What Is the Scenario of the Rest of Atopic Diseases?

Other than analyzing asthma, a European study (SCARPOL) that was conducted four times between 1992 and 2001, revealed evidence of stabilizing asthma and hay fever, but with a predominant increase in atopic eczema in girls that was stable in boys.
The same tendency was found in the Aberdeen evaluation when considered up to 2004. There, the three atopic illnesses demonstrated a stable prevalence that was a pattern in the past 10 years, with a continuous increase present in girls that makes no sex difference at the end. As in the former study, when evaluating
eczema, females were more prevalent.
However, an Italian evaluation demonstrated an increasing trend from 1994 to 2002 in wheezing, allergic rhinoconjunctivitis and atopic eczema in both 6- to 7-year-old and 13- to 14-year-old populations, except for wheezing in the last group.
A global time trend analysis of prevalence in rhinoconjunctivitis symptoms evidenced yet again a smooth increase, being more evident in LMIC and in the older age group, suggesting that environmental influences in the development of allergy may not be limited to early childhood.
Related to these asseverations, a recent evaluation in the tendency of aeroallergen sensitization for 25 years (from 1976–1977 to 1999–2001) evidenced a significant increase in the prevalence of sensitivity as well as in the mean age of allergic patients. Again, ISAAC is the option to have a global vision. A recent publication of a worldwide comparison of two phases in 6- to 7-year-old and 13- to 14-year-old populations, using the same methodology both times with a mean of 7 years of difference, allowed to evidence several projections of concern: (a) In 6- to 7-yearold, an incremental tendency in asthma, rhinoconjunctivitis, and eczema was observed in Asia-Pacific, India, North America, Eastern Mediterranean, and Western Europe.  In 13- to 14-year-old, this augmentation was evidenced in Africa, Asia-Pacific, India, Latin America, and Northern and Eastern Europe. (c) In asthma at 6- to 7-year-old, more centers reported increase of prevalence, while in the 13- to 14-year-old group, almost equal centers reported up and down tendency.

Those having larger prevalence in the first phase tend to have a decrease in the third phase and vice versa. (d) For allergic rhinoconjunctivitis, most centers at both ages. Changes (delta) and 95% confidence interval in prevalence of wheezing, atopic rhinoconjunctivitis, and atopic eczema in the past 12 months, reported by parents of children 6–7 years of age (left) and by adolescents 13–14 years of age (right) in six areas of Italy.

Is the Prevalence of Allergy Continuously Increasing?
For atopic eczema, the 6- to 7-year-old participants showed increased tendency in average, while in the 13- to 14-year-old samples, such tendency was not that evident. Taking all disorders together, the younger group had an increase from 0.8% to 1%, and the older one from 1.1% to 1.2%.
We can then preliminarily conclude that globally, there is still a growing prevalence of atopic disorders, predominantly in developing regions of the planet.

Is It the Same in Low- and Medium-Income Countries (LMIC) in the Planet?

Some years ago, Faniran et compared the prevalence of asthma and atopy in children between an affluent versus a non-affluent country, having a smaller prevalence of wheeze and persistent cough in Nigeria when compared to Australia (10.2% and 5.1% compared to 21.9% and 9.6%, respectively).

Anyway, a recent report from Aït-Khaled evidenced a wide range of atopic disorders prevalent all over Africa, not only with the highest presence of current asthma in urban areas with higher standard of living (concordant with the hygiene hypothesis) but also with a representative prevalence in endemic parasite and tuberculosis zones (opposed to the hygiene hypothesis).
In Latin America, protective factors to avoid having asthma seem not to play a role, and the non-allergic factors like pollution are not conditioning a higher prevalence of respiratory symptoms. However, this prevalence is similar to industrialized countries. In a recent survey of rural Asian children, 16.1% of wheezing prevalence in the past 12 months was found, not different from other developing regions of the planet.
The former reports, the International Study of Allergy and Asthma in Children (ISAAC), utilized the same methodology of evaluation, having strength enough to make conclusions and to compare different cultures and latitudes.

However, scarce tendency data are available from LMIC since the possibility of having these tools for evaluation has become recently available. An example is the ISAAC Phases I and III in comparison with Brazil, where nocturnal cough and wheezing slightly but significantly diminished; however, the generalization of these results is improbable when considering previous references.

Taken all together, we could conclude that globally, the prevalence of asthma is high and still demonstrates a slight increasing tendency, even though there is a lessening of differences.

Is the Prevalence of Asthma Continuously Increasing?

In Finnish young men, the incremental tendency of asthma diagnosis remained from 0.29% in 1966 to 1.79% in 1989. The possibility of confounding factors in the diagnosing is improbable, as the exemption of military service due to incapacitating asthma was correlated with the increase reported.

In another wider evaluation in the UK, from 1955 to 2004, several indicators of asthma such as primary care, prescriptions, hospitalizations, and mortality evidenced an increase until the 1990s, where the curve flattened and even decreased The opposing evolution of these effects compared to the sale of inhaled corticosteroids (ICS) is one explanation, since the recognition of the inflammatory component of asthma began in the 1980s.

However, also in the UK, an evaluation of prevalence in schoolchildren between 1991 and 2002 showed a significant increase in wheezing in the past 12 months, in severe speech-limiting episodes and night waking, but non-significant increase in medical visit because of wheezing. Here again, this last finding could be explained by the significant increase in steroids prophylactic treatment reported in this population.

This explanation will be reconsidered ahead.
Another trend study also evidenced a significant increase from 1990 to 2003 in doctor-diagnosed asthma, more evident in females (7.3–14.6%) than in males (7.8–9.4%), in all age groups but larger in people aged 55 and older.

Is the Prevalence of Allergy Continuously Increasing?

Health systems and investigators worldwide have been asking themselves for many years whether the prevalence of atopic illnesses has been increasing continuously.
It is mandatory to consider studies using comparable methods to validate these
results.

The Aberdeen study considered the presence of asthma diagnosis, wheezing, eczema, and rhinitis between the decades of 1960 and 1990, showing a significant increase in all of them, not attributable to a diagnosis fashion but to a truly change in prevalence, using the same methodology in two time points in 25 years. In this population and throughout these years, the proportion of wheezing increased from 10% to almost double, diagnosis of asthma from 4% to 10%, rhinitis from 3% to almost four times, and eczema from 5% to more than double. All these variables increase particularly noticeable in boys.

Perspectives

The challenge of primary and secondary prevention of atopy and asthma has stimulated a variety of prospective interventional trials that are currently ongoing all over the world. Unfortunately, pharmacotherapeutic trials that aimed at long-term disease modification with an inhaled corticosteroid, or prevention of asthma in children with atopic dermatitis by giving an H1-antihistamine such as cetirizine or levocetirizine, have failed to provide more than symptomatic relief during treatment.

A long-term prevention study with a calcineurin inhibitor is currently underway. On the basis of encouraging animal studies, avoidance studies including elimination of alimentary proteins as well as indoor allergens or tobacco smoke, and intervention with oral application of endotoxin, or exposure to mycobacteria or parasites are being conducted. Finally, trials aimed at nonspecific or specific induction of tolerance have recently been initiated.

Allergy immunotherapy has been based on antigen-specific stimulation of the adaptive immune system (by subcutaneous or sublingual specific immunotherapy) for a century. However, the most recent evolution modified our immune system in such a way that allergy is no longer the rare exception but is becoming increasinglym prevalent. Factors once abundant in our environment that normally stimulated our innate immune system to protect us from allergy development are now missing more and more often. Several categories of new intervention strategies for allergy prevention are based on this concept: induction of immune functions that are able to down-regulate unwanted immune responses against allergens and suppressm allergen-induced inflammation. These new preventive and therapeutic strategies are not limited to respiratory allergies, but involve food allergies as well.

The Avoidance Concept

Since indoor allergen exposure was shown to be associated with allergic sensitization, which on the other hand was associated with childhood asthma, it was understandable that the first intervention studies aiming at primary prevention of early sensitization and the development of allergic airway disease have concentrated on indoor allergen avoidance.

The earliest trial, the Isle of Wight study, showed that children at the age of 8 years tended to have less wheeze and a lower risk for mite sensitization following the avoidance of early house dust mite allergen contact. In contrast, the Study of Prevention of Allergy in Children in Europe (SPACE) was not able to show a significant benefit in the intervention group (mattress covers).

In the Manchester Allergy and Asthma Study (MAAS), 291 infants—at high risk because both parents were atopic and there were pets in the home—were recruited, and a number of avoidance measures were instituted to decrease inhalant allergen exposure. The group was able to demonstrate that the avoidance measures were capable of achieving and maintaining a low dust allergen environment during pregnancy and for the first 3 years of these children. At age 3 years, children in the active group had less wheeze and a lower airway resistance; however, the sensitization rate to mites was higher than that in the control group In the Dutch Prevention of Incidence of Asthma and Mite Allergy (PIAMA) study, the intervention had a significant effect on mite allergen levels, but no effect was seen on respiratory symptoms, atopic dermatitis, or total and specific immunoglobulin E levels.
So far, we must admit that recommendations to families for primary prevention of asthma should be given with caution, as no single approach can definitively prevent children from developing asthma.

Primary Prevention: The Challenge of the Future

In an attempt to reverse the observed epidemiological trend, primary prevention strategies for decades aimed at avoiding risk factors and inhibiting their mechanism of action. More recently, attempts were initiated to promote protecting factors and stimulate their mechanisms of action.

Alimentary Ways to Protect
For numerous reasons, breast-feeding is the preferred method of infant nutrition; however, there is still controversy as to whether breast-feeding protects against the
development of allergic diseases.

On the basis of the available data, an “Expert Group” of the “European Academy of Allergology and Clinical Immunology” recommends exclusively breast-feeding for 4 to 6 month irrespective of family history of atopy.

For a long time, primary prevention strategies for asthma were almost exclusively focused on allergen avoidance measures early in life, which were supposed to prevent primary sensitization to both food and inhalant allergens.

For several years, the use of hydrolyzed formula was recommended as an alternative for infants, for whom breast milk was not available and who were genetically predisposed to atopic diseases. Indeed, the German Infant Nutritional Intervention (GINI) Study demonstrated that extensively as well as certain partially hydrolyzed formulas compared to unhydrolyzed infant formulas resulted in a lower incidence of atopic eczema during the first 3 years of life. This study still represents the only large and well-designed trial when comparing different formulas in relation to primary prevention of atopic dermatitis and sensitization to food proteins.

More recently, new alimentary strategies to prevent allergic manifestations are being studied. These include supplementation with probiotics (e.g., lactobacilli) or prebiotics (oligosaccharides influencing the intestinal microflora). So far, the information from the initial studies on supplementation with probiotics is inconclusive.
It will be interesting to see the outcomes of well-designed intervention studies focused on the efficacy of this approach.

Endotoxin

Microbial exposures are abundant in these environments and microbial studies investigating stables report a large variety of gram-negative and gram-positive germs as well as a diversity of molds and fungi.
In addition, nonviable parts of microbes, such as endotoxin from the outer wall
of gram-negative bacteria, are found in abundance in stables and also in elevated
concentrations in indoor environments of adjacent farmhouses.
Endotoxins are a family of molecules called lipopolysaccharides (LPS) and are intrinsic parts of the outer membranes of gram-negative bacteria. LPS and other bacterial wall components are found in high concentrations in stables, where pigs, cattle, and poultry are kept engaged with antigen-presenting cells via CD14 ligation to induce strong interleukin (IL)-12 responses. IL-12, in turn, is regarded as an obligatory signal for the maturation of naive T cells into Th1-type cells. Endotoxin concentrations were recently found to be highest in stables of farming families and
also in dust samples from kitchen floors and mattresses in rural areas in southern Germany and Switzerland.

These findings support the hypothesis that environmental exposure to endotoxins and other bacterial wall components is an important protective determinant related to the development of atopic diseases. Indeed, endotoxin levels in samples of dust from children’s mattresses were found to be inversely related to the rate of occurrence of hay fever, atopic asthma, and atopic sensitization.
On the other hand, high exposure to endotoxins may only be a surrogate marker for other bacterial products such as nonmethylated cytidine-guanosine, dinucleotides specific for prokaryotic DNA (CpG motifs). Cell wall components from atypical mycobacteria or gram-positive bacteria, such as lipoteichoic acid, are known to affect immune responses in ways similar to endotoxin.

Farming Environment

In farming environments where animals such as cattle, pigs, and poultry are kept, microbial products are particularly abundant. Accumulating evidence indicates that children growing up on traditional dairy farms have a significantly lower prevalence of atopic sensitization, hay fever, and asthma when compared with children from the same rural areas but not raised on farms. Interestingly, no protective effect of a farming environment was seen for the prevalence of atopic dermatitis.

Contact with livestock and poultry was found to explain much of the relation between farming and atopy. Exposure to the farm environment during the first year of life or even before birth, and the dose and duration of exposure from the first to the fifth years of life were crucial for this protective effect. Children exposed to animal stables or unpasteurized milk in the first year of life, in contrast to later exposure, had a significantly reduced prevalence of asthma, whereas
continued exposure was relevant for the protection from atopy and hay fever.

Early Exposure to Infections or Microbial Products?

One hypothesis that has attracted considerable interest is that a decline in certain childhood infections or a lack of exposure to infectious agents during the first years of life associated with smaller families in the middle class environments of industrialized countries may be causal for the recent epidemic in atopic disease and asthma. Although this hypothesis is obviously very complex, various sources of information appear to support it. Studies from several countries provide indirect evidence for the hypothesis that early exposure to viral infections, although triggering lower airway symptoms during early life, may exert long-lasting protective effects. Children born into families with several siblings, especially older siblings, have been found to have reduced risk of allergic sensitization and asthma at school age. Studies in children who attended day-care centers during infancy support this concept. Infections are known to produce long-lasting nonspecific systemic effects on the nature of the immune response to antigens and
allergens. For example, recovery from natural measles infection reduces the incidence of atopy and allergic responses to house dust mites to half the rate found in vaccinated children.
Obviously, the fact that certain infections induce a systemic and nonspecific switch to Th1 cells may be responsible for inhibiting the development of atopy during childhood.

Observations from Japan suggesting that strong positive tuberculin responses in children predict a lower incidence of asthma, lower serum IgE levels, and cytokine profiles biased toward a Th1-type were supported by animal experiments demonstrating that IgE responses to ovalbumin in mice could be down-regulated by a previous infection with bacillus Calmette-Guerin (BCG).
Unfortunately, cohort studies from Europe were unable to describe any protective
effect of BCG vaccination.
Although these observations on the relationship of immune responses to infectious agents, atopic sensitization, and disease expression are stimulating and challenging, conclusions regarding the relevance of the atopic march should be drawn with care.

In different parts of the world, completely different infectious agents have been addressed in different study settings. It appears to be fashionable to join Rook and Stanford who, in a recent review article pleaded “Give us this day our daily germs”—but which germ, at what time, under which circumstances, and at what price?