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Corresponding author: Thomas A. E. Platts-Mills, MD, PhD, FRS, Allergy Division, PO Box 801355, University of Virginia Health System, Charlottesville, VA 22908-1355.
Before the first description of hay fever in 1870, there was very little awareness of allergic disease, which is actually similar to the situation in prehygiene villages in Africa today. The best explanation for the appearance and subsequent increase in hay fever at that time is the combination of hygiene and increased pollen secondary to changes in agriculture. However, it is important to remember that the major changes in hygiene in Northern Europe and the United States were complete by 1920. Asthma in children did not start to increase until 1960, but by 1990, it had clearly increased to epidemic numbers in all countries where children had adopted an indoor lifestyle. There are many features of the move indoors that could have played a role; these include increased sensitization to indoor allergens, diet, and decreased physical activity, as well as the effects of prolonged periods of shallow breathing. Since 1990, there has been a remarkable increase in food allergy, which has now reached epidemic numbers. Peanut has played a major role in the food epidemic, and there is increasing evidence that sensitization to peanut can occur through the skin. This suggests the possibility that changes in lifestyle in the last 20 years could have influenced the permeability of the skin. Overall, the important conclusion is that sequential changes in lifestyle have led to increases in different forms of allergic disease. Equally, it is clear that the consequences of hygiene, indoor entertainment, and changes in diet or physical activity have never been predicted.
Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.
Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.
Date of Original Release: July 2015. Credit may be obtained for these courses until June 30, 2016.
Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.
Target Audience: Physicians and researchers within the field of allergic disease.
Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
List of Design Committee Members: Thomas A. E. Platts-Mills, MD, PhD, FRS
Disclosure of Significant Relationships with Relevant Commercial
Companies/Organizations: T. A. E. Platts-Mills has received research support from the National Institute of Allergy and Infectious Diseases, has received consulting fees and royalties from Thermo Fisher, and has received travel support from Merck.
Activity Objectives
1.
To trace the onset and progression of asthma and allergies from 1870-2010 and, in particular, its relation to improvements in public hygiene.
2.
To understand the major theories behind the epidemic increase in asthma since 1960 and the supporting evidence for this increase.
3.
To review the relevant environmental and lifestyle changes that might be associated with the increasing prevalence of allergic disease.
Recognition of Commercial Support: This CME activity has not received external commercial support.
List of CME Exam Authors: Niti S. Agarwal, MD, Gina Coscia, MD, and Rachel L. Miller, MD.
Disclosure of Significant Relationships with Relevant Commercial
Companies/Organizations: The exam authors disclosed no relevant financial relationships.
The human race has come to dominate its environment so completely that any analysis of the increase or appearance of a disease has to take changes in our lifestyle into account. In the case of allergic disease changes in our environment, diet, water quality, and personal behavior over the last 150 years have played a dominant role in the specificity of these diseases, as well as in prevalence and severity. The first thing to address is when “the epidemic” started and how much the increase in different allergic diseases has occurred separately. It should be noted that some or most previous reviews have implied that the increase in allergic disease has been unimodal, but actually, that has never been a tenable analysis. Not only have increases occurred or are currently occurring at different times in different countries, but also hay fever, asthma, and peanut allergy have had strikingly different time courses both in Europe and North America.
Occasional descriptions of allergic disease occurred in antiquity, such as the suggestion that one of the pharaohs died of anaphylaxis after a bee sting.
The first convincing description of hay fever was by John Bostock, who described his own symptoms in 1828. The first investigations of hay fever were published in the 1870s by Blackley,
who studied ragweed pollen in the United States. At that stage, the only recognized allergic disease was hay fever, and reports of an increase came from Germany, as well as the United Kingdom and United States. It is important to recognize that there were no clear reports of an increase in pediatric asthma until 1970. Furthermore, the current “epidemic” of food allergy does not appear to have started until after 1990.
This review will attempt to evaluate both the evidence for those increases and the changes that have occurred in lifestyle that could have contributed to sequential increases in different allergic diseases.
The hay fever epidemic
In 1982, Lady Simon, with a startling level of confidence about her facts, asked the author of this review, “Why did hay fever start in 1870?”
She then explained that her father had symptoms of allergic rhinitis and conjunctivitis in Germany in June of 1875, but after several years of symptoms, he could not find a physician who was aware of the condition. By 1890, he knew a group of such patients, but none of them had symptoms before 1870. Blackley
started studying the disease in Manchester, United Kingdom, in the 1860s, but his studies, including skin tests and challenge tests with grass pollen out of season, were primarily performed on himself (Fig 1). By 1900, the disease was well recognized and sufficiently severe for 2 developments.
1.
Sites at which patients with hay fever could go during the season to avoid exposure to pollen were identified, and thus the island of Heligoland in the North Sea was kept free of grass pollen, and Bretton Woods Resort in New Hampshire was recognized as a retreat from the ragweed season by the United States Hay Fever Association (Fig 1).
The earliest investigations of the effects of injections of pollen extract were carried out with the objective of establishing immunity against pollen toxin. Those experiments were published by Dunbar
The question to address is what happened in the second half of the 19th century that could have contributed to the appearance and progressive increase in seasonal allergic rhinitis. It seems likely that changes in both airborne pollen and public hygiene contributed. In England major changes in agriculture followed the reform of the corn laws in 1847.
Between 1850 and 1880, dairy herds increased, and Italian rye grass (Lolium perenne) was introduced, which pollinated more heavily than any of the traditional grasses.
In the United States the progressive increase in arable farming is thought to have increased the growth of ragweed. Certainly ragweed became the most import cause of seasonal rhinitis in the United States.
Major changes in public hygiene started during the 19th century. Given the fact that the Greeks and Romans understood the need for clean water supplies, it is difficult to believe that London in 1854 and Chicago as late as 1890 were collecting “drinking water” from the same site that was used to discharge untreated sewage (Table I).
The critical studies that led to the acceptance of the relationship between sewage and enteric disease were carried out by John Snow in London, starting with the evidence about the Soho pump and cholera and following this with epidemiologic comparison in 1854 of typhoid cases among populations who obtained their water from the London River compared with those whose water came from farther up the river (Fig 2).
However, as late as 1880, there was still only limited acceptance of the germ theory of disease, even among physicians. Indeed, in 1881, President James Garfield was “murdered” by his physicians, who repeatedly probed a nonfatal gunshot wound using nonsterile instruments and fingers.
Starting in 1892, the city of Chicago reversed the course of the Chicago River so that sewage flowed into the Mississippi rather than into Lake Michigan, which was the source of drinking water.
Table IThe essence of hygiene: What elements are likely to be relevant to the onset of allergic disease?
Primary measures
Clean water
•
Complete separation of sources of drinking water from the discharge of untreated sewage
•
Water chlorination
Uncontaminated food
•
Separation of untreated sewage from farming, including strict enforcement of restrictions on defecation in fields
•
Strict enforcement of abattoir regulations
Helminth eradication
•
Wearing shoes—control of hookworm
•
Water and food control—Ascaris species
•
No swimming in contaminated water—schistosomiasis
•
Regular (annual) anti-helminth treatment
Secondary elements
Decreased exposure to farm animals—decreased diversity of bacterial exposure
Decreased exposure to older siblings caused by small family sizes with resulting decreased transmissible infections (exposure in day care might have the opposite effect)
Fig 2A, London water supplies in 1854 used by John Snow as evidence that typhoid and cholera were spread through the water. B, Typhoid fever deaths in Chicago in 1892, which were controlled by extending the water intake into the lake and pumping 407 million gallons per day from the Chicago River into the Mississippi. Fig 2, A: Robert W. Mylne. Map of the contours of London and its environs, showing the districts and areas supplied by the nine metropolitan water companies, published for the author by Edward Stanford, Charing Cross, London; published by Waterlow and Sons, 1856. Accessed at: http://www.ph.ucla.edu/epi/snow/watermap1856/watermap_1856.html. Fig 2, B: From the Annual report of the department of health of the city of Chicago for the year ended December 31, 1894. Department of Health, City of Chicago; 1895 (public domain).
By 1920, chlorination of water was widespread, and all the major cities in the United States had clean water, with the result that typhoid and cholera became rare. If you look at New York City, you could argue that the critical changes in hygiene were complete by 1920 (Table II). In keeping with that, allergy became more common, and by 1946, ragweed-induced hay fever was such a severe problem in New York that the city council initiated a ragweed eradication campaign (Table II).
Equally, in London Dr Frankland's allergy clinic had hundreds of patients in the 1950s, and he and Dr Augustin carried out the first controlled trial of immunotherapy for grass pollen hay fever.
In fact, the increase in allergic disease was already obvious when Dr Swineford was appointed professor of allergy and rheumatology at the University of Virginia in 1935. He had been called back from doing pathology research in Vienna to “help deal with the allergy epidemic,” and he opened the first subspecialty clinic in the Medical School in 1936.
The epidemic increase of asthma among children: 1960-2000
For further information, see Table III. Before 1960, most pediatrics textbooks did not regard asthma as common, let alone epidemic. During the 1960s, there were occasional reports that asthma appeared to be becoming more common, but the first convincing publication came in 1969. Smith et al
carried out a population-based study on schoolchildren in Birmingham, United Kingdom, which demonstrated a sharp increase in asthma between 1958 and 1968. In addition, they reported that many of the children with asthma had positive skin test responses to dust mites. Over the next few years, reports on the increasing prevalence of asthma came from several countries but predominantly from countries in which dust mites were the dominant allergen. Thus increases were reported from Australia, New Zealand, and Japan, as well as the United Kingdom.
Airborne allergen exposure, allergen avoidance and bronchial hyperreactivity.
in: Kay A.B. Austen K.F. Lichtenstein L.M. Asthma: physiology, immunopharmacology and treatment, Third International Symposium. Academic Press,
London1984: 297-314
That argument was helped by the fact that homes in the United Kingdom, Australia, and New Zealand had become warmer and tighter and had more carpets. In turn, this was thought to have provided improved conditions for the growth of dust mites and for the accumulation of debris from dust mite growth.
However, it is important to recognize that a large part of the reason for wanting homes warmer and less drafty was because of the increase in indoor entertainment.
Table IIIChanges that have been suggested as explanations for the progressive increase in pediatric asthma, 1955-2000
I. Increased number of immunizations in early childhood and possible changes in vaccines
II. Progressive increase in the use of broad-spectrum antibiotics
III. Use of paracetamol to treat fever in childhood, which replaced aspirin, after identification of Reyes syndrome in 1979
IV. Changes that occurred either because of or in parallel with the introduction and increase in indoor entertainment: primarily television programs for children, 1955 onward
A.
Decreased play outdoors with consequent decrease in exposure to bacteria and decreased physical activity
B.
Progressive increase in body mass index among children
C.
Changes in homes to increase comfort, including decreased ventilation, increased carpeting and furnishing, and increased temperature
D.
Changes in breathing patterns while watching television, including decrease in sigh rates
V. Increased exposure to indoor allergens secondary to less time outdoors and higher quantities indoors
Although it is well known today that asthma has increased in all Western countries, it might be forgotten that this did not become clear until 1990. In that year, data on asthma among recruits to the Finnish and Swedish armies came out, showing a progressive increase over 20 years.
Trends in asthma, allergic rhinitis and eczema among Swedish conscripts from farming and non-farming environments. A nationwide study over three decades.
In addition, evidence was accumulating that cockroach was a major allergen related to asthma among African Americans living in poverty in the United States.
By 1995, it was accepted that both the prevalence and hospitalization for asthma had increased among children living in climates or living conditions in which several different allergens dominated both exposure and sensitization.
At this point, it became very difficult to argue that the increase had occurred simply because of an increase in allergens in homes because there was no reason to think that dust mite, cockroach, cat, and Alternaria species had all increased in parallel. It is important to recognize that the best evidence about the role of allergens in asthma came between 1970 and 1980, with convincing demonstrations that chronic allergen exposure could make a major contribution to nonspecific bronchial hyperreactivity (BHR).
Airborne allergen exposure, allergen avoidance and bronchial hyperreactivity.
in: Kay A.B. Austen K.F. Lichtenstein L.M. Asthma: physiology, immunopharmacology and treatment, Third International Symposium. Academic Press,
London1984: 297-314
Any attempt to explain the increase in pediatric asthma has to deal with the progressive nature of the increase. Although major changes were present by 1980, the increase continued for at least 2 more decades. Although there is evidence for many different aspects of the increase in asthma prevalence and severity, most of these arguments cannot explain either the time course or the scale of the increase (Fig 3).
A typical example is the change from aspirin to paracetamol in 1979 after the identification of Reyes syndrome. This change might well have contributed to the severity of asthma but did not occur until halfway through the increase.
In most studies asthmatic children were found to be allergic to 1 or more of the common perennial allergens. In Australia Peat and Woolcock reported detailed studies on the “modifiable risk factors for asthma,” including diet and immunization, and they concluded that dust mite allergy was the most important of these factors.
Fig 3Published data on the increase in hospitalizations of children and young adults caused by asthma in 4 countries during the 20th century: A, asthmatic patients in the United Kingdom
Taking everything into account, the changes that fit the time course best are the ultimately disastrous changes that occurred after the introduction of television programs designed for children in the 1950s (Table III). There are 3 questions that need addressing in relation to this period:
1.
Were there changes in hygiene during this period that could explain the timing, scale, or severity of the increase in asthma?
2.
Could decreased physical activity or simply changes in breathing patterns secondary to sitting and watching a screen have had a major effect?
3.
Could any of the other changes, including obesity, increasing schedules of immunization of children, and the change from aspirin to acetaminophen, explain more than a minor part of the epidemic?
What is hygiene? Could changes in hygiene explain the increase in pediatric asthma from 1960-2000?
proposed that repeated exposure to respiratory tract or other infections could decrease allergic disease. At that time, his observations were primarily related to infections transmitted by older siblings. However, those observations were made on the basis of data within a country (the United Kingdom) where water had been clean for many years, parasitic helminths were not a major problem, and only a small proportion of the population was exposed to farm animals. By contrast, in Africa, India, and South America there are today many “prehygiene” communities where (1) water supplies are contaminated by untreated sewage, (2) helminth infection is common, (3) children go barefoot, and (4) houses are not a place where children would choose to stay during the day.
Differences in both prevalence and titre of specific immunoglobulin E among children with asthma in affluent and poor communities within a large town in Ghana.
In addition to studying differences between countries with a fully modern pattern of allergic disease and prehygiene communities, there are 3 models in which it is possible to study the effect of differences in “hygiene” within a community:
1.
countries, such as Kenya, Ghana, or Ecuador, where changes are occurring currently
Differences in both prevalence and titre of specific immunoglobulin E among children with asthma in affluent and poor communities within a large town in Ghana.
There are 2 sides to these analyses. First, what are the features of modern allergic disease that characterize a posthygiene state, and second, what elements of hygiene are essential for this change (Table I)? In prehygiene villages children and adults generally have increased total serum IgE levels and low-titer IgE antibodies to mite and other allergens and, if tested, often have IgE antibodies to parasite-related antigens, such as Ascaris species or the tick-related galactose-α-1,3-galactose.
Differences in both prevalence and titre of specific immunoglobulin E among children with asthma in affluent and poor communities within a large town in Ghana.
In posthygiene society mean total IgE levels are lower, and specific IgE antibodies to common inhalant allergens are common and often present in high titers. In addition, the presence of high-titer IgE antibodies correlates with both hay fever and asthma.
In some studies mean total serum IgE levels among nonatopic subjects are as low as 20 IU/mL. In posthygiene communities asthma is often severe, and many children require regular treatment. By contrast, in prehygiene communities, although wheezing is not uncommon, it is generally not severe, and treatment is unusual.
Given that the major changes in hygiene had occurred in London, New York, and Munich by 1920, it is difficult to ascribe the massive changes in the prevalence of asthma between 1960 and 2000 to the minor changes in hygiene that occurred over that period.
The original observations about family size have not been confirmed consistently.
Indeed, a major study in Denmark found that the presence of increased bacteria in the upper airways was associated positively with the development of asthma. Furthermore, they reported that the presence of older siblings increased the risk (ie, the opposite of the original observations).
Overall, the best definition of the hygiene effect relates to changes that started in 1870 and were largely complete in the major cities of Europe and the United States by 1920. Similar changes are occurring today in Africa, India, and South America. However, the shift to a Western model of asthma appears to occur rapidly (ie, within 5 years after a major change in hygiene). Thus there is no reason to think that the changes in public hygiene that occurred in 1920 can be used to explain the timing of the increase in asthma from 1960-2000 (Fig 3).
Relevance of decreased physical activity and changed breathing patterns to the increase in pediatric asthma
One of the most obvious effects of indoor entertainment was a progressive increase in the number of hours children spent sitting each day. There are a large number of secondary consequences of this change that include increased obesity, changes in diet, and more exposure to indoor allergens. However, our main concern here is with the lungs. Any form of physical activity will lead to full expansion of the lungs, but in addition, normal breathing includes periodic deep breaths or sighs.
carried out detailed studies on the physiology of bronchial smooth muscle. Those studies concluded that bronchial smooth muscle does not obey Starling's law and will start to contract at a shorter length if not stretched regularly. They went so far as to state that “stretching smooth muscle is a more potent bronchodilator than isoprenaline” and to describe sighs as the primary protection against bronchospasm.
Second, the alternative form of the same experiment has been to study the effects of prolonged shallow breathing in human volunteers. Those studies by several different groups have shown that prolonged shallow breathing will result in increased lung resistance and increased BHR.
The question then is whether watching a screen can influence the breathing pattern. At present, a properly designed study on children watching a television program compared with playing a computer game or texting has not been reported. However, students watching a screen have a significantly lower sigh rate compared with the same students reading a book.
Thus it is reasonable to propose that children watching a screen without interaction with the program not only lack physical activity but might also experience prolonged periods of shallow breathing of exactly that form that has been shown to increase BHR.
Remarkably, regular exercise is not part of the standard treatment for asthma.
National Institutes of Health; National Heart, Lung, and Blood Institute: National Asthma Education Prevention Program Expert panel report 3: guidelines for the diagnosis and management of asthma.
This is despite the fact that aerobic activity is recommended for cystic fibrosis, chronic obstructive pulmonary disease, and a wide range of cardiologic conditions. Many studies have shown a positive effect of exercise on asthma or BHR, but these have not been converted into a consistent recommendation about exercise as part of the treatment.
In addition, it is not clear whether the primary effect of exercise would be to decrease lung inflammation or a physiologic effect secondary to regular stretching of smooth muscle.
Other factors or changes that have been suggested as playing a role in the increase in asthma
The list of explanations for the increase in asthma is not short (Table III). Most of these could be relevant to the increase, but only a small number could have played a major role. Typical examples include broad-spectrum antibiotics, air pollution, global warming, obesity, and acetaminophen.
First, broad-spectrum antibiotics were widely available by 1965, and although their use has increased steadily, the major changes occurred very early in the epidemic. Clearly, it is possible that use of antibiotics early in life has played a role in changing the fecal biome; however, such changes tend to be transient, and most epidemiologic studies on antibiotic use have only shown a modest effect on the prevalence of allergic disease.
Second, increases in air pollution could well have played a role in asthma in places like Los Angeles. However, asthma has increased in many other areas where air pollution is an insignificant problem, such as coastal towns in New Zealand, or in places where air pollution has progressively decreased, such as London. There is good evidence about the possible effects of diesel particulates, both in relation to sensitization and as a cause of direct irritation of the lungs.
On the other hand, industrial pollution related to coal smoke is not a convincing cause of asthma. Indeed, in a town such as Katowice in Poland, where the industrial pollution was very severe, the children had bronchitis, but asthma was less common.
Third, obesity has been one of the major consequences of the indoor lifestyle, which includes a role for both dietary changes and decreased physical activity. Furthermore, there are strong correlations between time spent watching screens, asthma, and obesity.
Therefore the question is whether obesity itself has made a contribution to asthma prevalence?
There are 2 issues here. First, what is the evidence about an association with wheezing, and second, what is the mechanism if there is an association? The main problem with the epidemiologic data is that asthma diagnosis is generally based on questions, such as “Do you (or your child) become short of breath on exercise?” The problems with such a question in an obese population are obvious.
Our group recently reported that we could not find a difference in lung function between obese teenagers with and those without a diagnosis of asthma. The conclusion of our study was that many obese children receive a diagnosis of asthma because of symptoms that are primarily due to them being unfit.
Fourth, global warming is having major effects in many fields, but the changes in temperate climates thus far have been modest compared with the changes in exposure associated with adoption of an indoor lifestyle. There are interesting data showing that increased concentrations of CO2 in the air can increase growth and pollen production by some of the important plants related to allergy, including ragweed.
However, those data do not relate to the indoor allergens most strongly associated with asthma.
Fifth, increased use of acetaminophen instead of aspirin to treat fever in childhood occurred rapidly after the discovery in 1979 that aspirin could induce Reyes syndrome. Since then, multiple studies have provided evidence that acetaminophen use can increase both the severity and prevalence of asthma.
However, if we look at the time course of the increase in asthma, major increases had occurred before 1980. Thus if acetaminophen played a role, it was in the continued increase and not related to the onset of the epidemic.
Sixth, there was a progressive increase in the recommended immunization of children from 1950-2010. The number of injections that children receive in early childhood is a concern for many parents and pediatricians. In addition, several authors have suggested a possible role of these injections in the increase in allergic disease or in food allergy in particular. There are several elements that have been identified. First, there was the possible protective role of BCG immunization; however, after the first report, several studies did not confirm this effect.
Does BCG vaccination protect against childhood asthma? Final results from the Manchester Community Asthma Study retrospective cohort study and updated systematic review and meta-analysis.
In addition, there was evidence that the increase in asthma prevalence did not look significantly different in countries where BCG vaccination was routine (eg, Brazil or Ireland) compared with those, such as the United States, where BCG was never adopted. Second, many of the vaccines contain alum, and some investigators have implied that the total quantity of alum used could play a significant role in enhancing TH2 responses.
In addition, there was an important change in the pertussis vaccine from a cellular form to an acellular form. This last change took place around 1992 (ie, too late to play a significant role in the asthma epidemic but in time to be relevant to food allergy). Interestingly, the effects of pertussis vaccination have been investigated both before the change to the acellular form and also after the change.
Vaccine- and antigen-dependent type 1 and type 2 cytokine induction after primary vaccination of infants with whole-cell or acellular pertussis vaccines.
they found that the cellular vaccine downregulated IgE and IgG4 antibodies to tetanus toxoid and diphtheria toxoid. By contrast, 2 separate groups have reported a strong pro-TH2 effect of the acellular vaccine.
Vaccine- and antigen-dependent type 1 and type 2 cytokine induction after primary vaccination of infants with whole-cell or acellular pertussis vaccines.
Needless to say, a proper controlled trial comparing the effects of cellular versus acellular pertussis vaccine on allergic disease has not yet been conducted.
The dramatic increase in food allergy from 1990 to the present
Allergic or anaphylactic reactions to peanuts and other foods have been recognized for many years. However, starting about 20 years ago, most clinics in the United States and United Kingdom observed an increase in the number of cases. Furthermore, it was clear that, at least for peanut, the titers of IgE antibodies to the relevant proteins were often very high. The observations made in clinics have been confirmed in population-based birth cohorts.
This epidemic cannot possibly be ascribed to the changes in water quality that occurred 70 years earlier or to changes in physical activity that started at least 30 years earlier (Table IV).
Table IVPre-existing factors and changes that could be relevant to the increase in peanut allergy in the United States, 1990 to the present
I.
Differences in the preparation of peanut products
A.
Roasted vs boiled
B.
Emulsified peanut products in the United States
II.
Delayed oral consumption of peanut proteins
A.
Comparison of Israel and London
B.
American Academy of Pediatrics policy regarding avoiding peanut products
III.
Changes in skin as a result of daily bathing with soap or detergents
A.
Removal of lipids from skin
B.
Other damage that could allow increased skin penetration
The cause of the increase in the United States and London is not clear, but several elements of the argument have been clarified. First, it is clear that early exposure is not the cause of increased peanut allergy. Indeed, it is now certain that oral exposure during the first 5 years can be protective,
The important implication is that for children who avoid oral exposure, the presence of peanut products in the house that will inevitably get on the child's skin can increase the risk of sensitization.
However, it is not clear that there have been big enough changes in the presence of peanut products or the preparation of peanut products over the period of the increase.
If the skin is an important route for sensitization, is it possible that there have been changes in the skin secondary to diet or to skin care? The skin care issue is interesting because the washing of babies has undoubtedly increased. With progressively smaller family size, there is a tendency to wash babies daily, which was certainly not normal 50 or even 25 years ago. Thus it is conceivable that skin permeability to foreign proteins has changed.
Interestingly, the proposed explanations for the increase in food allergy relate to changes that could be reversed.
Regional outbreaks of Asian lady beetle allergy and delayed anaphylaxis to red meat
In the United States there have been 2 regional outbreaks of allergic disease in the last 10 years. One was caused by infestation of homes by the Asian lady beetle (Harmonia axyridis), which had been introduced to control aphids.
Interestingly, lady beetles had not previously been identified as a source of allergens. The diagnosis had to be made with locally or individually made extracts, and thus it is difficult to know anything about the overall prevalence.
In this case the cause appears to be a major increase in tick bites from the lone star tick, which is best explained by the truly dramatic increase of deer in both rural and suburban areas of the east coast.
It is not clear how this epidemic could be controlled because both larval and adult lone star ticks are remarkably enthusiastic about biting human subjects.
The increase in allergic disease did not start until the most important changes in hygiene had been achieved. In keeping with this, the forms of allergic disease that are most common in developed countries are not present today in Kenyan, Ethiopian, and Ecuadorian villages or in poor areas of a major city in Ghana.
Differences in both prevalence and titre of specific immunoglobulin E among children with asthma in affluent and poor communities within a large town in Ghana.
However, the real epidemics require more than hygiene alone. Hay fever appeared in the latter part of the 19th century and the first half of the 20th century, when grass pollen in the United Kingdom and ragweed pollen in the United States were already present at high levels (Fig 4). The increase in pediatric asthma started in 1960 and has become obvious in all posthygiene societies. However, the timing does not match any major changes in hygiene. Indeed, the changes that fit the timing of the increase in asthma relate to the move of children indoors that started with the introduction of television programs for children. The move indoors has had many consequences, including the increase in obesity and decrease in physical fitness. However, the consequences that seem most relevant are the steady increase in sensitization to perennial indoor allergens, the decrease in outdoor exercise, and the remarkable amount of time children spend watching a screen.
Fig 4Sequential increases in the prevalence of allergic rhinitis, pediatric asthma, and peanut allergy with respect to key events in the adoption of modern hygiene of Western society.
We are all familiar with the time course and scale of the increase in symptomatic wheezing, as documented so well by the International Study of Asthma and Allergy in Childhood.
However, the increase in asthma has also been seen in treatment and hospital admissions (Fig 3). Furthermore, the shift to poor populations in the United States was also clear in mortality statistics between 1970 and 1990.
The evidence that allergic rhinitis increased over that same period was based on soft questions about nasal symptoms. By contrast, several surveys on hay fever confirmed a prevalence of around 10% before 1970, and 2 surveys in 1969 and 1997 suggest that the increase was not significant over that period.
Many or most of these admissions in children and young adults are triggered by viral infections. In infants and toddlers many different viruses are involved, but in children older than 3 years and young adults, more than 90% of the virus-induced episodes are triggered by rhinoviruses.
Given that these viral infections have always been very common, the increase in acute episodes is best explained by changes in the number of subjects with increased BHR and inflammation of the lungs. Taken together, the best explanation for the increase in asthma is that it resulted from an increase in sensitization to indoor allergens and the loss of a lung-specific protective effect of regular deep inspiration.
Although some studies suggest that both hay fever and asthma prevalence have continued to increase, there is other evidence that the severity of both hay fever and asthma have decreased. In the case of hay fever, several developments might have contributed to a decrease in the severity of symptoms. These include improved antihistamines and nasal sprays but equally less time spent outdoors. The move of adults indoors has been facilitated by the availability of home air-conditioning (starting in approximately 1965), which makes it possible to exclude pollen from houses.
The decrease in the prevalence and severity of asthma in the United States could have had several different causes. The most obvious is the introduction of combination inhalers, which include both steroids and long-acting β2-agonists. However, it is also possible that the breathing patterns of children are different when they are working on a computer or texting. As was mentioned earlier, the correct study comparing children's breathing patterns while on a computer compared with a television program has not been reported. However, in addition, there is considerable public awareness of the significance of allergen exposure in the home, and it is not difficult to obtain full advice about avoidance measures for dust mite from an allergist or online.
The real conclusion of this review is that allergic disease has developed in large part as a result of changes in lifestyle. The development of public hygiene was driven by a logical desire to avoid enteric, insect-borne, and helminth infections. However, that has had the major consequence of allowing up to 50% of the population to become sensitive to otherwise irrelevant foreign proteins. Initially, these were predominantly the inhaled pollens associated with hay fever and then were extended to the perennial indoor allergens associated so strongly with asthma. Most recently, a range of foods has become the focus. Although avoidance might have a role in relation to pollens and indoor allergens, it is now clear that avoiding oral exposure is the wrong strategy for foods.
What is also clear is that none of the consequences of changes in the way we live have been predicted. John Snow was not worrying about hay fever. The inventors of the Mickey Mouse Club did not imagine that they would help to put thousands of children in hospital with asthma. Equally, those of us (in fact most of us) who earnestly advised mothers to avoid peanuts for their child's first 2 years did not imagine that the strategy would make the situation worse. Equally, when leash laws were introduced into thousands of suburban subdivisions, no one warned that an increased deer population would increase tick bites and sensitization to the oligosaccharide alpha-gal. Unfortunately, it seems most unlikely that we will correctly predict the allergic consequences of future so-called improvements in the way we live. However, we should do our best to continue “the unequal attempt to keep up with the consequences of real changes in life style.”
The major changes relevant to hygiene (ie, clean water and helminth eradication) started in 1850 and were established in the major cities of the United States and Europe by 1920.
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The relevance of pollen to hay fever was first defined in 1870, and by 1900, the disease was common among the “leisured classes.” By 1940, hay fever was epidemic.
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Pediatric asthma increased steadily from 1960 to 2000, and the clearest correlation is with the move of children indoors.
What is still unknown?
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Which consequences of the move indoors were most important to the increase in asthma: (1) increased sensitization to indoor allergens; (2) long periods of time spent sitting with inadequate expansion of the lungs; or (3) changes in diet?
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The reasons why peanut allergy has become more common might include (1) changes in vaccines, particularly the change from cellular to acellular pertussis; (2) excessive washing of the skin that could have increased penetration of the skin by peanut proteins; and (3) attempts to avoid oral peanut.
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After the primary changes in hygiene, has the move indoors added a further element that can best be reversed by having a dog in the house?
I thank the many colleagues who have contributed over the years to understanding this history, as well as those who provided the many helpful comments on the text. In particular, I would like to thank Matt Perzanowski and Philip Copper for discussions about the nature of the hygiene effect and Jane El-Dahr, Scott Commins, and Pat Holt for helpful discussions about the effect of vaccination.
References
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History of allergy in antiquity.
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Airborne allergen exposure, allergen avoidance and bronchial hyperreactivity.
in: Kay A.B. Austen K.F. Lichtenstein L.M. Asthma: physiology, immunopharmacology and treatment, Third International Symposium. Academic Press,
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Trends in asthma, allergic rhinitis and eczema among Swedish conscripts from farming and non-farming environments. A nationwide study over three decades.
Differences in both prevalence and titre of specific immunoglobulin E among children with asthma in affluent and poor communities within a large town in Ghana.
Does BCG vaccination protect against childhood asthma? Final results from the Manchester Community Asthma Study retrospective cohort study and updated systematic review and meta-analysis.
Vaccine- and antigen-dependent type 1 and type 2 cytokine induction after primary vaccination of infants with whole-cell or acellular pertussis vaccines.
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