Archive for the ‘Allergy Diagnostics’ Category

Skin-prick tests
This is an indirect method of detecting true allergic reactions. It is one of a family of skin tests that use a similar approach. The three different tests in this family are known as: skin-prick tests or prick tests, puncture tests, and scratch tests.
For the skin-prick test - the technique used in Britain - a small drop of liquid containing an allergen, such as grass pollen, is placed on the arm. The doctor makes a small prick in the skin, under the drop of liquid, allowing a minuscule amount of the allergen to get into the skin. A positive reaction is recorded if a red bump develops soon afterwards. For accuracy, the bump must be compared to positive and negative controls (see below).
The puncture method is very similar to the skin-prick test but uses a slightly different technique for breaking the skin. The term prick-puncture test covers both techniques.
With the scratch method, the skin is scratched lightly, and the allergen solution is then applied over the scratch. This method gives less consistent results than prick-puncture testing.
It is important to include a negative control in the test - a skin-prick test with plain salt water (saline). This should not produce much of a bump - if it does, the skin is clearly over-reactive and the tests more difficult to assess. The doctor should also include a positive control - a skin-prick test with histamine, the substance that plays a central role in allergic reactions. This should always produce a bump. If it does not, the skin is decidedly under-reactive, and the tests are invalid.
Taking antihistamines will make the skin under-reactive, and you should stop taking them before the testing, for a period ranging from a day to several weeks - it varies depending on the particular antihistamine. Ask your doctor for specific instructions about stopping these and other drugs before testing.
Skin tends to be over-reactive to testing in people with dermatographism (see p. 52). Blood tests for specific IgE,
such as RASTs (see p. 92), are needed for anyone who has this condition. Eczema sufferers with a rash over large areas of the body may also require blood tests, if there is too little clear skin for testing.
Skin-prick tests can produce both false positives and false negatives (see box below). Some allergic diseases will give a lot of false negatives and relatively few false positives, while for others the reverse is true. The allergen itself influences the rates of misleading reactions: for example, tests for soya allergy are notoriously unreliable, whereas those for peanut are far more accurate. The age of the person being tested also makes a difference. With all these influences at work, interpreting the test responses is a real art, and the doctor’s experience counts for a lot.
All sorts of people offer skin-prick tests, including alternative practitioners. Get them done by a qualified doctor, preferably by an allergist, who will know how to make sense of the reactions.
Note that the purpose of these tests, and of blood tests for specific IgE, is to identify the allergens that are bringing on your symptoms, not to predict how strongly you will react to those allergens. The tests may give some indication of the intensity of your reaction, but they cannot be regarded as a good guide to how you will respond to the allergen in the future.
The safety record of skin-prick tests is very good. Occasionally a systemic reaction (anaphylaxis) occurs with these tests, but there are no records of any deaths. Nevertheless, if you suffer from severe asthma or have experienced anaphylactic shock in the past, it is advisable for the doctor to have adrenaline and resuscitation equipment available. Those with strong allergic reactions to latex may also react badly if they are tested with an allergen that cross-reacts with latex (e.g. cypress pollen), not just when tested with latex itself. Taking beta-Mockers (see box on p. 150) increases the risk of a life-threatening reaction for anyone in these higher-risk categories.
False positives and false negatives
Apart from challenge tests, none of the tests used for allergy works with 100% accuracy. Most give both false positives and false negatives.
A false positive means that there is a positive test but no actual reaction when the allergen is encountered (e.g. eaten or inhaled). A false negative means that there is a negative test result despite a genuine reaction (as shown by a challenge test, for example).
A test that gives relatively few false positives has good positive predictive value - in other words, if it suggests you are allergic to something, you probably are.
A test that gives relatively few false negatives has good negative predictive value. If it comes up negative, you are probably not allergic to that allergen.
Some tests for allergic reactions show good positive predictive value but poor negative predictive value, while for other tests the reverse is true.
Fresh is best
The fruit and vegetable allergens that provoke Oral Allergy Syndrome (see p. 63) are chemically unstable, so commercially produced extracts for skin-prick testing quickly lose their potency and give false-negative results. Most allergists now favour using a drop of fresh juice from the fruit or vegetable concerned.
Intradermal tests
These tests (also called ‘intracutaneous tests’) put allergen more deeply into the skin than prick-puncture tests. The skin tends to react more when penetrated to this depth, so there are more false positives. There is also a greater risk of a serious reaction which may require emergency resuscitation. Don’t undergo these tests if you are taking beta-Mockers (see box on p. 150).
Blood tests for IgE
There are blood tests that look at the total amount of IgE (the allergy antibody), which is sometimes useful in diagnosis. But more important are blood tests for specific IgE – against egg or grass pollen or latex, for example. There are different ways of measuring the IgE in the blood, the most commonly used being a radio-allergosorbent test or RAST.
Research shows that RASTs are no more accurate than skin-prick tests in confirming real-life allergic reactions. However, they are useful for patients who can’t discontinue their antihistamines without developing severe symptoms, and for those with dermatographism or very severe eczema (see p. 91).
Patch tests
These tests, used primarily for contact dermatitis, are similar to straightforward challenge tests, because the suspect substances are applied directly to the skin.
The test substances are placed on the skin – usually on your back – in small chambers. They are held in place with sticky tape, and left there for several days. Ideally, the reaction of the skin should be checked three times: after two days, again the next day, and again the day after that. It really is worth going back for all these separate visits, because the accuracy of the test increases greatly with repeated checking.
The substances chosen for testing are a standard set of antigens that most commonly cause contact dermatitis. This standard set will pick up 60-80% of all sensitivity reactions in contact dermatitis. If you have substances that you suspect may be causing symptoms, such as cosmetics, the doctor can usually test for these too.
You should not be tested while you still have a rash, as the testing will probably make the existing rash flare up, even though the test patches are applied well away from the rash.
Use of steroid creams and any light treatments (including exposure of the test area to ordinary sunlight) must stop at least a week before testing starts, or the results will not be accurate.
Interpreting patch tests requires a huge amount of skill, plus extensive knowledge of the finicky details of the different test substances. You need a dermatologist with considerable experience in this area.
False positives (see box on p. 91) can occur, especially if you react very strongly to one of the substances tested – some people develop what dermatologists call an ‘angry back’, and this generates false positives to various other substances being tested at the same time. Should you be told that you are sensitive to a great many different things, you may want to query this reading of the test. Ernest N. Charlesworth, an allergist and dermatologist at the University of Texas, describes patients who ‘develop into environmental cripples’ after being told that they are definitely sensitive to multiple antigens, on the basis of misinterpreted false-positive patch tests.
False negatives (see box on p. 91) are also possible, even with very careful testing. Should this occur, a type of challenge test known as a ROAT (Repeat Open Application Test) is possible. The suspect substance is applied to the inner fold of the elbow twice a day for a week. Get your doctor’s agreement before trying this test.
Endoscopy and biopsy
Miniaturised cameras and sophisticated fibre-optics have allowed modern doctors to do something that their predecessors could never have imagined possible – look right inside the human body. This procedure is called endoscopy, and it has a useful role in a few sensitivity reactions.
Looking inside the sinus cavities can assist in understanding exactly what is going wrong in chronic sinusitis. Inspecting the digestive tract can be valuable in several of the non-IgE immune reactions to food, such as coeliac disease (see p. 70) and eosinophilic gastroenteritis (see p. 72).
A biopsy is often carried out at the same time as endoscopy.
s involves taking a small sample from the affected area, such as
I ning of the gut, and studying it in detail under a microscope.
One purpose of a gut biopsy is to look for characteristic :goes of damage to the lining of the gut – such as the distinctive charges produced by untreated coeliac disease. A biopsy can also reveal what kind of immune cells are present. Abnormal numbers of certain immune cells, for example, eosinophils (see p 19), may suggest a particular diagnosis.
Another way of looking at what kind of immune reactions are going on, used for lung diseases, is a bronchoalveolar lavage – iterally a ‘washing out’ of the airways and lungs, allowing immune cells to be collected and studied. This diagnostic technique is lased for Heiner’s Syndrome (see p. 72).
Tests for food intolerance
The only really effective way of testing for food intolerance is an el ruination diet (see pp. 194-7). This is the gold standard. However, it is neither easy nor quick – which has led to a constant search for alternative tests.
The proposed alternatives are all indirect tests, that is to say, non-dietary. The results of the tests are used as a basis for an avoidance diet. In other words, the foods that give a positive test result are avoided.
Some of these tests use samples of hair or blood, others use pulse testing, pendulums, or muscle strength tests (’applied kinesiology’). A few of these tests do show some promise. Pulse tests, and a blood test called the ‘lymphocyte transformation test’. for example, can give a general indication of sensitivity reactions – sometimes. However, even in the most expert hands, these do not give a result that is accurate enough to be useful.
Of the other tests that are available, most have not been evaluated at all objectively.
Many of them are advertised directly to the public, and one of the problems with this approach is that the testing company starts by assuming that food is the problem. The same is usually true of ‘dietary therapists’ and others in the alternative health field offering tests of this kind.
Almost everyone who undertakes such tests is given a fairly long list of foods which have come up positive in the tests. This does not fit with the evidence from medical trials in which a group of people with irritable bowel or migraine (typical food intolerance symptoms) undertake an elimination diet. A significant proportion of them always find that they do not have food intolerance. Of the rest. many find that they react to one or two foods only. The long lists of foods produced by the commercial tests are, to put it mildly, implausible.
With tests that require a sample of blood, sending off two blood samples from the same person, under different names, is a simple way of assessing the tests’ validity. This exercise has been tried several times with different testing companies, and every time two completely different lists of foods have been sent back.
Covert studies of this kind have also shown that the tests overlook genuine reactions. In one alarming case, a woman with a true allergy to peanuts was assured by a ‘dietary therapist’ that she really could eat peanuts safely.
Many people with food intolerance will tell you that they did well after following a diet based on such tests – and they may well have done. Given that common foods such as wheat and milk are regular offenders in food intolerance, and that these foods very frequently feature on the lists of positive test results generated by commercial testing companies, quite a few people should do well. The problem is that these people may also be avoiding many other foods quite unnecessarily.
Furthermore, if people have sensitivities to some other foods that are not on the list, they will be missing out. They could enjoy a far better level of health if all the foods causing symptoms were Identified and removed from their diet.
In the end, an elimination diet is both cheaper and far more likely to give the right answers.
Testing for IgG antibodies
In diagnosing food intolerance, a few doctors offer tests for a type of antibody called IgG. This antibody is formed to any food molecules that get Into the bloodstream after a meal – and some do, even in entirely healthy people. So finding IgG antibodies to food molecules is not indicative of any disease at all. It occurs in everyone and is perfectly normal.
Nevertheless, some doctors feel that by measuring the level of IgG antibodies to foods, they can get a general idea of the permeability of the gut wall (which might possibly be true) and of particular foods that could be causing intolerance reactions (very doubtful – the tests just tell you what you eat most, and you know that already).
This test does measure something real, unlike some of the alternative tests for food intolerance. But the relevance of what it measures to the health of the individual concerned is partial and indefinite. A recent study of IgG testing for irritable bowel syndrome has confirmed this view.
In short, blood tests for IgG antibodies to food molecules seem like very poor value for money, and potentially misleading, whereas an elimination diet is a far more precise way of pinpointing food intolerances.

If you have a child with allergies, sooner or later some friend or relative will tell you not to worry

because your child ‘will probably grow out of it’. Your doctor may well say the same thing. But what

does this mean? Do all children shake off their allergic symptoms as they get older? If the symptoms

go, is the underlying disease completely cured? And why treat allergies if they disappear of their own

accord? The truth is that the relationship between allergy and age is incredibly complex, and doctors

only understand a tiny part of it. The best anyone can offer is a broad overview of how allergies

change with age, with few explanations of the underlying mechanisms, and absolutely no predictions of

what the future holds for any particular allergy sufferer.
It is certainly true that the classical allergic diseases, such as atopic eczema, hayfever and

childhood asthma (see box on p. 11), frequently disappear as children grow up. Babies tend to shrug off

food allergy and eczema by the time they are toddling, and a fair number of asthmatic children lose

their symptoms before they are ten years old, while others do so in their teens or early twenties.
Unfortunately, the disappearance of symptoms does not mean that the underlying disease has necessarily

disappeared, particularly in the case of asthma. Quite a few young adults find themselves wheezy and

breathless again in their late twenties or thirties, especially if they take up smoking. One study of

children who wheezed before the age of seven found that:
• 25% lost their asthma for a time – anything between two years and 25 years – only to get it

back again by their early thirties. Some recovered and relapsed more than once.
• Over 70% shook off asthma and were still symptom-free by their early thirties when the study

ended.
• Only 2% remained asthmatic throughout. Realistically, anyone who has ever been asthmatic should

regard themselves as ‘at risk’ indefinitely and never be careless with their health – don’t smoke, keep

away from smoky bars and clubs, eat a good diet with plenty of fruit and vegetables (206) and avoid

activities that involve an asthma risk, such as strenuous exercise in cold air.
Workplaces with high exposure to allergens, such as saw mills, bakeries or laboratories using animals

(see pp. 133-4) are not recommended for those with a history of allergy. Anyone who has ever had eczema

should also take care with cosmetics and soaps, choosing the gentlest brands. They should also protect

their hands (57) and avoid hairdressing or bricklaying as an occupation, or anything else where skin

irritation is likely.
Moving on
Growing out of classical allergies seems to be a consequence of the child’s immune system changing and

maturing as it grows. This same process, unfortunately, can also substitute one allergic disease for

another.
`When Alex developed eczema as a baby I hoped that she’d grow out of it in time. Well she did,

gradually, and by the time she was five it seemed to have cleared up, but then she started having a

snuffly nose that never really went away. A year or so later, she began wheezing whenever she got a

cold, and this has now developed into asthma.’ The pattern described by Alex’s mother Jenny will be

familiar to many parents, who watch their children slowly work their way through all the allergies in

the medical textbooks. Doctors call it the atopic march or allergic march.
Fortunately, even this type of allergic pattern can have a positive outcome eventually. Many such

children become allergy-free in time, and develop into healthy adults.
In the meantime, there are several itchy, wheezy or sneezy years to get through, and since childhood is

a time to be enjoyed, not endured, treatments that alleviate the symptoms of allergies are generally

welcomed. Being energetic, healthy, ‘normal’ and able to join in with sports and other activities is

particularly important for a child’s social development and self-confidence.
Treating the symptoms also prevents any long-term and irreversible damage, such as the thickening and

loss of elasticity that occurs in the airways of children with untreated asthma.
At the same time as treating the symptoms, it makes sense to maximise the chance of the child growing

out of the allergy. Parents can tip the odds in the right direction by providing an environment that

reduces the chance of new allergies developing. A detailed action programme is described on pp. 248-9.
Allergies that begin in adult life
What about those people who develop classical allergic diseases for the first time as adults - or even

in old age? Will they too ‘grow out of it’ with the passing years?
Only a minority of people develop such allergies for the first time as adults, although the numbers

seem to be increasing. The older you are when your allergies begin, the less likely you are ever to

throw them off. On the positive side, they are unlikely to get a great deal worse than they are at the

outset, especially if you take care of yourself and keep the air at home as unpolluted and

allergen-free as possible (see pp. 114-31).
In the case of asthma that develops in adulthood, there may not be an allergic reaction involved.

Whereas allergies play a part in asthma for 80-90% of children, the figure is thought to be lower for

adults. Nevertheless, it is well worth investigating the possible role of allergens, because avoiding

them is one of the most effective treatments.
The outlook for food intolerance
Food intolerance causes a wide variety of symptoms, from baby colic to migraine. A full list is given

on p. 76. Although far less is understood about food intolerance than about true allergies, there is

much more certainty about the future for affected individuals. With rare exceptions, people find that

the problem clears up as long as they totally avoid their problem food for a year or two. After this

period of strict avoidance, they can eat the food again in moderation but should never forget that the

problem can return. Eating the culprit food very regularly will turn the clock back and all the

original symptoms will return. This change for the worse may be irreversible for people with severe

reactions such as rheumatoid arthritis.
Safety first
Anyone who suffers the life-threatening allergic reaction known as anaphylactic shock (58) is probably

going
to have this for the rest of their days. Some children do become tolerant of food allergens in time

(allergies to milk, eggs or soya may well disappear, whereas fish or peanut allergy is probably going

to be permanent) but before concluding that there is no longer any risk, some extremely careful and

cautious testing should take place. Talk to your doctor about how to proceed. Skin-prick tests may be

helpful, but there must be resuscitation equipment close to hand as anaphylaxis can occur. Never give

the child any of the food to eat, until you (or, preferably, the doctor) have first tested it in other,

less risky, ways. For example, you can smear a little on the face to see if there is any reaction. If

there is none within 24 hours, put a tiny amount on the outer lip and watch again.
If both these tests produce absolutely no reaction then a very small amount of the food can be eaten as

a test: this should be done under medical supervision. The amount can be slowly increased with

successive tests, until it seems certain that no reaction will occur even with a normal portion.

`I can’t think of any of our friends where there isn’t at least one member of the family with asthma, and often it’s both children,’ says Dee Gill, a university lecturer from Melbourne, and herself asthmatic. Australia is one of the countries worst affected by the allergy epidemic. ‘If you go to a primary school sports day, you’ll see the teachers going along the line of kids, saying, “Have you taken your asthma medication?” It’s so much a part of everyday life now.’
The word ‘epidemic’ is now being freely used, even by the most conservative of medical scientists. All the classical allergic diseases seem to be on the increase, including:
• atopic eczema – in the United States, up from 3% of children in the 1960s to 10% in the 1990s; in Britain, more than 16% of 12- to 14-year-olds are now affected
• hayfever – extremely rare in the 1930s (26), affecting 3% of children in 1964, and now seen in 18% of 12- to 14-year-olds in many parts of the world
• asthma – the figures for children in one Scottish city are: 4% in 1964, 10% in 1989, nearly 20% in 1994
• peanut allergy has clearly been on the increase since the 1960s; a very alarming UK study shows that rates of allergy to peanuts have doubled in less than a decade (between children born in 1989 and those born in 1996).
To the question ‘why?’ there is no simple answer – the causes are many and various. But one thing is abundantly clear: this is a disease of modern, Westernised society. Travel to rural Africa or
Are other immune diseases increasing?
These two pages deal solely with the classical allergic diseases . Many doctors have the impression that eosinophilic disorders are also becoming more common, and some think that there are more cases of adult-onset coeliac disease than previously.
Asia, among people living a simple subsistence lifestyle, and you will find little or no sign of allergic diseases. There are no words in their languages for asthma or hayfever, because these are virtually unknown.
As soon as these people become more affluent, and change their lifestyle, allergic diseases appear, and the number of cases steadily rises over the years. Sometimes this coincides with a move to the towns, but it can also occur when people stay right where they are – as in Taiwan, where allergies rose dramatically with increasing affluence and a more Westernised way of life.
In the case of asthma, everyone is keen to blame air pollution, particularly traffic pollution. But a look at the research shows the link to be largely a myth. Certainly, polluted air can trigger off attacks in someone who already has asthma – but the effect is not huge, and this is not the same as causing asthma to develop in the first place. And while growing up in polluted air can increase the chances of children developing asthma, it makes only a small difference, one that simply cannot account for the massive asthma epidemic. The hollowness of the pollution argument is spectacularly evident when you consider rural New Zealand, where asthma rates are among the highest in the world, yet there are no factories, and sheep heavily outnumber motor cars.
Allergy to house-dust mites has also received a lot of publicity, and it does play an important part. Our warm, draught-free and thickly carpeted homes allow these tiny creatures to breed with abandon and many people with perennial rhinitis, asthma or atopic eczema have an allergy to dust mites. Recent research shows that dust mites play a far larger role than anyone previously suspected: the dust-mite allergen actually provokes immune cells, and once an allergy to dust mite has begun, other allergies become more likely.
But blaming house-dust mite as the supreme cause of the allergy/asthma epidemic (as some do) is as mistaken as blaming pollution. The proof in this case comes from the highlands of New Mexico where dust mites cannot survive because the air is much too dry. Allergies, including asthma, are just as common as elsewhere in the Western world.
Spoiling the immune system
Thanks to discoveries made during the past decade, we are now beginning to understand what has made the younger generations – those born since the early 1960s – so much more susceptible to allergies. The new data reveal that the way you bring up a child’s immune system matters as much as the way you bring up the child itself. You can ’spoil’ an immune system all too easily, by protecting it from life’s natural challenges and obstacles.
As a small child, I ate a spoonful of soil. My mother was horrified (she was still telling the story twenty years later) but research now shows that she should not have been. Exposure to certain bacteria in the soil, known as mycobacteria, is probably just the kind of education that a young immune system needs. These bacteria cause no 111-health, no symptoms at all, but they are thought to have an effect on the immune system, pushing it away from allergic reactions.
Children playing outdoors have probably always eaten soil, either intentionally or by accident – licking a grubby finger. Country people used to say, philosophically, ‘You eat a bushel of dirt before you die’, and they were probably right. Indeed, you may well need to eat a bit of dirt before you can live happily in an allergen-packed world. Now researchers are trying to make a vaccine using soil bacteria, to simulate this effect.
A study from the University of Bristol shows that children who wash their hands more than five times and have two baths a day are almost twice as likely to get asthma as children who wash their hands less than three times a day and have a bath every other day. The grubbier children are probably being protected from asthma by acquiring minor infections, with few or no symptoms. These infections could include both soil bacteria and germs that are spread from one child to another.
Other research reveals that children with older brothers and sisters are less likely to suffer from certain allergic diseases than only children or firstborn children. This may be due, in part at least, to the spread of infectious diseases, because mixing with lots of
other children in a nursery produces more infections but also gives protection against allergy. Studies from the former East Germany, where sending children to day nurseries at an early age was once the norm, demonstrate that if children from small families went to nursery aged 6-11 months they were substantially less allergy-prone than if they went later. The allergy risk was highest for only children who did not go to nursery until they were over two years.
Researchers in Colorado have recently tackled this subject from a different angle completely, analysing house-dust for the levels of bacterial endotoxin – substances that come from certain kinds of bacteria and which have a powerful effect on the immune system. If the house-dust contained high levels of endotoxin, babies brought up in that house were less likely to give positive skin-prick tests to common allergens such as cats, milk or house-dust mite. The babies from very clean houses, with low levels of endotoxin in the dust, were the ones with allergic reactions. (Fortunately, it is possible to have a dusty house with very little house-dust mite)
The hygiene hypothesis, as it is known, could also explain the strange history of hayfever. For the first century of its existence, hayfever was a disease of the urban upper classes, only gradually working its way down to the poor and to rural communities: this fits in well with the gradual spread of more hygienic ways of life. In most parts of the developed world today, it shows no class distinctions, but recent investigations have found a lower rate of hayfever among children raised on a farm with animals compared to children living in the same villages without farm animals.
In addition to greater hygiene, the following aspects of modern living appear to promote an allergic tendency in children:
• smoking by the mother during pregnancy and after, which may boost IgE levels
• breathing nitrogen dioxide from gas cookers, and formaldehyde from various household sources ; exposure to substances called phthalates, from plastics, may also be important; the poor ventilation of many modern houses, and the far greater time spent indoors aggravates the problem by increasing exposure to these irritants, and to allergens such as house-dust mite and moulds.
• taking antibiotics during the first two years of life
• bottle-feeding and/or abrupt and early weaning
• exposure to a virus called Respiratory Syncytial Virus (RSV) during infancy, which provokes an IgE-reaction (37)
• caesarean births; simply being born in a hospital might also raise the risks by exposing newborn babies to Staphylococcus, which adversely affects the immune system.

`When I first arrived in Charlottesville in 1982, the senior allergist said “I’ve got to warn you that here in Virginia we have patients who have very severe fungal infection of their feet, and they also have urticaria. If you treat their feet, their urticaria gets better.”‘ Professor Tom Platts-Mills of the University of Virginia in Charlottesville is recalling how his innovative studies of fungal infections and allergy began. That surprising observation about athlete’s foot (a fungal infection) and urticaria (nettle rash) was made by his predecessor, Professor John Guerrant,
‘I followed his advice,’ Platts-Mills continues, ‘and found he was right. Then I started noticing asthmatics in our allergy clinic who also had fungal infections of their feet. They were mostly men with severe adult-onset asthma. We gave them skin-prick tests with the fungus Trichophyton and these were positive – showing they had an allergic reaction to it. So we tried treating them with anti-fungal drugs and the asthma got much better.’
This discovery is not an isolated instance. Research over the last decade or so has revealed that allergic reactions to long-standing infections (chronic infection is the medical term) are far more common than anyone expected. Infections by fungi are frequent offenders.
An infection becomes chronic because, although the immune system tries to rout the infectious agent, it never succeeds. Making IgE may be part of that futile defensive effort. Once the immune system starts making IgE against the allergens produced by the infectious microbe, new symptoms may begin, or existing allergic symptoms may get much worse. The link between the infection and the allergy is far from obvious, however. Both the allergens and the IgE can be carried in the
Fungal infections
‘Fungus’ means everything from an edible mushroom or a huge bracket fungus to the specks of mould on stale bread or a shower curtain. Fungal infections are caused, not by mushroom-like fungi, but by inconspicuous mould-like forms, or by yeasts (which are single-celled fungi).
Once they are flourishing, some fungal infections may be seen as whitish or creamy-coloured patches. But at an earlier stage, the fungi are so small that they cannot be seen without a microscope. They spread as invisibly as bacteria or viruses.
Some infectious fungi can exist in two different forms – a mycelial form (long thin strands, as in a mould) or a yeast form (single cells).
bloodstream, so the symptoms may be somewhere else in the body, far away from the site of infection.
If the symptoms of the infection itself are relatively mild, they may not receive medical attention. Infection-plus-allergy often explains severe long-term allergic problems for which no cause could previously be found. This is the kind of case that gets labelled as ‘intrinsic’ or ‘endogenous’, because all the allergy tests have proved negative. Most patients in this category have had years of simply being treated with steroids (often at high doses) to suppress the symptoms.
Sometimes the infection-plus-allergy is part of a larger picture, with other allergens or irritants also contributing to the symptoms, but with no stunning improvements when they are avoided because the allergic stimulus from the infection remains.
The links between allergy and fungal infections – all those that have been discovered so far – are described below. In such cases, anti-fungal drugs, taken by mouth, usually in capsule form, could be of value. However, they must be taken for an adequate length of time, normally several months.
Bear in mind that, with the possible exception of chronic sinusitis, an allergic reaction to fungal infection is a relatively uncommon cause of symptoms. It is important that, with the help of your doctor, you start with the more likely suspects such as airborne or contact allergens. These are described in detail, for each allergic disease, in the relevant sections of Chapter 2.
Asthma
the common causes and usual treatment of asthma.
Trichophyton – the fungus that causes athlete’s foot – can provoke allergic reactions that contribute to asthma, as already described. This fungus may also infect other parts of the body. Trichophyton diseases have names that begin with tinea (athlete’s foot, for example, is tinea pedis). Other terms you may come across are intertrigo (an itchy rash which develops in skin folds) and onychomycosis (also called `ringworm of the nails’ or tinea unguinum). The research on the link with asthma was published in a respected medical journal, The Lancet, but has been widely ignored, so if you think you have this problem, you may have to be quite persistent with your doctor. Very thorough treatment with anti-fungal drugs (swallowed in capsule form) is required.
Chronic urticaria
many possible causes of chronic urticaria.
Trichophyton infections in any part of the body (see above) can provoke allergies, producing chronic urticarla. A great variety of other infections, including fungal, viral and chronic bacterial
infections, can be the root of the problem in chronic urticaria . However, this may not be an allergic reaction. It could be a direct effect of the infection, provoking the immune system in such a way that it triggers mast cells by itself, without IgE.
Chronic sinusitis
 the causes and treatment of chronic sinusitis.
Long-standing (chronic) sinusitis may be due to a fungal infection with a subsequent allergy. This is now called allergic fungal sinusitis. Some doctors believe that a sensitivity reaction to fungal infection (not necessarily an allergic reaction) could account for 96% of chronic sinusitis. However this is widely disputed .
Atopic eczema (atopic dermatitis)
the causes and treatment of atopic eczema.
The Trichophyton fungus can infect eczematous skin, though this is far less common than infection by Staphylococcus aureus (see below). Among patients infected by it, there can be an allergic reaction to Trichophyton which then makes the eczema worse.
There can also be an IgE reaction to a yeast, Pityrosporum ovale (also called Malassezia ovalis), in atopic eczema. This yeast is a commensal – i.e. a natural, and normally harmless, inhabitant of healthy skin. The inflammation of eczema makes the immune system far more tetchy so that it reacts allergically to this yeast, an innocent bystander which it normally disregards.
Candida  can also provoke an allergic reaction in eczematous skin. This is a more complex story, because while Candida is a commensal in the gut, it does not normally live on the skin. However, it may flourish in the disturbed skin of eczema patients.
Those with atopic eczema may also develop an allergic reaction to toxins from Staphylococcus aureus, a bacterium that often infects skin which is inflamed by eczema and damaged by scratching. Antibiotics are needed to treat the infection .
Seborrheic dermatitis
Not so long ago, this disease – which causes a red, scaly rash on the forehead, nose and cheeks, and sometimes on the chest –was labelled ’cause unknown’. Now most doctors believe that the yeast Pityrosporum ovale could well have a role in causing it. This yeast is part of the normal skin flora (see above), but it is found in greater numbers on the skin of seborrheic dermatitis patients. As well as overgrowth of the yeast, there is an immune reaction against it, usually involving the antibody known as IgG, rather than Fungi in the lungs
One form of infection-plus-allergy has been well recognised for many years - allergic bronchopulmonary aspergillosis, often shortened to aspergillosis.
The problem starts with the fungus Aspergillus fumigates, a ubiquitous mould that is found in special abundance in damp straw, compost heaps, bird cages and any decomposing material. Its spores are everywhere, and most immune systems quickly defeat them, but in some people, especially those with asthma, the spores begin to grow in the lungs. The fungus is found in the lung mucus, but does not actually invade the lungs. However, an allergic reation then occurs to the fungus.
This disease often goes together with asthma, or can be mistaken for asthma. There are three clues that point to aspergillosis:
• rubbery plugs of phlegm, either golden-
brown or green in colour
• fever whenever the asthma is severe
• worsening symptoms despite treatment.
Allergic bronchopulmonary aspergillosis is treated with steroids to control the allergic reaction, and physiotherapy to clear the mucus from the lungs.
Anti-fungal drugs have not proved very effective in the past. There are some newer anti-fungal drugs that may well be more useful, such as itraconazole and terbinafine. These are not widely used for aspergillosis at present, except in patients who also have cystic fibrosis or an immune deficiency. Because there has been no large-scale trial of these drugs, they are not usually given to people who simply have aspergillosis. However, they are sometimes prescribed for people who are unable to take steroids, or are not responding to steroid treatment. Anti-fungal drugs may become more widely used in the next few years, so it is worth discussing the possibility of this treatment with your doctor.
the allergy antibody IgE. Only about 12% of people who suffer from seborrheic dermatitis make IgE against the yeast.
One problem with seborrheic dermatitis is that, while it may improve with anti-fungal treatment, it usually comes back when the treatment stops. Doctors have therefore been looking for ways of keeping seborrheic dermatitis at bay after a successful course of anti-fungal treatment. One method that seems to work is to use a good anti-dandruff shampoo, in place of soap, to wash your skin once a week.
A medical earthquake
The recent discoveries about infection-plus-allergy have not posed any serious challenge to conventional thinking about allergy, because a disease of just this kind - aspergillosis (see box at left) - was already well known. A far more fundamental shake-up of traditional ideas about allergy and sensitivity has been necessitated by new research into atopic eczema. It is little short of an earthquake in the basic concepts of allergy and sensitivity.
To understand the extent of this earthquake, you need to know about the time-honoured system for classifying hypersensitivity reactions, which recognises four distinct types:
• Type I hypersensitivity — the IgE-mediated allergies  such as hayfever.
• Type II hypersensitivity - irrelevant to allergy, these antibody reactions mainly occur after transplant surgery, if the transplanted organ is rejected.
• Type III hypersensitivity - caused by a massive overload of antibodies and antigen in the blood. It is a feature of certain infections and autoimmune diseases, and can also occur in allergic reactions, though this is rare (13).
• Type IV hypersensitivity - the odd man out, because antibodies are not involved, or are not of central importance. Immune cells that can launch a direct attack are the movers and shakers here. These attacking-cells are sensitised for a particular antigen, such as dust mite or lanolin. Type IV hypersensitivity is a very slow reaction. Generally speaking, 48 hours pass, after an encounter with the offending substance, before the symptoms appear. The most common form of Type IV hypersensitivity is contact dermatitis (54).
Mystery has always surrounded atopic eczema. Although it crops up in the same atopic families that suffer from hayfever and asthma, and high levels of IgE in the bloodstream are typical of the disease, the actual role played by allergies in causing the symptoms is far from obvious.
The results of skin-prick tests - the standard test for an IgEmediated reaction - are puzzling. Patients tend to give a lot of positive results, many of which don’t mean much - the substances concerned do not provoke actual symptoms. On the other hand, skin-prick tests are often negative for substances that clearly do cause symptoms in challenge tests. Many children who regularly get eczema when they drink cow’s milk, for example, give a negative skin-prick test to milk. This conundrum has puzzled allergists for decades.
New discoveries about eczema do not entirely solve the puzzle, but they do go some way towards an answer, by revealing an immune response that cuts across the traditional categories. The most surprising fact is that even where skin-prick tests are positive and milk-specific IgE is involved in milk-induced eczema, this is not necessarily a standard IgE-mediated allergy.
While IgE antibodies may be involved, they are not necessarily teamed up with mast cells, their usual partners in crime (see box on p. 12). Instead, the IgE molecules are attached to special skin cells called Langerhans cells and dendritic cells. These have the role of picking up the antigen and showing or ‘presenting’ it to attacking-cells in the skin (a task called antigen presentation which is the ‘go’ signal that starts off all immune reactions).
The involvement of these attacking-cells, which are sensitised for a particular antigen, was a big surprise when first discovered. It makes this resemble a Type IV hypersensitivity reaction rather than a Type I.
IgE is not essential here, it seems — some patients do not have IgE for the substance that triggers their atopic eczema — but when Langerhans cells and dendritic cells are associated with IgE they do become far more zealous. This excitement is communicated to the attacking-cells, which mount a more powerful attack.
It looks as if what really matters in atopic eczema is the presence of antigen-specific attacking-cells in the skin, plus the heightened activity of the Langerhans cells and dendritic cells. If the individual has IgE for the antigen, it can play a part, but it is not essential.
In other words, this reaction cuts across two different categories of immune response — Type I and Type IV. (However, the kind of antigens that provoke the reaction are typical of IgEmediated allergy, rather than the kind of antigens that provoke contact dermatitis.) This has been exploited in a new and more sensitive set of diagnostic tests for food-induced atopic eczema (69).
Why atopic eczema is a feature of atopic families is the crucial question that remains unanswered. One factor may be that high levels of IgE in the bloodstream (not IgE for a particular allergen, but total IgE) make the whole immune system more excitable and prone to over-react. The next few years will no doubt solve this part of the puzzle too.
Peace-keepers or aggressors?
`It is bad enough having a child on an ultra-strict diet — Tim can’t have even a trace of cow’s milk or else he becomes violently ill. What makes it worse is when people — teachers, for example —ask what’s wrong. I take a deep breath and say “eosinophilic oesophagitis” then watch their eyes roll in disbelief.’
Tim’s disease is caused by a particular type of immune cell called an eosinophil. In the right circumstances, eosinophils can be valuable — like IgE and mast cells, they are geared to destroying parasitic worms . They produce some very toxic substances to kill these invaders, and it is the toxins that cause serious symptoms for Tim and others like him.
Any disease with ‘eosinophilic’ in the name involves vast numbers of eosinophils converging on some unfortunate part of the body. The stimulus that attracts them often remains unknown but once there, the toxins they generate cause inflammation (140) of a particularly violent kind.
It is only in recent years that doctors have begun to distinguish between patients such as Tim and children with classical food allergy, and to understand the cause of Tim’s symptoms. Several different forms of eosinophilic food sensitivity are now recognised (72). The exact relationship with IgE-mediated allergy remains a puzzle, because some sufferers make IgE to the culprit food but others do not.
That is not all — the eosinophil is finally coming out of the shadows and being recognised as an important agent in classical allergic diseases as well.
The fact that eosinophils appeared during the aftermath of an allergic reaction had long been known, but their role was misunderstood. What confused researchers was that eosinophils can break down histamine, the substance that kick-starts allergic symptoms. This ability gave eosinophils the appearance of peacekeeping troops, coming in at the close of battle to restore order. In fact, eosinophils are major aggressors — they do a whole lot of other things besides breaking down histamine, most of them pro-inflammatory. They can release toxins, just as they do in eosinophilic diseases, and they attract other inflammatory cells into the area. In short, eosinophils play a big part in keeping allergic reactions going once the initial burst of activity is over. This `Late Phase Reaction’ is enormously important .

Cross Reactions in Allergy

For the rabbi’s doctor, discussing the results of the allergy tests with his patient, it was an embarrassing moment. An allergy is not inborn, it is an acquired reaction — a response by the immune system to a substance it has already encountered at least once. So, in theory, nobody can be allergic to a food they have never eaten.
Naturally enough, the rabbi had never eaten shellfish - like pork, it is a forbidden food in Judaism. But the nurse carrying out the skin-prick tests was unaware of this, and she had been told to test for all the common food allergens, so shrimp allergen was included. The test came up positive.
Fortunately, the rabbi had also been tested for inhaled allergens and had given a very strong positive reaction to house-dust mite. The likely explanation was clear: the rabbi had formed antibodies to a muscle protein of house-dust mite called tropomyosin, which is also found in shrimps and prawns. His antibodies against house-dust mite had cross-reacted with shrimp tropomyosin.
This does not mean that everyone who is allergic to house-dust mite will also react to shrimp. Firstly, they must have made antibodies to tropomyosin, rather than some other dust-mite antigen. Secondly, the antibodies must be recognising a particular feature of dust-mite tropomyosin that closely resembles (chemically speaking) a particular feature of shrimp tropomyosin.
The important point about antibodies is that, on the one hand, they achieve results by being specific for their antigen , but on the other, they do make mistakes. In the case of allergies, this is sometimes an added problem for patients but is rarely life threatening. More seriously, there are other conditions, like coeliac disease, where cross-reactions initiate attacks on the body’s own components, causing severe symptoms.
Antibodies make mistakes because they recognise antigens by homing in on tiny chemical markers, not by looking at the antigen as a whole (see box on p. 15). Although this is a nuisance for allergy sufferers, it can be a bonus in fighting diseases. For example,
Antigens and allergens
An antigen is anything which elicits an antibody reaction. Each antibody is specific for a particular antigen.
When they tend to cause allergies (by provoking IgE antibodies rather than other kinds of antibody -  these antigens are called allergens. Something such as grass pollen is both an antigen (because it elicits an antibody reaction) and an allergen (because it often elicits IgE antibodies in those who are allergy-prone).
when viruses (such as those that cause influenza) revamp their outer coat proteins to evade the immune system, the chances are that some antibodies will still recognise them because a few of the original chemical markers persist.
Understanding cross-reactions
Many cross-reactions are between related species, and this makes sense in biological terms. The tropomyosin story is a good example - not only is tropomyosin found in dust mite and shrimps, but it also occurs in other crustacean shellfish, such as crabs and lobsters, in molluscan shellfish such as clams and oysters, and in insects. If one goes back over 300 million years, all these animals were just a twinkle in the eye of some primeval invertebrate, the common ancestor of them all.
Tropomyosin is one of those triumphs of the evolutionary process - a protein that reached near-perfection hundreds of millions of years ago, in the long-vanished ancestral species, and remains so good at its job that it has only been tinkered with by natural selection since then, never radically altered. In other words, because it works so well, it has been ‘conserved’ by the various animal groups descended from the shared ancestor. Although there are some differences between the tropomyosins from different descendants, the similarities are considerable.
Relatedness counts here. Shrimps and prawns are pretty closely related, as anyone can see by looking at them. Their tropomyosins are extremely similar, as are many other allergens. You’re unlikely to be allergic to prawn but not shrimp. The more distant the relationship, the more differences accumulate in the antigens, so a cross-reaction between dust mite and shrimp is far less likely (the rabbi was unlucky).
Another conserved protein, parvalbumin, explains why people who are allergic to one type of fish are usually allergic to all kinds of fish (in spite of the fact that fish belong to several different families which are only distantly related). Those allergic to hen’s eggs will probably be allergic to the eggs of all birds, because the primary allergens (e.g, ovalbumin) are so similar.
These conserved proteins produce cross-reactions across huge gulfs, in terms of zoological and botanical relationships. Far more easily understood are the cross-reactions between close cousins, such as dust mite and storage mites, wheat and rye, pine pollen and pine nuts, or ragweed and sunflower (both members of the daisy family).
Relatedness can be useful in explaining cross-reactions, but often fails when it comes to predicting them. Some related species do not show as many cross-reactions as one might expect. Peanuts are legumes, and highly allergenic. One would expect some peanut-allergic individuals to be allergic to other members of the legume family, such as peas, beans, carob and soya. In fact, although some patients give positive skin-prick tests, very few show actual symptoms when they eat these foods. Where symptoms do occur, they tend to be mild.
Paradoxically, those who are allergic to peanuts very often develop an allergy to tree nuts, and this usually spans several different kinds of tree nuts – yet botanically all these are very distant relatives. No tree nut is a legume and while walnuts and pecans belong to one plant family, almonds belong to another, hazelnuts to another, cashews to a fourth, and Brazils to a fifth different plant family. Here relatedness seems irrelevant, and it is shared lifestyle (surviving as a nut-producing plant) that is crucial.
A nut is just an over-sized seed that has to survive being buried in the soil – either by the plant itself (in the case of peanuts) or by a nut-eating animal such as a squirrel. All nuts must resist rotting in the soil until the following spring, and therefore contain powerful bactericidal and fungicidal compounds. Some of these may have chemical similarities that cause cross-reactions.
These functional ‘lifestyle’ allergens of nuts may be even more widely shared, with many seeds having something similar: recent research shows potentially cross-reacting allergens in wheat, rye, hazelnuts, sesame and poppy. It is interesting that many of those developing new allergies to sesame or poppy are already allergic to wheat and nuts.
A few cross-reactions seem to defy any explanation, such as that between house-dust mite and kiwi fruit – this appears to be just a case of chemical coincidence. Other cross-reactions can appear equally bizarre but actually have a biological basis, notably that between latex (as used in medical gloves) and various fruits and vegetables, principally chestnut, banana, avocado and kiwi fruit. This cross-reaction is due to a shared enzyme called a chitinase that protects plants against insect pests. Latex, of course, comes from the sap of the rubber tree: the tree needs such insect-protection and its sap is richly laced with chitinase.
How antibodies work - and why they make errors
Antibodies are catapult-shaped, with two antigen binding sites at the ends of the two arms. The other end of the antibody molecule – the handle of the catapult – is free to bind to cell receptors.
When an antibody binds to its antigen there is a ‘chemical handshake’: a very specific recognition event involving one of the antigen binding sites and a particular small site on the antigen molecule called the epitope. The two lock together. Different antibodies may recognise different epitopes.
The antibody is recognising its antigen, but it is as if we recognised other people by homing in on one small part of them, choosing a different feature for each person, whatever is most distinctive about them – the quirky right eyebrow, the hook in the nose, or the mole on the cheek. The antibody does not ‘look at’ the whole antigen molecule, but simply recognises a characteristic cluster of chemical features at the epitope.
Cross-reactions can occur so readily because an antigen molecule only has to resemble another molecule in one or two small areas (the epitopes) for a mistake to occur.
antigen antibody molecule binding sites
cell receptor antigen molecule
epitope
surface of immune cell
(e.g. a mast cell)

how does allergy begin?
A mast cell, magnified about 10,000 times. The black granules contain histamine.
`At the beginning, I thought I just had a cold. I kept sneezing and coughing, and my nose was dripping. It got better at the weekend, and I thought — that’s good, it’s gone — but then on the Monday evening it started up again. The next thing I knew, I kept getting breathless. I’d been at the sawmill a month when it began. We were cutting planks of red cedar all day, and the dust was bad, it’s true. But I didn’t know that sawdust could cause you allergies. We were given dust masks, but they made you too hot. No one wore them. I found out later, from the doctor, that some men could work years at it before they got allergic to the dust, but with me it was just a month.’
Like many people with work-related allergy, Dan can actually pinpoint the time he became sensitised – when he began making IgE antibodies against the red cedar dust allergen. For allergies that are not caused by workplace allergens, this is rarely possible. The moment when symptoms begin may be obvious, but that is often long after sensitisation (making IgE to the allergen) first occurred. Long-term studies of children show that they may start giving positive skin-prick tests to pollens (a sign that they are making IgE to those pollens) while they are toddlers, but not develop hayfever until ten years later.
The basics of immunity
The immune system defends the body against infections and cancerous cells. One of its key jobs, before going on the offensive, is to recognise the difference between:
• self and non-self (e.g. the cells lining the lung, and bacteria trying to infect the lung)
• safe-non-self (e.g. a sandwich) and dangerous-non-self (e.g. Salmonella bacteria in the sandwich).
Through mis-regulation the immune system can cause:
• allergies (perceiving safe-non-self, such as pollen, as dangerous-non-self)
• autoimmune diseases (perceiving self as non-self).
The immune system consists of dozens of different kinds of cells (the immune cells) and a number of different antibodies – specialised ‘guided missiles’ (see box on p. 15) which are produced by certain immune cells.
There is also a huge array of messenger chemicals, which send general instructions (e.g. ‘calm down!’, ‘go for it!’ or’exterminate!’) from one type of cell to another.
Immune cells are self-contained units, many of them mobile and dispersed throughout the body. They travel around in the blood, and can move out of the blood vessels and into the surrounding tissues (skin, lung, nose, etc.).
These different components – immune cells, antibodies and messenger chemicals – interact in very complex ways. When an immune reaction occurs – i.e. the immune system recognises something, or mounts an attack on something – numerous different players are involved. All the reactions described in this book are very simplified versions of what actually happens.
Research shows that the first two years of life is the most vulnerable time as regards sensitisation to allergens. Very often, sensitisation occurs in the first few months, and sometimes even before birth.
Why is a young infant so easily sensitised? The answer lies not with the baby, but with the pregnant mother-to-be, whose immune system has to overrule its natural inclination to attack anything that is non-self. Potentially, a woman’s immune system could reject a foetus in just the same way that heart transplants are rejected. To prevent attacks on the foetus, the immune system is re-tuned during pregnancy, with one aspect of immunity – the part that’s most keen to attack a foreign body – being damped down.
This aspect of immunity is coordinated by cells known as T-helper-1 cells, or Th1 cells for short. To protect the foetus, these Th1 cells are asked to ease up during pregnancy. Meanwhile, since immune protection is still needed, their colleagues, called T-helper-2 cells or Th2 cells, become more active.
The classical allergic diseases
These four pages are concerned only with the classical allergic diseases, that is:
hayfever (an allergy to pollen)
perennial allergic rhinitis (a nasal allergy to a year-round allergen such as house-dust mite)
asthma where this includes an allergic reaction atopic eczema (42)
urticaria (nettle rash or hives) where this is allergic in origin, and the accompanying angioedema (swelling due to fluid escaping from tiny blood vessels into the surrounding area; it is sometimes called ‘water retention’)
anaphylaxis (a violent allergic reaction to food, insect stings, penicillin, latex, etc.)
food allergy (in most cases, an immediate and marked reaction to food, with symptoms in the mouth; there may also be anaphylaxis).
Running the immune system
T-helper cells are, in a way, mis-named, because they do not help at all – they just give orders.
These are the supervisors of the immune reactions, telling other immune cells either to lie low or to get busy. Where Th1 and Th2 cells differ is in the types of immune cells they send into action. Among those who get their go-ahead from Th1 cells are immune cells that attack directly, without producing antibodies – these are the ones that reject transplants and could, if given free rein, reject a foetus or retard its growth.
The Th2 cells, on the other hand, have among their preferred troops the immune cells that produce IgE antibodies – the allergy-causing antibodies. So one effect of protecting the foetus from rejection is to push the immune system towards a greater tendency to allergy.
This shift of emphasis occurs in the mother’s immune system, but it carries over into the immune system of the foetus because they are sharing the same blood supply, and the blood contains the messenger substances which fine-tune the immune system. Immediately after birth, the baby’s immune system is still following the same pattern, continuing to upregulate Th2 cells and downregulate Th1 cells. This is a crucial factor in setting the stage for allergic sensitisation.
Ideally, the world that the baby encounters just after birth should nudge the immune system in the opposite direction and get it operating in a non-allergic way. But the world in which we live is far from ideal in this regard.
For one thing, it is much too clean. As far as the immune system is concerned, ‘ideal’ would mean encountering quite a bit of dirt, such as garden soil, in the early stages of life. The soil contains harmless bacteria which do not cause any symptoms, but do tweak the immune system towards Th1 cells and away from Th2 cells. Bacterial products in household dust may do the same thing (21).
A long period of consuming nothing but breast milk would also suit the baby’s immune system rather better than being fed on cow’s milk formula or being suddenly weaned onto a number of highly allergenic foods, such as egg, wheat, soya (ubiquitous in The basic cause of classical allergy is an immune reaction involving mast cells and IgE antibodies.
Mast cells are plentiful in the lining of the nose, the airways, and the digestive tract. They have counterparts in the blood, called basophils.
Seen under the microscope, both mast cells and basophils look very granular inside. The granules are tiny storage compartments, containing stockpiles of messenger chemicals, notably histamine.
Histamine causes several different reactions:
• contraction of muscle around the airways. This reduces the diameter of the airway, producing an asthma attack.
• widening of blood vessels
• increased leakiness of the smallest blood vessels, allowing fluid and immune cells to escape into the surrounding area – for example, the skin or airway lining
• as a result of these two above effects, local swelling (called oedema or angioedema) and irritation – in the skin this is experienced as urticaria, or nettle rash, in the nose it causes blockage, itching and sneezing
• if sufficient histamine is released into the blood, a drastic fall in blood pressure, due to widespread opening of blood vessels, and leakage of fluid into the tissues; this occurs in anaphylaxis (58).
Histamine is released when mast cells are activated, a process called degranulation because the cells discharge their storage granules.
Mast cells release other substances at the same time, some of which attract more immune cells to the area, causing more inflammation. They help to produce a ‘Late Phase Reaction’ which occurs after the initial allergic reaction has died down, and lasts about 24 hours (13). Once activated, mast cells also start making messenger chemicals called leukotrienes which are highly inflammatory.
What causes a mast cell to degranulate? The answer is found on the surface of the cells, where the allergy antibody, IgE, sits. One end of the IgE molecule is bound to the mast cell, and the other end can bind to the allergen concerned. In someone allergic to egg, for example, egg allergen will bind, with great specificity, to egg-specific IgE antibody.
For the receptors to pass a message to the mast cell there have to be two IgE antibodies specific for the same allergen on the mast cell – and the allergen has to bind to both these IgE molecules, cross-linking them. This is the ‘go’ signal for the mast cell to degranulate.
processed foods), fish or peanuts, before it can handle them. Not taking antibiotics before two years of age would also help (although it might, of course, be very bad for the baby in other ways). Exactly why is not yet fully understood .
An ideal world for the immune system would also lack the by-products of cigarette smoking, whether in the blood of a pregnant woman or in the air that a baby breathes – both seem to promote the allergic tendency. In addition, the perfect world would lack central heating, fitted carpets, draught-proofing and thick upholstery. A house like this is heaven for house-dust mites but not for innocent young immune systems.
The problem with house-dust mites – apart from the fact that they breed like wildfire, and hole-up in mattresses, armchairs and soft toys – is that they produce a highly allergenic protein in their droppings. This protein interferes with the membranes of cells, making them less stable. It irritates various immune cells, including mast cells (see box at left), and can even make mast cells degranulate, as if there were a true allergic reaction happening.
Once mast cells have done this, they release messenger substances that arouse the immune system and make a genuine allergic reaction –beginning with the production of IgE to the dust-mite allergen – much more likely. In other words, dust-mite allergen is an agent provocateur, an aggressive substance that actually provokes the immune system into reacting allergically.
Until recently it was widely assumed that allergens were just inoffensive, passive substances which the immune system happened to take objection to, in a distinctly unreasonable way. The new discoveries about dust-mite allergen raise the question: could other allergens be more aggressive than previously thought? Certainly the peanut allergen, or other substances found in peanuts, seems to destabilise cell membranes, which may explain why this allergen so easily sensitises young children.
The role of genes
Faced with this non-ideal world, many children pull through without developing allergies, but others do not. This is where genes come in, making one child more susceptible to our allergy-promoting lifestyle and another child less so. Exactly how the genes make this difference is still not fully understood, but there are at least twenty genes involved , and it is clearly going to be a complex story. The overall effect of these genes is a greater tendency to make IgE, combined with mast cells and basophils  that are distinctly trigger-happy –much more eager to degranulate than in healthy individuals.
Given all the mayhem caused by mast cells and IgE, why does the body produce them at all? They cause a lot of damage to allergy sufferers and do little apparent good, at least for people in the Western world. The value of the mast-cell-IgE-reaction, for most of us, is historical – it wages war against large-bodied parasites such as tapeworms and schistosomes. (They are large by comparison with bacteria and viruses, and not easily tackled by other immune cells.) These unpleasant invaders have largely been eliminated in the developed world but are still rife in other countries. For millions of years such parasites were an inevitable part of human life, and this bit of our evolutionary past survives in our immune system.
The complexity of allergic reactions
`Each time the pollen season came around. I would start to get these pains, especially in my knees. I asked my doctor about it but she just looked at me rather oddly and said “take a paracetamol”. I couldn’t be sure it was linked to my hayfever, but the pains always came on just after the sneezing started. One year, it was all worse than usual, and I felt very tired too. My face was all puffy and I could feel that something was seriously amiss. That, as I now know, was because my kidneys were being affected. It was years before the doctor would refer me to an allergist, and I actually got an explanation for all this. I think for a long time my doctor thought I was making it up, or just imagining the pain in my knees.’
Karen suffers from a rare complication of hayfever involving an overload of pollen antigens and antibodies in the blood. Very large numbers of both are involved, and are bound to each other in dense tangled masses called immune complexes. Because these are carried around in the blood they are known as circulating immune complexes. They may be too large to be cleared quickly by the normal junk-munching systems that keep the blood clean.
Like a river choked with fallen leaves, which deposits some of the debris on its banks as it flows past, the blood inevitably
The other antibodies
Other than IgE, four main types of antibody exist – IgA, IgD, IgG and IgM. Although some of these antibodies help fight bacterial and viral diseases, they lack IgE’s ability to tackle certain large parasites. These other antibodies do not generally bind to mast cells, and therefore do not cause IgEstyle allergy. But they can be involved in various other sensitivity reactions – it is IgG antibodies that are active in coeliac disease for example, and IgA in dermatitis herpetiformis. And any kind of antibody can participate in circulating immune complexes, causing multiple symptoms (see below).
leaves behind some of the circulating immune complexes. They mostly become deposited in the tiny blood vessels called capillaries, particularly those in the skin, the kidneys and the joints. Inflammation (140) here can cause a range of symptoms.
This problem is known to doctors either as serum sickness or as Type III hypersensitivity. It is a well-known feature of several infections and of some autoimmune diseases.
Unfortunately, the potential for Type III hypersensitivity in allergies such as hayfever is much less well known among doctors, as Karen discovered. As well as affecting hayfever sufferers, Type III hypersensitivity can also be a complication of reactions to penicillin and certain other allergic reactions, such as insect-sting allergy.
When a reaction occurs to snake anti-venom – and it only occurs in an individual who has received snake anti-venom before – this too is Type III hypersensitivity. The snake anti-venom is cultured in horses, and the snake-bitten human who has received the snake anti-venom previously mounts a massive immune reaction to the horse proteins when snake anti-venom is injected for a second time. Large and numerous circulating immune complexes are formed, and although IgE is not involved, a very severe anaphylactoid reaction (see box on p. 59) follows.
Circulating immune complexes do not affect most allergy sufferers. But there are other immune responses that follow on from the initial allergic response in everyone with allergies –they are generally summed up as the ‘Late Phase Reaction’. This reaction starts 4-12 hours after the exposure to the allergen, and lasts about a day. It involves a number of different immune cells (including eosinophils – p. 19) and an even more varied array of messenger chemicals, making everything very complicated for medical researchers to investigate. When allergic symptoms become entrenched and difficult to treat, the Late Phase Reaction is usually implicated. But it has not been given much attention by doctors until recently, because the details are so complex and so poorly understood.

Allergies and
inheritance
WHY IT RUNS IN
FAMILIES
`My father had asthma as a child, and his sister had it too. In fact she died from it. My mother has never had any allergies, but one of her brothers had terrible hayfever all his life. Out of us four, only my brother Peter is completely allergy-free. I had bad eczema when I was small, as did my sister. So when our son developed eczema, and then asthma, and an allergy to house-dust mite which made his nose run all the time, I wasn’t entirely surprised.’ What Janet’ is describing is a good example of an atopic family — one where classical allergies, of one kind or another, affect several family members. The members of such a family are called atopics.
Atopics have an underlying tendency to allergy which, with luck, may never be expressed. But if they are unlucky, the tendency will lead to allergies, which can settle on the skin (atopic eczema), the nose (hayfever or perennial allergic rhinitis), the airways (asthma) or the mouth and digestive tract (food allergy). These diseases, which recur down the generations in atopic families like Janey’s, are known as the classical allergic diseases.
The atopic tendency is coded into our DNA –in the genes that are passed from parent to child. There are also other genes that make asthma more likely to develop, and these can work in concert with the allergy-promoting genes to produce asthma in a child. And there are probably genes for dry skin, which contribute to atopic eczema.
Genes alone are not enough, however. Environment (which means, in medical terms, everything external that affects an individual,
including diseases, diet, air, allergens such as dust mite or pollen, and even medical treatment) also plays a large part in promoting allergic reactions. In other words, genes and the external world interact to produce allergic disease. What happens in the months and years immediately after birth seems to be a crucial element.
This helps to explain why allergies are on the increase even though we are, genetically speaking, not so different from our grandparents or great-grandparents. It is also a cause for optimism, since it means we can largely reverse the trend in coming generations. All we have to do is adjust the environment, especially for newborns and young children. Luckily, most of the problem factors are ones over which we have personal control, such as smoking by parents, diet, infant feeding, hygiene (less is better), antibiotic treatment, house design and furnishings Generally speaking, inherited traits such as height or skin colour are governed, not by a single gene with a large effect, but by a great many genes each with a small effect. This is called multi-gene inheritance. The many small effects add up to produce the final outcome. Atopy is probably inherited in a similar way, which would explain why some people have a very strong tendency to allergies (they have lots of the wrong genes) while other people have only a mild tendency (they have just a few).
Current estimates hold that at least twenty different genes are involved in determining atopy. This means that no two atopic individuals are going to be quite the same, because each will have a different combination of the possible variants on these twenty genes. In the words of Dr Vincent Beltrani, of Columbia University, New York, ‘it is not surprising that, as a result of all the possible genetic combinations and permutations, each atopic individual possesses a unique “allergic fingerprint” and that not all atopic individuals have identical findings’.
Multi-gene inheritance has another important effect, in terms of predicting who will develop allergies. The genetic risks from the two parents add up, so if both parents have allergies themselves or come from atopic families, the risks of the child developing allergies are much higher than if only one parent is atopic. The actual figures are uncertain because the results vary considerably from one study to another. If one parent is atopic, the risk can range from 20% to 58%, whereas if both parents are atopic, the risk ranges from 50% to 80% or even more.
Note that these are just risks: there are no certainties here because the actual mix of genes that a child receives is a selection – half of the mother’s genes and half of the father’s. There’s no saying which half a child gets, because this is a random selection process, similar to the shuffling and dealing of playing cards. Luck plays a big part.
Naturally enough, both atopic parents and their doctors have asked whether there is any test that could assess the number of pro-allergy genes in a newborn and so predict the chances of allergy developing in particular children. That would allow more stringent anti-allergy measures  to be taken for the children most at risk.
Various tests have been tried, and one does work, to a limited extent. It involves measuring the level of the allergy antibody, IgE, in a blood sample taken from the umbilical cord just after birth. Very high levels of IgE give some indication of the chances of allergies developing later, but the accuracy of the prediction is, unfortunately, not that good when the test is carried out in atopic families. The test doesn’t reveal much more than is already known – that the baby has atopic parents.
This same test, when carried out on newborns who are not from atopic families, sometimes gives a much more useful and accurate result. In one study, 75% of those babies with high levels of cord-blood IgE developed allergies a few years later, compared to only 6% of those with low levels. Unfortunately, the test does not always give such impressive results, and some disappointing studies have led doctors to conclude that it is not worthwhile as a standard test for all newborns.
This finding of high IgE in children from non-atopic families highlights an important point: pro-allergy genes are everywhere. A lot of healthy people have them, but at levels which do not cause any symptoms – yet. This explains why, with the allergy epidemic, many new allergy sufferers are coming from families never affected by allergy before. As our lifestyle becomes more pro-allergy, a baby needs fewer of the pro-allergy genes to grow into an allergic individual.
Other forms of sensitivity
The multi-gene inheritance of classical allergy is very different from the inheritance of diseases such as primary lactase deficiency  where there is a single gene that is at fault. Generally, speaking, all metabolic abnormalities are inherited in this straightforward way, so they are an all-or-nothing affair: one child in the family gets the defective gene while another does not. No environmental triggers are needed to activate the defect.
In the case of food intolerance, if minor metabolic abnormalities play a part, as they may do for some sufferers, then there could be inheritance of the defect, but this will not necessarily lead to symptoms unless other intolerance-promoting factors (such as disturbed gut flora) are present. Those who suffer from both food intolerance and chemical intolerance (also called chemical sensitivity) are the most likely to have metabolic abnormalities, and it is interesting that such problems do sometimes affect several members of the same family. (Doctors who are sceptical about such diseases will dismiss this as simply ‘learned illness behaviour’ among family members, a theory that is difficult to test without a lot of expensive research.)
Inheritance plays a part in several other forms of sensitivity. It is very important, for example, in coeliac disease and dermatitis herpetiformis , which both stem from the same genetic feature. They are only expressed when wheat is eaten but the timing is important here – introducing wheat into a child’s diet later, rather than during the first year of life, seems less likely to provoke the disease. When coeliac disease comes on in adult life, it suggests that some other environmental trigger was needed, in addition to eating wheat, to start off the disease process.

What is Allergy?
Words matter, particularly in medicine. Using the same words to mean different things is a major difficulty for patients when discussing allergies with a doctor. Unfortunately, few patients realise this, and doctors are frequently too busy to explain what they themselves mean. The result can be a great deal of misunderstanding, confusion and mutual irritation.
Unclear meanings can also create problems if you start exploring other treatment options. The word `allergy’ is like one of those cats that eat at six different houses in the neighbourhood: everyone feels as if they own it exclusively. A conventional allergist will understand one thing by ‘allergy’, while a more unorthodox doctor may have a broader definition, and a herbalist or naturopath may be using the word in a completely different way again.
This is an absolute jungle for the medically unqualified, and it can be an expensive jungle if you are looking around for an answer to your health problems. With the help of this book, you should be able to make sense of all this, and understand the seemingly contradictory advice on offer.
The word allergy was coined in 1906 when it was used to mean altered reactivity - any change in the way the body responds to the environment, whether immunity to a disease already encountered, or a sudden fit of sneezing from pollen. Immunity to disease was soon shunted off into a separate category
altogether, leaving allergy with a narrower meaning:
any adverse reaction to substances that are normally harmless - definition 1. In this book, that meaning is covered by the word sensitivity.
One group of American doctors, who later became known as clinical ecologists, stuck with this definition. Their broad view of allergy is still found among some other doctors today, generally those whose approach to medicine is fairly unorthodox. It is a concept of allergy that is also shared by most practitioners of alternative medicine or complementary therapists.
The rift between the clinical ecologists and mainstream medicine came in the 1920s when the definition of allergy used by conventional doctors was narrowed further to mean reactions to harmless items where the immune system is definitely involved -definition 2. The term immune sensitivity is used in this book to convey that meaning.
In the 1960s, conventional allergists narrowed the definition of allergy again. It was an exciting time because the antibody known as IgE (sometimes called the allergy antibody - see box on p. 12) had just been discovered. The new, tighter meaning of allergy was
reactions to harmless items where IgE is involved -definition 3.
If asked to define allergy, most doctors would give the second of these definitions.
However, when they talk of ‘a tendency to allergy’, ‘allergy treatment’ or `the allergy epidemic’, doctors are generally using the third definition, and just mean IgE-mediated allergy. They may not be conscious of the fact that they are switching from one definition to another. This is not an ideal situation but, generally speaking, it does not create too many problems.
This book deals with ‘allergy’ in the very broadest sense of the word - all kinds of sensitivity. However -and this is purely for the purposes of clarity - where the word allergy is used in the text it always means IgE-mediated allergy (definition 3).
Other immune-mediated problems are called non-IgE immune sensitivity in this book.
Finally, any reaction where the immune system has no proven central role is called an intolerance. (As for other technical words, if you want to find the full definition, look in the index and turn to the page number shown in bold type.)
If you are reading widely on this topic, you may come across sensitivity used either according to definition 1 above, or as another name for intolerance. You may also encounter the word hypersensitivity. This is actually a precise medical term,
but be warned that some writers use ‘hypersensitivity’ very loosely to mean just ’sensitivity’ (definition 1).
Remember that medical politics and economics are powerful forces in all this debate over meanings. Words are quite often redefined by medical interest
groups (such as professional associations) with the clear intention of staking out territory and claiming sole access to medical truth. What is at stake, ultimately, is the right of different doctors to treat patients with certain conditions - and the right of patients to choose for themselves. To add to the longstanding battle over ‘allergy’, there are now rival claims about the meaning of intolerance (74) which have distinctly political overtones.
When you talk with doctors, using the most appropriate terms will help enormously. Talking to a mainstream doctor about ‘food allergy’ when the symptoms suggest food intolerance, for example, is very likely to cause annoyance. This is not unreasonable because IgE-mediated food allergy, unlike food intolerance, is a disease that can very suddenly kill an otherwise healthy person. Using the term `food allergy’ for a headache or mild bowel symptoms is, doctors feel, trivialising a potentially fatal condition.
The important thing is to get along well and communicate clearly with doctors, not to get into a battle about what words mean (in that sense, words don’t matter - they are just labels). Avoid using the word ‘allergy’ unless you are sure it fits in with your doctor’s perception of what is wrong. Just describing how you react - the actual symptoms - is usually the best approach. If you need a general word for your condition, ’sensitive’ is usually a much more diplomatic choice than ‘allergic’.