the physical development of children with food allergy is closely monitored and that their parents get nutrition advice, especially when there are multiple foods involved.

Unfortunately, non-IgE-mediated GI food allergies seem to be becoming more common and taking longer to outgrow, with around a quarter of affected children still needing to eliminate certain foods from their diets at the age of 8.

The upside is, if you’re plagued by gastrointestinal food allergies, you know you’re not alone. And the fact that they, like other food allergies, are becoming more of a problem has resulted in a lot more interest in and research being done on the subject in recent years. Help is out there and it’s getting better.

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