HAY FEVER IS a modern epidemic. Two hundred years ago, the medical world was largely unaware of it. In the first accurate account, published in 1819, a London physician described his own hay fever as ‘an unusual train of symptoms’. That physician was John Bostock, and for many years doctors called hay fever ‘Bostock’s catarrh’. In a series of lectures delivered in 1830, John Elliotson, professor of medicine at the University of London, spoke of hay fever as a rare and ‘very extraordinary affectation’. And as recently as the 1930s, a medical student with a regular and prolonged summer ‘cold’, whose symptoms grew worse in the countryside, could find no explanation from any doctor he met.
In northern Europe today, early June brings a spate of runny-nosed people crowding into doctors’ surgeries, as millions of grass plants suddenly release their pollen. Estimates of hay fever’s prevalence vary greatly, but probably between 10 and 18 per cent of us will suffer from hay fever at some time in our lives.
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In less than two centuries, hay fever has progressed from being a medical curiosity to a commonplace illness. Among Swiss town-dwellers, its prevalence rose steadily from 1 per cent in 1926, to 5 per cent in 1958 and 10 per cent in 1986. Between the early 1970s and the early 1980s, cases almost doubled in Britain and Sweden. Numbers are still increasing rapidly today, despite the fact that the pollen count is falling, as farmers switch from hay to silage as a feed for their cattle. Silage-making involves harvesting the grass earlier, before it flowers.
The same dramatic increase has happened in the US, although it probably began a little later. The first American description of hay fever to grasses and ragweed appeared in 1852, apparently uninfluenced by the European reports. Reported cases climbed steadily in the US to reach 9 per cent by the 1960s. In Japan, the rise began much later: hay fever was virtually unknown before the 1950s, but its prevalence has rocketed in the past 40 years to reach 10 per cent or more today.
Some of these increases may be due to people’s mounting awareness of allergic illness, their growing tendency to consult doctors for minor complaints, and more accurate diagnosis by the doctors. But detailed historical studies, such as those carried out by Michael Emanuel at the University of Oxford, show that there was a genuine, and very rapid, increase during the 19th century. Epidemiologists who have studied hay fever are equally convinced that the present-day escalation is a real one.
Pollen has been around for about 130 million years. Our ancestors emerged from the forests onto the savannas of Africa at least 5 million years ago, and successive generations must have inhaled huge quantities of grass pollen as Homo sapiens slowly evolved. After millennia of peaceful coexistence with pollen, what has now gone wrong? As early as 1926, researchers in Switzerland found a ten-fold difference in hay-fever cases between city-dwellers and those living in the country. But the higher numbers were not in the country, as one might expect: it was the town-dwellers who suffered more. Wind-dispersed pollen travels far, and even in large towns there is plenty of pollen. But the countryside does harbour pockets of high pollen concentration, so the greater prevalence in town-dwellers was unexpected.
This same pattern is seen today, particularly in Scandinavia, although the difference is not so large; there are roughly twice as many cases of hay fever in towns as in the country. Curiously enough, the difference in Switzerland has now disappeared. A study of 2500 people in 1985 revealed little difference between towns and villages. Brunello Wuthrich, of the University Hospital in Zurich, believes that there is a single explanation for both these observations: air pollution. Wuthrich suspects that the hay-fever ‘epidemic’, originally a consequence of urban pollution, has now spread to the countryside with the growing numbers of cars and lorries driving through it.
The idea of a link with pollution is a popular one, and it owes much to research done in Japan, where public disquiet over air pollution is unusually high. Concerned about the soaring rates of allergy to Japanese cedar pollen, the predominant form of hay fever in Japan, Shigeru Takafuji of the University of Tokyo began to suspect a link with diesel-powered vehicles, which had increased from about 15,000 in 1951 to more than 5 million in 1983. When he repeatedly injected soot particles from diesel exhaust into mice, along with an antigen, they stimulated the production of an antibody called IgE that precipitates allergic reactions . Takafuji found that the IgE was made in response to the antigen, not the soot particles, so he concluded that the diesel exhaust had merely acted as an ‘adjuvant’ – something that influences the course of an immune response. When he put the diesel particles and antigen into the noses of mice, the same thing happened: their bodies produced up to 100 times more IgE when the diesel particles were present as when they were absent. Just 1 microgram of particles given at three-weekly intervals was enough to produce this effect. (Urban commuters could inhale 500 micrograms of diesel particles every working day.)
Pollution fuels the fever
Other Japanese researchers, looking at the distribution of hay fever, have corroborated Takafuji’s laboratory studies with mice. According to their findings, allergy to Japanese cedar is commonest in those living alongside cedar-lined trunk roads with heavy traffic. More than 13 per cent of people living on such roads suffer symptoms of hay fever in the cedar-pollen season. Among those living close to cedar forests, where the pollen in the air is equally plentiful but traffic minimal, the figure is only 5 per cent. In farming and city areas with traffic that is lighter than on main roads, the figure is about 9 per cent, regardless of whether pollen levels are low or high. Another Japanese study found an astonishingly high level of hay fever and other nasal allergies among children from highly polluted areas: no less than one in three showed symptoms.
Unfortunately, there are no comparable studies from elsewhere in the world, and one fact stubbornly refuses to fit with the pollution hypothesis. When hay fever first made its appearance in the 19th century it was not among those most exposed to factory smokestacks – the urban poor – but among the aristocrats and the wealthy upper classes. It is tempting to dismiss this by suggesting that the oppressed masses of Britain’s industrial cities had better things to worry about than runny noses. But detailed studies of pharmacy records and medical diaries by Emanuel suggest otherwise; there really was no sign of hay fever among poor town-dwellers in the 1820s and 1830s. By 1859, a German professor who had made a point of trying to find out whether there was hay fever among the lower classes was able to cite only a few instances. This historical anomaly has, up to now, been fairly easy to ignore. But a new study by David Strachan, an epidemiologist, suggests that it may be significant after all.
Strachan, then working at the London School of Hygiene and Tropical Medicine, looked at data from 17 414 children born during one week in March 1958. As part of the National Child Development Study, researchers had collected extensive data on those children at 7, 11 and 23 years of age. Included among the data was the prevalence of hay fever during the past year at age 11 (as assessed by parents) and age 23 (self-assessment). Strachan was then able to compare these figures with many other factors and see which ones correlated best.
Surprisingly, whether someone was born in the town or the country showed no appreciable effect on the likelihood of their developing hay fever. Cigarette-smoking mothers had not produced more pollen-sensitive children, contrary to some other reports, so a link with this particular form of pollution seems unlikely. And breast-feeding, which is generally believed to protect against allergic disease, was associated with a very slight increase in cases of hay fever.
The one factor that did correlate remarkably well with hay fever was family size: an ‘only child’ was much more likely to have hay fever than one with several brothers and sisters.
Explaining away such a finding seems simple enough at first sight. Minor illnesses tend to attract less attention and concern among large families than they do in the cosseted only child, and parents with few children might have noticed hay fever more readily with few children. Yet the difference was equally pronounced at age 23, when the young adults were reporting their own symptoms.
There is another possible explanation. We know that susceptibility to hay fever and other allergic diseases is genetically inherited . Perhaps atopic parents – those predisposed to allergy – simply have fewer children? However, geneticists studying the inheritance of atopy, such as Julian Hopkin at the Churchill Hospital in Oxford, think this unlikely.
By taking the analysis of family membership one step further, Strachan feels that he has effectively countered all these suggestions. When he classified children according to the number of older and younger brothers and sisters that they had, he obtained his most striking results: the strongest correlation was between hay fever and the number of older children in the household. At 11 years old, children with no older siblings were four times as likely to have hay fever as those with four, five or more older brothers and sisters. There was a weaker, but pronounced, correlation with the number of younger children.
What impressed Strachan greatly was the size of the difference and the consistency of the results. Although the results at age 23 showed more cases of hay fever in all groups, the correlation between hay fever, older siblings and younger siblings was almost exactly the same (see Figure). Strachan acknowledges the drawbacks of asking people if they have hay fever, rather than making a proper medical diagnosis, but feels that the startling differences must indicate a genuine relationship. ‘The difference between the small households and large households is so big that if it was all a reporting artefact there would have to be some extraordinary differences in reporting between them,’ he says.FIG-mg17194301.GIF
Eczema in infancy is also far more common among children with no older siblings, and this strengthens the findings about hay fever, in his view. Eczema is often, though not always, allergic in origin. Data from another large group of children born in 1970 suggest the same link between hay fever and the number of older siblings.
Strachan’s discovery, if correct, could make sense of the puzzling association in the 19th century between hay fever and the upper classes. He suggests that the crucial factor is the amount of ‘unhygienic’ contact between a young child and older children. Normal play and close contact would readily expose children to each other’s saliva and nasal secretions. Diminishing family size, and more sophisticated notions about hygiene, could have reduced this sort of contact among upper-class offspring before this began to happen among the rest of the population. It is a speculative idea, but an interesting one.
If Strachan is right, how might the link be explained? He suspects that the younger children of larger families suffer far more childhood infections than older ones; this, he suggests, might somehow protect them against allergy. It is this theory that has most disconcerted the immunologists, for all the evidence – and there is a great deal of it – suggests that respiratory infections by viruses trigger off the allergic reactions that lead to hay fever and asthma. What Strachan proposes is that these symptoms are short-term effects of viral infections, although they may have lasting consequences for those strongly predisposed to allergy. He suggests that, in some people at least, exposure to infection might, in the long term, educate the immune system not to overreact to harmless substances such as pollen. He speculates that there might even be one particular viral infection, perhaps a retrovirus, which, if picked up in early childhood, could infect certain cells of the immune system, known as mast cells, making them permanently less reactive.
The idea of disease as a protector against allergy fits in with impressions gained from tropical countries, where allergic diseases seem to be relatively rare as long as people remain infected with their traditional parasites. Once people are treated for parasites and adopt a more hygienic lifestyle, asthma, hay fever and eczema seem to increase. As Emanuel puts it: ‘Man evolved with his parasites and there may be a price to pay for their removal.’
Infection may not necessarily be the explanation, however. Older children who expose their younger brothers and sisters to pollen in saliva and sneezes might desensitise them more directly. There is some evidence – but no hard data – suggesting that exposure to small amounts of pollen during childhood could make allergies less likely.
For example, when new crops came into widespread cultivation, or new weeds proliferate, the novel pollen frequently seems to trigger hay fever. Oil-seed rape, now decorating the European landscape, thanks to EEC subsidies, with rectangles of brilliant yellow, is apparently causing an outbreak of hay fever in Scotland and elsewhere. The Mexican mesquite tree, currently in vogue in India for land reclamation and firewood, has set thousands sneezing; plane trees have caused problems in some French towns; and tree plantations in irrigated deserts have brought hay fever to Saudi Arabia. European people with hay fever or other allergies who move to North America often develop very severe reactions to that most potent native allergen, ragweed pollen.
It is also true that massive exposure to pollen shortly after birth can sensitise a vulnerable child for life. Scandinavian studies show that children from atopic families are far more likely to develop hay fever if they are born just before the birch trees release their pollen in April and May. This does not conflict with the idea that small amounts of pollen might be beneficial. The whole basis of desensitising treatment for hay fever, a method that is successful for many patients, is that treatment begins with a tiny dose and gradually builds up.
There could be a crucial stage in infancy, before a baby is exposed to the pollen-loaded outdoor air, when limited exposure to pollen might educate the immune system not to launch an attack. Pollen that has already landed in one nose before passing to another via a sneeze may even be modified in some way that makes it less potent. The initial contact with an older sibling’s nose would relieve the pollen of its cargo of wall-held proteins, which first provoke the immune response . Such pollen, lacking its immediate allergenic effect, might be able to induce tolerance in a baby. Alternatively, the pollen’s proteins could become modified in some way in a sibling’s nose. Immunologists working on improved vaccines for hay fever know that they can achieve greater desensitisation with antigens that are partially broken down, or bound to another molecule. Such antigens may retain their power to interact with the T cells of the immume system, which control the allergic response, while failing to stimulate the production of IgE, or trigger off mast cells .
Strachan is currently keeping an open mind about the reason for his observed link. ‘My explanation is just speculative. I don’t really know enough about the exact functioning of the immune system to be able to propose a detailed mechanism, but I hope immunologists will take up this lead and investigate further. Epidemiology just offers a different type of clue – it’s certainly not a substitute for laboratory observations.’ He does not discount the findings of a link with pollution on the basis of his work. ‘There may be many things going on – I don’t think any of these explanations are mutually exclusive.’
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Pollen proteins pack a punch
WHEN a pollen grain lands on the stigma, or female receptacle, of a flower, it is unlikely to be alone. Other pollen grains will be competing to fertilise the egg cell. They can do so only if they are the first to penetrate the stigma surface and tunnel downwards to the ovary, by means of an invasive ‘pollen tube’. From the moment the pollen grains arrive and soak up moisture from the stigma, the race to reach the egg cell is on.
The exquisitely sculpted wall of the pollen grain is an important element in winning this race. Crypt-like hollows in the surface of the pollen grain act as stow-holds for proteins. Among these proteins are enzymes that break down the stigma surface, and proteins that act as so-called ‘compatibility factors’, blocking fertilisation (in outcrossing species) if the pollen comes from the same plant, or from a closely related plant.
The proteins are sealed into the wall crypts by a fatty layer that contains carotenoid pigments that give the pollen its yellow colour. By holding its proteins in these pits on the surface, the pollen grain can release them within seconds of landing on the stigma. The swelling of the pollen grain, as it soaks up water, cracks open the fatty layer and allows the proteins to escape.
Initially at least, a pollen grain in the nose behaves in the same way as one on a stigma, releasing the mobile proteins held in its walls within seconds. From the point of view of the immune system, this may well be highly suspect behaviour, suggestive of an aggressive invading microorganism. Yet there must be some mechanism for distinguishing pollen from microbes in healthy people.
Some of the proteins that escape from the pollen grain are very powerful antigens and allergens. In other words, they provoke vigorous reactions by the immune system. Researchers believe that these are probably the incompatibility factors, which would need distinctive chemical features to fulfil their function of plant-to-plant recognition. Those same chemical ‘calling cards’ might well act as sites that the immune system can recognise: it is the distinctive features on a protein molecule, which immunologists call epitopes, to which antibodies bind.
No one knows whether the enzymes that the pollen grain releases can attack human tissues. Twenty years ago, John Heslop-Harrison, then working at the Royal Botanic Gardens at Kew, near London, found that pollen-grain proteins made mammalian cells more permeable in culture, but no further work has been done in this area.
Eventually, pollen grains that have landed in the nose burst open and the inner contents spill out: some of these internal proteins may also act as allergens. But it is the mobile wall-held proteins that are most likely to provoke allergic reactions. To make matters worse for the victim of hay fever, some plants also release these proteins as tiny particles that are even smaller than pollen grains (New ÐÓ°ÉÔ´´, Science, 19 May 1988). These minute particles arise from the tapetum, a membrane within the anther which lays down the wall-held proteins. As the anther breaks open to release the pollen, the tapetum, which still contains residual proteins, disintegrates and disperses.
Not all pollens produce hay fever. The most common culprits are wind-pollinated plants such as grasses, ragweed and birch trees, which must release vast amounts of pollen to ensure that some of it reaches its target. Insect-pollinated plants – those with colourful flowers or strong scents – produce far less pollen because their targeting is much more accurate. The pollen is also heavy and sticky, so it is less inclined to become airborne. Nevertheless, some insect-pollinated flowers can give people hay fever, especially when they inhale large amounts of the pollen. Among scientists, plant breeders are especially vulnerable.
The scent of certain flowers, especially roses, can have an irritating effect on the nose, and this may exacerbate a mild reaction to grass pollens in the air around, setting off a bout of hay fever that is easily mistaken for an allergy to rose pollen.
On the whole, the quantity of pollen inhaled seems to be the crucial factor, but there are puzzling exceptions. Maize and pine trees both release huge quantities of wind-borne pollen, yet they rarely produce hay fever. The chemistry of the pollen proteins clearly plays a part in determining the effect on the immune system.
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Mast cells fly the allergic flag
IN AN allergic reaction, a set of immune cells called mast cells attacks a harmless substance – pollen, in the case of hay fever – producing inflammation. Mast cells store vast quantities of chemical messenger molecules know as inflammatory mediators, which they can release when they receive the right sort of signal. The strongest form of signal comes from a special type of antibody, immunoglobulin E or IgE.
IgE originates in other cells (the B cells, which produce all antibodies) and attaches itself, by its stem, to a mast cell. The other end of the IgE molecule remains free to bind to antigen – in this case, proteins from pollen grains. As with other antibodies, a given molecule of IgE is specific for a particular antigen. When the appropriate antigen binds to molecules of IgE on a mast cell and links them together, this triggers the release of mediators.
A highly complex set of control mechanisms prevents B cells from making IgE in normal circumstances. These control mechanisms involve a great many different immune cells, numerous messenger molecules and some other types of antibody. Of major importance are regulatory immune cells known as T helper cells and T suppressor cells.
What goes wrong in the allergic individual is not entirely clear. One interesting discovery is that people infected with HIV, who have suffered from allergies as children but not in adulthood, frequently develop allergic symptoms as they develop AIDS.
In temperate climates, with hygienic living conditions, most people who are free of allergies produce relatively little IgE. In the tropics, IgE levels are often much higher, although allergies may be rare, and when people become infected by parasites such as nematode worms, their bodies respond with massive numbers of IgE antibodies. From these observations, immunologists have argued that IgE evolved to guard against such parasites and has become largely redundant in the Western world. But this leaves certain puzzling questions unanswered.
Most parasites enter the body through the gut. A few burrow through the skin, but the flying nematode has yet to be invented. So why is the nose so well equipped with mast cells? And why should many antigens provoke an IgE response when they enter the nose and lungs, but do not do so when they are swallowed? These paradoxes suggest that mast cells and IgE in the nose must have some other function, perhaps in bacterial or viral infections. More research into this area might throw some light on the question of what goes wrong in hay fever.
Long before researchers understood the underlying mechanisms of allergy, doctors were aware that these diseases had a genetic component. Some family members might have hay fever, others asthma or eczema, and the idea of ‘atopic’ families came into being. ‘Atopy’ means ‘no particular place’ implying that there is an underlying weakness which can manifest itself in various parts of the body. Recently, researchers have pinpointed a single dominant gene for atopy (New ÐÓ°ÉÔ´´, Science, 24 June 1989) and further work by the same research team suggests that the rogue gene is far more widespread than previously suspected: well over a third of the population carries it.
Not all ‘atopic’ people develop allergic disease, and the genetic background is obviously very important. Environmental factors must also be at work, as studies of identical twins show that one may develop allergies while the other does not. What is particularly interesting is that 30 per cent of allergic children are born into families that previously showed no sign of allergy. This supports the idea of some new environmental factor provoking an allergic response in families who are only weakly predisposed to allergy. What that environmental factor might be is an open question.
Linda Gamlin is a science writer and editor based in Bath.