Vincent St Aubyn Crump FRACP, FRCP (UK) – September, 2009
Over the last 20 years there have been numerous reports in the media on the “Childhood Allergy Epidemic” worldwide, but specifically in developed countries, like New Zealand, Australia and the UK. There have also been an increasing number of stories on increasing asthma rates, increasing food allergy and anaphylaxis, &ldquo:the peanut allergy epidemic”, and talks of “banning peanut from schools”. There have also been recent media reports – mainly overseas – of children dying from peanut anaphylaxis. There is no doubt that, this increased media attention has led to an increased allergy awareness, and because there is an apparent “epidemic” of a disease that has potential life-threatening consequences for children, there is undoubtedly some amount of “hype”, and some sceptics might even say “parental hysteria”.
There are also sceptics who claim that “the food allergy epidemic is due to inconsistencies in the diagnosis of food allergy and in the definition of the cases and defects in the methods of some of the studies”. There is some truth to all of these criticisms. However, is there enough scientific evidence to justify an “Allergy Epidemic”? This paper will try to answer these questions in the form of an overview of the increasing prevalence of allergic diseases in New Zealand & in other developed countries, and will also look at the possible causes for this rapid increase.
Definitions in Epidemiology relevant to the Allergy Epidemic
Epidemiology is the study in a population of the correlation between diseases, and the factors that regulate the appearance, spread (diffusion) and outcome of these diseases in human population
An epidemic occurs when new cases of a certain disease occurs in a given human population, during a given period, substantially exceeds what is “expected” based on recent experience.
Cohort is a set of people in a population sharing a common attribute e.g. age or ethnicity.
Hypothesis is a theory that is held to be true and seems like it might be true until it is confirmed or proven wrong by empirical testing or evidence. In other words, an assumption or a mere guess.
Incidence of a disease is the frequency, that is, the number of new cases of a particular disease in a defined population, identified during a given time. (usually 12 months, or the previous year, and usually referred to as annual prevalence)
Prevalence of a disease is the total number of cases of a disease in a given population at a specific period of time or the percentage of the population that is affected with a particular disease at a given time.
Personal experience and experience of friends from my generation clearly suggest that 30 years ago peanut anaphylaxis was “unknown” amongst our classmates, but now all our children and grandchildren will have at least one child, and sometimes up to ten children, in their class with a life threatening food allergy. My allergy practice also confirms this dramatic increase: twenty years ago I would probably have 1 child with peanut allergy referred to me every 6 months, but now I am seeing an average of about one new peanut allergy case each week. So there has been a personal and public perception of an apparent increase in the prevalence of allergic diseases over the last 30 years.
However, scientists do not like anecdotes, and unbiased evidence as the preferred way of proving that a genuine increase in the prevalence of allergic diseases has occurred over the last quarter of a century. The purpose of this paper is to convince my readers that there is enough scientific evidence, through epidemiologic studies, to support the argument that there is an increase in the prevalence of all allergic diseases over the last quarter of a century, and that the magnitude of this increase warrants the term “epidemic”.
Evidence for an allergy epidemic
Problems with some of the poor epidemiologic studies (which are not included in this paper) on allergies, which make it difficult to make international and even national comparison difficult, include:
Inconsistent definition of what constitute, an allergy, asthma, eczema, and anaphylaxis
Poor design due to small samples, un-controlled, non-randomized
Diverse diagnostic criteria for diagnosing allergies, some equate sensitization with allergies
Different cohorts being compared
There are several poorly designed questionnaire-based studies which are very subjective, have poor recall and bias because of parental interest – or lack of it – in allergy.
In this overview, the evidence used below to make my case for an Allergy Epidemic is from high quality studies, from peer-reviewed literature. The three main studies that supports the argument are the International Study of Allergy, Asthma in Children (ISAAC), the Global Allergy and Asthma European Network (GA²LEN), and one very interesting objective serologic study looking at increased IgE sensitization, that have shown an increase in atopy (allergic sensitization).
The first study, the International Study of Asthma and Allergies in Childhood (ISAAC) (1) is a unique international, questionnaire and video-based epidemiologic study on allergies, which was established in 1991, and led by Professor Innes Asher of the University of Auckland. The study started out of concern for the increasing prevalence of asthma, eczema and rhinitis in Western and developing countries. This study has become the largest worldwide collaborative study, involving over 100 countries. The ISSAC findings to date have suggested that these allergic diseases are increasing more in developed and developing countries. For example, the Phase 3 of the study which was conducted between 2000 and 2003 and surveyed children from 233 centres in 97 countries found that the prevalence of wheeze (asthma) in the past 12 months (current asthma) ranged from 32.6% in Wellington, New Zealand to 0.8% in Tibet, China in the 13-14 year olds. Also, the study has found that although the asthma symptoms are more prevalent in more affluent countries, they appear to be more severe in less affluent countries.
So far the ISAAC study has been unable to find the cause(s) for this increased prevalence and the wide global variation in asthma prevalence, but they have highlighted some clues and enough questions for further ongoing studies. Also, even though there are not a lot of answers, Phase 3 of the study has shown a reduction in the severity and prevalence of asthma symptoms in 6-7 year-old and 13-14 year-olds in New Zealand, in the period 2001-2003, when the same age groups were compared to the period 1992-3. The most likely explanation for this improvement in symptoms in this phase, is improved awareness that the study as brought about along with better management of asthma due to national and International Asthma management Guidelines.
The second study, The GA²LEN study (2) is a pan-European multidisciplinary collaboration which was set up in 2005, to increase networking for scientific projects in allergy and asthma around Europe. The network consists of 27 research centres, 60 collaborating centres, and 500 researchers in 25 countries. The aim of the researchers is to become the world leader in the field of allergy research and to develop and implement allergy guidelines. Its vision is: “to address all aspects of allergic diseases in order to create a better understanding of allergic diseases among the general public, patients, health professionals and policy makers”.
What they have discovered so far is that:
“Allergic diseases including allergic rhinitis, asthma, rhino-conjunctivitis, gastrointestinal symptoms, urticaria (hives) and eczema are among the most common chronic diseases in the world and rank first in Europe. Their prevalence continues to grow with one child in three now affected by an allergic disease. Trends indicate that half of all Europeans will suffer from allergy by 2015”.
“There is significant under-diagnosis and under-treatment in all areas of allergy, with the majority of patients left untreated according to existing medical standards.”
Some of the epidemiologic questions regarding allergies that GALEN is currently looking at include:
Pollution and its effect on allergic sensitization.
Sensitization and symptoms – Understanding the reasons why patients with IgE sensitization develop allergic symptoms will be crucial to our understanding of the “allergy epidemic”. One of GALEN’s recent studies has shown that only very few of the “asymptomatic” patients that were sensitized to birch and Parietaria pollen did develop symptoms when they underwent nasal challenges, when compared with the general (non-sensitized) population.
Studies on the interaction between nutrition and allergic immune response.
The third important study is an objective serologic study showing increasing prevalence of atopy (3). This is one of the few studies where objective measurements are made to show that the prevalence of allergies (asthma, eczema and hay fever) have increased over the past 20 – 30 years is a study from the UK done in 2005. The researchers looked at frozen serum samples of men aged 40 -64 years, who attend the British United Provident Association (BUPA) for routine medical examinations. One good feature to this study was that all these men were socioeconomically similar, being all professionals or businessmen. Three groups of samples (containing 513 each) were matched by age and month of attendance for 1996, 1981, and 1975. The samples were tested for specific IgE sensitization to 11 common inhaled allergens (including cat, grass, house dust mites) and a highly significant increase in IgE sensitization over time. The average rate of increase was equivalent to an additional 4.5% of men becoming positive (IgE sensitized) each decade. This study objectively showed through serological measurements at three time periods that earlier birth cohorts are less likely to have become atopic than more recent ones.
Other well designed global studies supporting an Allergy Epidemic
Increasing asthma prevalence in New Zealand
The increasing prevalence of asthma in New Zealand was noted way back in 1989 in a survey of 435 asthmatic adolescents looking at asthma symptoms and spirometry. (4) The survey used identical questionnaire in 1989 as they used in 1975, and found that the prevalence of reported asthma or wheeze significantly increased from 26.2% to 34.0% over the 14 year period.
Asthma increase in the USA
The US centre for Disease Control and Prevention noted an increase in the prevalence of asthma in children in the US from 3.6% in 1980 to 5.8% in 2003.
Food Allergy Epidemic
Rising Prevalence of Peanut allergy in Children from 2 Sequential Cohorts in Isle of Wight (5)
This is probably one of the most famous and frequently quoted studies on peanut allergy internationally. Researchers looked at 2878 children born between 1994 and 1996, doing questionnaires, and 1246 had skin prick tests at age 3-4 yrs and those with positive response to peanut had an oral peanut challenge. This was compared with a similar cohort from the same area born in 1989. There was a 2-fold increase in reported peanut allergy, and a significant 3-fold increase in peanut sensitization from 1.1% in 1989 cohort up to 3.3% of the children 6 years later (the 1994-1996 cohort).
Increasing prevalence of peanut allergy in Australia (6)
A recent study by Ray Mullins in Canberra, Australia examined the characteristics of 778 patients with confirmed peanut allergy between 1995 and 2007, and found that the incidence of peanut allergy in Canberra (Australian Capital Territory) more than doubled in the children born in 2004 (1.15%) compared to those born in 1995 (0.47%).
Evidence for an Anaphylaxis Epidemic (7)
On reviewing the medical literature, there was only rare and scattered reporting of anaphylaxis, up until in the 1960s when the first small case series of individuals with anaphylaxis to foods, drugs, and insect venoms was published. This was followed by:
In the 1970s the first case series of idiopathic anaphylaxis
The first case series of exercise-induced anaphylaxis and latex-induced anaphylaxis were reported in the 1980s
The first epidemiologic study looked at the incidence of anaphylaxis in the Minnesota, USA noted an increase from 20 per 100,000 in 1993 to a high of 70 per 100, 000 in 1998
Recent time trend studies in the UK showed that hospitalization for anaphylaxis increased recently by 700% (8, 9).
Anaphylaxis fatalities and admissions in Australia (10)
Liew, Williamson and Tang looked at the causes, demographics and time trends of anaphylaxis fatalities in Australia between January 1997 and December 2005, and found that food-induced anaphylaxis deaths increased by about 300% , and drug-induced deaths by about 150% over the eight year period. The authors found drugs were the commonest cause of anaphylactic deaths about 60%, followed by insect stings (18%), and foods (6%).
Trends in hospitalization for allergies in Australia (11)
Data on hospital admissions and deaths for anaphylaxis, angioedema (swelling of soft tissues), and urticaria (hives) were examined for the periods 1993-1994 to 2004-2005 respectively. Over the 8-year period, the researchers found 106 deaths from anaphylaxis and a continuous increase in the rate of hospital admissions for angioedema (3% per year), urticaria (5.7% per year), most strikingly, anaphylaxis (8.8% per year).
Allergic sensitization in infants with atopic eczema from different countries (12)
2184 infants with atopic eczema were randomly screened in 12 countries, and it was found that 55.5% of the infants were sensitized to at least one allergen. There was a wide difference in sensitization to foods and aeroallergens globally. The highest prevalence rate of sensitized infants was found in Australia 83%, the UK 79%, and Italy 76%. Belgium and Poland had the lowest sensitization rates.
The Latex Allergy Epidemic
Latex glove were first used by William Halstead back in 1890. Since then their use has progressively increased in medicine, until roughly 100 years later when the latex allergy epidemic occurred. The latex allergy epidemic is probably the best example of an allergic disease that increased in prevalence to “epidemic” proportions in the last two centuries and due to careful planning the “epidemic” has been contained, and the prevalence has fallen over the last 8 years. Latex is a common component of many medical supplies including disposable gloves, intravenous tubing, syringes, stethoscopes, catheters, and bandages. It was therefore not surprising that the latex epidemic was confined to health care workers and patients that have had several previous surgical operations.
The sudden rise in the use of latex gloves to prevent the spread of AIDS and Hepatitis B in the 1980s is blamed for the latex allergy epidemic which peaked between 1996 and 2000. To keep up with the demands of increased glove production the manufacturing time had to be decreased by reducing the number of washing and purifying steps. This resulted in increased amounts of sensitizing protein that the gloves could transmit. Another very interesting finding in this epidemic was the fact that the prevalence was much higher in genetically susceptible individuals, atopics. So this highlights the belief that increased exposure to a highly allergenic substance in a genetically susceptible population could contribute to the allergy epidemic.
In 1994 Blanco coined the term ‘latex-fruit syndrome”, due to the fact that 52% of their patients with latex allergy were sensitized to fruits: 36% were sensitized to avocados, 36 to chestnuts, 28% to bananas, and 20% to kiwis. This example of adult-onset fruit allergy is very much like the “birch-fruit syndrome” which is responsible for the “epidemic” of fruit allergy that is being experienced in New Zealand adults at the moment.
Causes of the Allergy Epidemic
The causes of the allergy epidemic are complex interplay between genetics and environmental changes. The time frame for the increased prevalence of allergies is too short to explain a genetic change in the population. Therefore most of the current epidemiological research has focused on identifying possible environmental factors that are associated with the increased prevalence of allergies. Some of the proposed reasons due to environmental changes over the last 30 years, that could be contributing to the allergy epidemic include:
Parental cigarette smoking has been strongly correlated with increased prevalence of allergies in offspring
Formula feeds instead of exclusively breast-feeding for the first 4-6 months, which is known to decrease the risk of allergies. Breastfeeding promotes colonization of the infant’s gut with bifidobacteria and lactobacilli, which in necessary for the development of normal oral tolerance to foods
Dietary factors are being explored, since the modern dist is very different from the diet 20 years ago. Researchers are looking at vitamins, especially Vitamin D, Folic acid and the effects of sunlight in terms of their effects on allergies
Use of antacids may prevent the destruction of potential allergens, and infants are increasingly being given potent acid suppressing drugs for reflux disease
Hygiene Hypothesis – is the most popular theory that supports the “allergy epidemic”. Over the last 20 years there have been striking improvements in medical science and hygiene, and this has led to increased life expectancy due to decreased infections from harmful microorganisms. This reduced microbial load early in life could have a down side; it could be one of the causes of the increased incidence of allergic diseases, seen over the last 2 centuries. A review of the medical literature between 1966 until 2004 identified more than 20 prospective studies which showed an inverse relationship between allergies and microbial infection or endotoxins related to microbes. Some well designed studies supporting the hygiene hypothesis include:
The risk of allergies is higher in children growing up in smaller families, and families of higher socioeconomic status, as seen in developed countries. One study showed lower incidence in younger siblings, when there is 3 or more older siblings, and another showed decreased incidence in children who attend day care but only if they are without siblings
Low incidence of allergies in children growing up on farms
One study showing a positive association between infections in early life and a reduced risk of atopic eczema
Several studies showing antibiotic use in early life and even in the antenatal period associated with increased risk of atopic eczema
A study done in Italy, and published in the BMJ in 1997, showed that young men with antibodies to Hepatitis A virus had a lower prevalence of allergic diseases. Hepatitis A, in this case could be considered a marker for poor hygiene
A few small randomized controlled trials have shown that probiotics could reduce severity and prevalence of some allergies.
To put it briefly, we can say that the allergy epidemic which is occurring in developed countries, with a higher living standards, is probably a result of modern life style, where there is an almost obsession with cleanliness. Infants are not getting exposed to bugs and germs as they use to, there fewer childhood infections, families are smaller, along with more frequent use of antibiotics in infancy are all contributing to the “hygiene hypothesis”.
Increased prevalence of peanut allergies possibly related to advice given by health care professional (13)
One study in the UK showed that when peanut was introduced to children at about 12.6 months for a cohort born in 1989, the peanut allergy rate was 0.5%, and when it was introduced around 36 months for a cohort born between 1999 and 2000, the peanut allergy rate went up to 1.8%. Also Du Toit and others have found that the prevalence of peanut allergy among Jewish schoolchildren in the UK was 1.85% compared to 0.17% in schoolchildren living in Israel. This almost 10-fold higher rate is probably due to the much lower consumption rate of peanut in UK children. Peanut is introduced earlier and is eaten more frequently and in larger quantities in Israel. The median monthly consumption in Isreali infants from 8 – 14 months was 7.1 g compared to 0 g in their UK counterpart. Another study in the UK showed that high levels of environmental exposure to peanut in infancy, when associated with no ingestion of peanuts appear to promote peanut sensitization.
The low peanut consumption in infancy is probably related to the 1998 UK Department of Health’s Committee on the Toxicology of Chemicals in food advice on the consumption of peanut and peanut products in preventing peanut allergy. The Committee advised that peanut should be avoided by pregnant breast-feeding atopic women and those children with a parent or sibling who is atopic should avoid peanuts up until three years. Incidentally, this advice was adopted in New Zealand and other developed countries that are experiencing this peanut allergy epidemic.
Looking into the future: How can we reverse or halt the epidemic?
The good news is that, it has been shown that these diseases can be controlled effectively through increased awareness, National and International Guidelines (protocols), which leads to better management The health proffessionals’response to the asthma and the latex epidemic has led to stabilization or even reduction in symptoms and new cases (in the case of latex epidemic). Through National Guidelines and policies we have seen that the epidemic can be managed until a “cure” is found. Also we might be learning from the peanut allergy epidemic, that until the studies on allergy prevention are completed, we need to be careful with the advice we give to our patients.
Hospital policy and Guidelines used to effectively combat the latex epidemic (14)
Since 1999 the US FDA has regulated the need for manufacturers to apply warning labels on medical devices containing natural rubber latex. Also medical device companies have developed many latex-free alternatives.
Internationally, over recent years hospitals have developed policies and guidelines recommending the use of non-powdered, reduced-latex, or latex-free (non-latex), “hypoallergenic” gloves. Follow-up studies have shown reduced latex sensitization and asthma in HCW, and even shown a reduction in latex-specific IgE antibodies after latex use has been substantially reduced in the health care workplace.
In the UK prior to 2002, several health care workers have been compensated by their employers for developing latex allergy. A trainee nurse was awarded more than £300,000 compensation in an out of court settlement with Scarborough General Hospital NHS Trust after developing allergy to latex gloves. In another case, a nurse was awarded ₤354,000 compensation after “she was forced to abandon her nursing career due to an allergy to latex.” Probably because of these cases, in the UK, natural latex rubber is now classified as a substance hazardous to health, and as such it falls under the Control of Substances hazardous to Health regulations 2002. (COSHH). Under COSHH, employers must access all the circumstances in which employees may be exposed to substances hazardous to health.
In Belgium the use of powdered latex gloves fell from 80.9% in 1989 to 17.9% in 2004, and this is paralleled with the national compensation-based data confirmation of a persistent decline in the incidence of latex-induced occupational asthma has occurred since late 1990s.
We can learn from this epidemic that atopic adults are likely to become allergic to an allergen if the allergen exposure is high enough. We might not necessarily be able to extrapolate this to prevention of food allergy in infants, but in genetically susceptible adults, we can prevent certain occupational allergies, with the possible cross-reacting allergens.
Phase 3 ISSAC study showed a decrease in asthma symptoms due to better control (15)
As discussed earlier, the Phase 3 ISAAC study has demonstrated a reduction in asthma symptoms in 6-7 year-old and 13-14 year-olds in New Zealand.
However, one should not get complacent, because this same study has showed that “asthma reported ever” has increased in both age groups, suggesting that the improvement of asthma symptoms is due to better management of the disease.
In conclusion, allergies, including, asthma, eczema, hay fever, food allergy, and anaphylaxis have increased in New Zealand and other developed countries by epidemic proportions over the last 25 years. The “Hygiene hypothesis” or diminished microbial stimulation of the immune system of infants has been cited as one of the main cause for this “epidemic”, and there are some good studies to support this theory. However, the exact cause is far from being certain, at the present time.
We know from the response to the latex and asthma epidemic that we can reduce symptoms and increase quality of lives in allergy suffers. However, controlling the symptoms of the diseases in the “allergy epidemic” is only apart of the solution. We also need to reverse the increasing allergic sensitization in developed countries. However, we can only do this when we have figured out the cause(s) for this increase, and this will only be done through more very good international studies like GALEN and ISAAC. New Zealand needs to follow the example set by the GA²LEN study in Europe, and invest more into funding of research into allergies.
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