What these are and implications for Infant Nutrition
Introduction and overview Adverse reactions to food have been reported for centuries. Many parents believe that their children/infants are allergic or intolerant to a food, which in the majority of cases will not be confirmed by the necessary tests, food exclusion and food challenges/re-introduction. For some of them, however, these allergies or intolerances could be life threatening or have a huge impact on their quality of life as extreme avoidance of the culprit food may be the only way to avoid severe symptoms. For others such stringent avoidance measures may not be applicable or practical which could results in an unnecessary reduction in their quality of life.
It is very important to have a diagnosis made by medical professionals dealing with food allergies/intolerances. The final diagnosis should be confirmed by a medical history, blood tests/skin tests (where applicable) or keeping a food and symptom diary followed by a special test diet to identify the foods causing their symptoms. Once a diagnosis is made, dietary changes can be advised to eliminate or moderate the intake of offending foods. Ultimately, the most appropriate tests used will depend on the “type” of food allergy/intolerance one is dealing with. A European Academy of Allergy and Clinical Immunology task force1 has proposed that any adverse reactions to food should be called food hypersensitivity (Fig. 1). When the immune system is involved, they suggest that the appropriate term to use is food allergy. If the food allergy involves IgE, then it will be known as IgE-mediated food allergy. Other reactions, previously referred to as ‘food intolerance’ should be referred to as non-allergic food hypersensitivity. Severe, generalised allergic reactions to food are classified as anaphylaxis1. For more information on each of these2, see figure 2.
Figure 1: Proposed nomenclature for food hypersensitivity.1
Figure 2: Examples of conditions classified as food hypersensitivity
IgE mediated food allergy:
Gastro-intestinal: oral allergy syndrome, gastro-intestinal anaphylaxis
Cutaneous: urticaria, angioedema, morbilliform rashes, red flushes, usually facial flush
Respiratory: acute rhinoconjunctivitis, acute asthma
Generalised: anaphylaxis, food-associated exercise-induced anaphylaxis,
Non-IgE mediated food allergy (cell-mediated FHS):
Gastro-intestinal: Food protein–induced proctocolitis, Food protein–induced enterocolitis, Food protein enduced enteropathy syndromes. (Clinical indicators for these are growth faltering and hypo-albuminemia41),coeliac disease
Cutaneous: contact dermatitis, dermatitis herpetiformis
Respiratory: Heiner syndrome (food-induced pulmonary hemosiderosis).
IgE and/or Non-IgE mediated (cell mediated) :
Gastro-intestinal: Allergic eosinophilic esophagitis, Allergic eosinophilic gastroenteritis
Cutaneous: atopic dermatitis
Respiratory: asthma
Non-allergic food hypersensitivity:
Lactose intolerance, galactosemia, alcohol intolerance;
Pharmacological reactions caused by Caffeine (jitteriness), tyramine in aged cheeses (migraine), alcohol, histamine.
Mechanisms unclear:
Colic, Mucous production (i.e. nasal symptoms) and constipation
The term food hypersensitivity (FHS) will be used throughout this article according to the above nomenclature.
It is important to take these different “types” of FHS into account when designing protocols for the diagnosis of these. A diagnostic protocol should provide a step by step guide to aid Health Care Professionals (HCPs) in the diagnosis of FHS. Using these protocols is important to ensure correct diagnosis as just making a diagnosis based on the history provided is not ideal. It is known that despite careful history taking, the correlation between suspected FHS and actual FHS as confirmed by food challenges is between 12 - 21% of patients3-5. In a recent study performed on the Isle of Wight, researchers showed that out of suspected food allergy/intolerance in 807, 0-3 year olds, it was confirmed in only 60 infants4. This is important as false positive diagnoses on the one hand can lead to unnecessary restrictions on life style and possible disease from nutrient restriction6-8. However, false negative diagnoses on the other hand can lead to the risk of ongoing symptoms with further (possibly severe) reactions.
In this article, we are hoping to provide HCPs, with user friendly protocols for the diagnosis of FHS in particular cows` milk hypersensitivity (i.e. IgE mediated cows` milk allergy [CMA], non-IgE mediated CMA and lactose intolerance). (See figure 2) Diagnosis of FHS There are many routes that could lead to a diagnosis (or false diagnosis) of food allergy and intolerance such as taking a history, tests and food challenges/food reintroduction (figure 3). The role of different HCPs in the diagnosis of FHS is summarised in figure 4.
Figure 3: Diagnosis of Food hypersensitivity
* In some cases (i.e. some primary care settings) these tests may not be available or it may take a long time to obtain results. However, the history could give a good indication of the type and time of onset of symptoms, which should assist HCPs to decide if symptoms are IgE or non-IgE mediated reactions, taking into account that eczema could initially present with delayed symptoms27 and then may turn into a presentation of immediate, more severe symptoms
* In some cases emergency medication will need to be discussed with appropriate training by a nurse/allergy nurse/clinician.Allergy nurses/paediatric nurses in some hospitals/centres may perform food challenges.
Taking a good clinical history is very important for all suspected types of FHS.
Blood tests and skin prick tests will only be helpful in the diagnosis of IgE mediated food allergy, but they are not 100% reliable. Some people may have a positive blood or skin test, but able to tolerate the food. The best method of diagnosing IgE-mediated allergy and the only method for non-IgE mediated allergy and food intolerances (non-allergic food hypersensitivity) is an elimination diet followed by re-introduction of the food, or a food challenge. The accessibility of these tests/procedures varies around the UK and this will be incorporated in the following discussion.
1) Clinical history
The clinical history is relevant in the diagnosis of IgE mediated FHS, non-IgE mediated FHS and non-allergic FHS. Careful history taking and physical examination form the basis of diagnosis of FHS. Taking a history can give useful information to the health care professional regarding:
1) Which diagnostic tests should be used e.g. skin prick tests, blood tests or patch tests
2) Whether a food and symptom diary is needed, although it is not always possible to identify the offending food(s) from these diaries alone
3) Which foods should be avoided during the diagnostic test diet*
4) Whether a food challenge at home/hospital or gradual introduction of the food(s) may be required (see discussion under food challenges).
* The difference between a diagnostic test diet (or using a formula for diagnostic reasons) and a maintenance diet is that a diagnostic diet always eliminates the culprit food completely and this should always be followed up after a period of 2-6 weeks with a food challenge or food re-introduction. A maintenance diet can be followed for a much longer period (in some cases for life) and the level of avoidance required may vary from patient to patient.
2) Diagnostic tests
IgE mediated food allergy
Both skin prick tests (measures specific IgE attached to mast cells in the skin) and specific IgE tests (measures levels of circulating specific IgE to allergen in the circulation) are useful in the diagnosis of IgE mediated FHS. However, the presence of IgE in the skin or in the blood only indicates that an individual is sensitised to an allergen (i.e. produces specific IgEs to the food), but not necessarily clinically allergic (i.e. may be able to eat the food without any reaction). One can therefore not make a diagnosis of food allergy based on SPT or blood test alone. In some cases, a positive skin prick test or blood test coupled with a very clear history of a reaction to the food, is considered sufficient proof for diagnosing IgE mediated food allergy. However, a positive skin prick test or blood test in patients that have never knowingly eaten at least 10g of the food on more than one occasion should always be followed with a food challenge in order to confirm or refute FHS.
Skin prick tests
When performing SPT, glycerinated food extracts (1:10 or 1:20) weight per volume dilutions are placed on the skin and pricked with a lancet or needle. A positive (histamine) and negative (saline) control should always be used 9. The positive control gives an indication of skin reactivity (i.e. whether the skin will develop a wheal once exposed to histamine) and the negative control can identify patients with dermatographism (patients who will produce a wheal upon any prick or scratch to the skin completely unrelated to the allergen used). SPT can be performed using commercial allergens (which are not standardised, but improving) or using fresh foods also called prick-to-prick test (which also needs standardisation)10-12 . The main reasons for using prick-to-prick tests are that food allergens, specifically fruit and vegetables, may be destroyed during the preparation of commercial extracts, or when no commercial allergen extract is available e.g. spices.
There is no lower age limit for performing an SPT. In general, an SPT is considered positive if the wheal is 3mm larger than the negative control 13-15 in children over 2 years and 2mm larger in children younger than two years 16. This is supported by the fact that the histamine induced wheals in children increase by 125% from 4 days - 2 years and 150% from 2-18 years indicating that skin reactivity may increase over time, affecting SPT wheal size 17. A positive SPT indicates with 50% positive predictive accuracy that the patient may have a true IgE mediated allergy to the food i.e. a positive SPT indicates that there is a 50% chance that the child is truly allergic. A negative SPT is extremely useful in ruling out IgE mediated food allergy. However, a small proportion of children (about 5%) may react immediately to foods to which they had a negative SPT (figure 5).
Source: Isabel Skypala, Royal Brompton Hospital
There are now more specific clinical decision points available in the literature which indicate to clinicians if a food challenge is needed and how likely the challenge is to be positive (figure 5). Most importantly, SPT size does not predict the severity of the reaction.
Specific IgE tests
Specific IgE tests used to be conducted by employing radioallergosorbent tests (RAST). Nowadays, specific IgE is measured as fluorescent enzyme-labelled IgE (CAP-RAST FEIA). This test seems to be more sensitive (89%) and specific (91%)18 in other words more accurate. Specific IgE levels can be monitored as specific levels of kilo – units of allergen/litre (kUA/l) or as “graded” levels (grade 1 – 6). Some clinicians will use the graded system for diagnosis, whereas other will use the particular levels of allergens measured. Generally, level 2 and above is considered as positive in clinical practice, although this is not evidence based. Specific IgE levels of >15 kUA/L for milk, >7 kUA/L for egg and >14 kUA/L for peanut corresponds with grade 3-6 (personal communication Sheffield laboratories).
The preferred method of dealing with specific IgE levels is to assess the particular level of kUA/l. In general, the higher the level of specific IgE the more likely the child is to be allergic, but there is no clear cut-off point between being allergic or not. Therefore, in order to establish the reliability of specific IgE tests researchers have established cut off points for diagnosis of FHS (figure 6). As with the SPT, these cut off points should be viewed as guidelines rather than set diagnostic points.
The preference for using either SPT or specific IgE tests varies between clinicians and locations in the UK. SPT is often regarded as the method of choice due to the ease of use, low cost and immediate results. However, specific IgE tests of any type are very useful in children with severe skin disease, dermatographism or when it is impossible to discontinue the use of antihistamine. SPT facilities are not available everywhere in the UK, but all GP’s do have access to specific IgE tests even though results may take up to 6 weeks in some cases. However, many of these HCPs may be unfamiliar with the interpretation of specific-IgE test results and a referral to an allergy specialist may be required. As with SPT, specific IgE levels do not predict the severity of the reaction.
Figure 6: Food hypersensitivity: expected food challenge outcomes for specific IgE and skin prick test results
Non-IgE mediated FHS
Skin prick tests and specific IgE tests
SPTs and specific IgE tests are not useful in the diagnosis of delayed type/non-IgE mediated food allergy or non-allergic FHS, basically due to the fact that IgE producing mast cells are not the main cells involved in the development of these symptoms.
Patch tests
Food allergens are applied to a healthy area of the patient’s skin and the effects evaluated 48-72 hours later. It is used in the USA in the diagnosis of allergic eosinophilic disease19;20 and in Europe for the diagnosis of atopic dermatitis, 19;20 but not generally in the United Kingdom. However, there are a few centres where this diagnostic procedure is used.
Non-allergic FHS
No tests have been sufficiently validated to test so-called food intolerances. Lactose intolerance, however, can be diagnosed by means of the hydrogen breath test or testing the pH of the stools.
How do we deal with tests advocated by complementary and alternative medicine
The prevalence of complementary and alternative medicine (CAM) in allergic disease appears to be growing. Between 18 – 40% patients21 ending up in allergy clinics reported to have used CAM services.
Alternative testing for food hypersensitivity can be divided into two main groups;
1) Tests which use the body’s “energy” such as Vegatesting (electrodermal testing), hair analysis, applied kinesiology, and the pulse test. However, literature does not support the use of these tests22;23.
2) Blood analysis tests include IgG testing, Antigen Leukocyte Cellular Antibody Test (ALCAT) and Food Allergen Cellular Test (FAC-test). In terms of ALCAT and FAC-tests, neither of these tests have a rational scientific basis nor is there research in the literature regarding the effectiveness of such testing. With IgG testing, it is believed that an increase in IgG with certain foods could indicate food hypersensitivity. Zuo et al 24 and Atkinson et al 25 both showed that there was an increase in IgG to certain foods in patients with irritable bowel syndrome but more research is required to see if this also relates to food hypersensitivity. 3) Diagnostic exclusion diets In many patients seen in clinical practice or in primary care, particularly those suffering from non-IgE mediated allergy or non-allergic FHS, diagnosis can only be made by means of a combination of clinical history and dietary investigations (diagnostic exclusion diets) followed by a food challenge or food re-introduction.
There are four types of diagnostic exclusion diets:
i) Single exclusion diet
This excludes all sources of a single food (e.g. milk) as identified from the patient’s dietary history. (See table 1 for hydrolysed/amino acid based formulas in the UK)
ii) Multiple food exclusion diet
A multiple exclusion diet excludes a number of foods at the same time. Foods most commonly associated with a particular disorder are usually avoided such as milk and egg for eczema26, and milk, egg and wheat for eosinophilic diseases20.
iii) Few Foods diet
A few foods diet includes only a few foods that 1) are known to rarely cause allergic symptoms in the population and 2) are not regularly eaten by the patient. It generally includes 2 meats, 2 starches e.g. rice, 2 fruits, 2 vegetables and only water as a drink. If no improvement occurs it may be considered to construct a second Few Foods diet not using any of the food in the first diet. If this also produces no relief, the regimen should be discontinued and further investigation carried out.
iv) Elemental and protein hydrolysate formula diets
This diet requires the use of amino-acid based formula or an extensively hydrolysed whey or casein formula such as Cow & Gate Pepti (see table 1) in infants and children up to 2-10 years (depending on the formula). These formulas are mainly chosen due to the low risk of having a reaction to extensively hydrolysed formulas and almost no risk of reacting to an amino acid based formula. In some cases, fortified rice milk or soya milk may be used in children over 2 years, but this will require dietetic supervision.
Table 1: Different hydrolysed/amino acid based formulas available in the UK
* Always try maternal avoidance of cow’s milk first; in some children who have been breast fed, amino acid based formulas and hydrolysates based on casein may be refused due to poor palatability despite maternal best efforts. In these cases, a whey hydrolysate may be a better alternative.
Soy formulas maybe trialled in CMPA infants who are older than 6 months of age who are neither soy allergic nor have symptoms suggestive of an enterocolitis. It is important that patients/parents should be well educated before embarking on a diagnostic test diet:
- For all types of exclusion diets, patients need to be clearly educated regarding:
- Avoidance of food(s)
- Label reading
- Suitable alternatives
- Following a healthy balanced diet, despite the dietary restrictions
- Dietetic expertise is of particular importance when dealing with children’s diets, although a range of HCPs in the primary care setting may be able to initially assist in this role.
- As well as foods and beverages, non-dietary sources of substances, which can provoke reactions, may also need to be excluded, but this is very individual and may not always be necessary.
Food exclusion diets are usually followed for a period of 2-3 weeks but in case of fluctuation of disease patterns such as eczema, it may be necessary to continue for up to six weeks.
Monitoring progress
Patients/parents should keep a food and symptoms diary whilst on the diet, starting one week prior to commencing the diet so that alteration in symptoms can be related to any dietary change.
If improvement does not occur, the dietitian (or a health care professional with suitable experience) must carefully review the patient`s food intake to ascertain whether the procedure was followed correctly and, if so, must then decide whether other foods should be excluded or whether food hypersensitivity is unlikely to exist.
Food reintroduction and food challenges
Dietary exclusion needs to be followed by re-introduction of the food either during a food challenge or a reintroduction plan at home. Deciding which method to use provides another grey area in dealing with FHS. Generally speaking, all patients with either a history of immediate symptoms or a positive SPT/specific IgE tests, should be invited to a controlled setting for a food challenge. However, HCPs should take into account that eczema could initially present with delayed symptoms27, but may turn into a presentation of immediate, more severe symptoms. This does prove difficult in large areas of the UK, where food challenge facilities at hospital/allergy centres are not readily available and some patients may have to wait some time for a food challenge to be performed. However, paramount in all of this is patient safety.
All other patients could either undergo a food challenge at home or a food reintroduction plan depending on the facilities and staff available.
There are a number of issues that should be taken into account when performing food challenges or re-introduction of food such as:
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The type of challenge used
Decide whether an open, single – blind, placebo controlled food challenge (SBPCFC) or a double – blind, placebo controlled food challenge (DBPCFC) will be used.
For clinical purposes, the open food challenge would probably be the challenge of choice in most cases when dealing with children suffering from objective symptoms e.g. urticaria, angioedema etc28. Some guidelines recommend using open food challenge (OFC) in children under 2-3 years of age29.
For clinical purposes, the SBPCFC or DBPCFC would probably be the challenge of choice in most cases when dealing with children suffering from:
- Subjective symptoms e.g. tummy ache, feeling sick, headache etc.
- Symptoms that could be difficult to assess due to the nature of the disease e.g. eczema (28).
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Where will the challenge be conducted: hospital or home?
OFC may occasionally be performed at home rather than in the hospital providing that there is no risk of the patient developing immediate severe symptoms and the patient showed no sensitization to the food.
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The amount of food given
Dealing with immediate/IgE mediated symptoms: There is no recommended “starting dose” that should be used for all patients/challenges, but it should be at least half of the dose the patient reacted to in the past29.Some clinicians prefer to start the challenge, with a labial rub of the lip. The development of symptoms is considered a positive test and a negative labial rub can be followed by the oral challenge doses30.
No internationally accepted guidelines exist regarding the total dose of food that should be used for a food challenge. Some researchers use a total of 8-10g of the dried food for challenge purposes31;32 whereas others14;26;33-36 used 8g as the final dose, thus giving about 18g dried food in total. The latest position paper by EAACI recommends that the top dose should be “the normal daily intake in a serving of the food in question, adjusted for the age of the patient”29. When using real food as opposed to dried food, it is recommended that 60 – 100 g of wet food should be used for challenge purposes. In principle, the food challenge should provide a sufficient amount of the allergenic food to either prove or rule out a food allergy. In some cases however, subsequent reactions may still be experienced at home, even after consumption of a normal portion of food on the challenge day37.
Dealing with delayed symptoms/non-IgE mediated food allergy or food intolerance: Apart from the amount reported by the history, there are no specific recommendations regarding the dose used when performing food challenges to diagnose delayed symptoms such as eczema or constipation38. This raises practical issues where the patient is a very vague historian. Another difficult area is with infants suffering from eczema. It is not clear in most cases whether the eczema is caused by a single dose of a food or the total daily consumption of a food.
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The required challenge duration should be discussed.
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Sufficient after care should be provided to the patient once the challenge is completed in terms of further elimination or re-introduction of the food.
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Always take informed consent prior to the food challenge.
Issues arising when dealing with Food Hypersensitivity
There are a few issues that arise when dealing with the diagnosis of FHS in young children and infants.
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Which formula should be used as a diagnostic tool? Although some guidelines exist regarding the choice of formula39 for diagnostic purposes (table 1) it is not always clear whether a child/infant is presenting with IgE/non-IgE mediated allergy or food intolerance.
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There is also the debate between using extensively hydrolysed whey (e.g. Cow & Gate’s Pepti-Junior or Cow & Gate Pepti), extensively hydrolysed casein (e.g. Mead Johnson’s Nutramigen or Pregestimil) or an extensively hydrolysed pork/soya (e.g. Aptamil’s Prejomin) formula, which is quite often a clinical decision. This relies on a health care professional with sufficient knowledge and experience in the field of food allergy/intolerance.
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Another (and almost the most important factor) is mothers and infants getting quite distressed by changing formulas all the time i.e. formulas on which child presents with symptoms, followed by diagnostic formula, formula for food challenge and then finally the formula that will be used longer term. Ideally, one should choose a diagnostic formula that will be suitable for longer-term use, once the patient is diagnosed with cow’s milk allergy.
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It is also difficult to define “severe” symptoms. It is a debatable issue if potentially all patients with IgE mediated allergy40 (immediate onset) or children with eczema27 could present with severe symptoms and should be challenged in a hospital/allergy clinic setting.
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HCPs should also be careful not to just dismiss food allergy/intolerance if no improvements are seen upon avoidance of just one food (see figure 3)
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Finally, food challenge procedures need to be standardised with clear, practical guidelines and recipes that ensure sufficient blinding to ensure unequivocal diagnosis.
These issues will hopefully lead to more research, which could ensure evidence based, practical, clinical guidelines.
In summary, this article covered the classification of food related problems and how this impacts on the diagnosis of FHS. There are still a number of issues that are being debated by HCPs and researchers. This will hopefully ensure more research, leading to evidence based clinical guidelines. The future holds much promise for the evaluation and treatment of food hypersensitivity. We can certainly be optimistic that over the course of the next decade, treatment modalities will be improved and standardised.
At the moment, HCPs need to be able to obtain a good clinical history, primarily to find out if symptoms are immediate or delayed in nature, how reproducible they are and how much food (if known) is needed to elicit a reaction. Suitable tests should be performed where possible to assist in finding out if the reaction is immune mediated and if so, is it IgE-(potentially severe), non-IgE mediated or a combination of both – or is it simply an intolerance. However, in clinical practice, it very often happens that HCPs have to deal with patients in whom the exact mechanism of the reaction is not known or could not be established. A diagnostic test diet can then be decided on, which include the choice of a diagnostic test formula. In brief, if symptoms improve, a food challenge or re-introduction of the food(s) should be carried out. Based on the outcome, food should either be excluded or re-introduced. If no improvement is seen on the diagnostic test diet (or chosen formula), other foods should be considered or the formula should be changed.
Practical advice for mums and HCPs:
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Be clear about symptoms experienced and foods consumed
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Follow the diagnostic diet very carefully
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Always follow this up by a food challenge or re-introduction plan.
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Based on the final result, ensure that the appropriate food is avoided or re-introduced into the diet as guided by a dietitian.
Further information can be found at www.infantandtoddlerforum.org . For more information on food challenges see: Venter C. 2004. Appendix. Different type of food challenges. In: Year in Allergy 2004. Arshad SH, Babu KS, Edwards A, Venter C. 2004, pp. 197 – 210. Oxford: Clinical Publishings Ltd. References
