What About Infections and the Hygiene Hypothesis?

In 1989, Strachan  proposed that allergic diseases could be prevented by infections in early childhood, and the transmission of them by unhygienic contact with older siblings. Smaller family size, higher standard of living, and personal cleaning reduced the chances of spreading “protective” infections, originating the hygiene
hypothesis.
A recent comparison of two genetically related but cultural and socio-economic different populations (Russian and Finnish) evidenced higher specific IgE levels in Finnish but more total IgE and specific microbial antibodies in Russians.
Enterovirus infection represented the strongest protective factor against allergen
sensitization.
In this direction, farmers’ children from a rural environment were evaluated for atopic symptoms (by questionnaire) and atopy (by skin test), as well as endotoxin measurement. Compared to non-farmers’ children, they presented significantly fewer symptoms of current asthma (adjusted OR 0.67; 95% CI 0.49–0.91; P = 0.01) and rhinitis (OR 0.50; 95% CI 0.33–0.77; P = 0.002). If having unpasteurized milk
also, a significant reduction of atopy (OR 0.24; 95% CI 0.10–0.53; P = 0.001) and current eczema symptoms were added (OR 0.59; 95% CI 0.40–0.87; P = 0.008), while reducing IgE (P < 0.001) and increasing IFNg (P = 0.02). Pasteurized milk, vaccinations, early use of antibiotics, and the westernized lifestyle with less exposure to infectious agents could contribute to this lack of stimulation, essential in the first years of life to change the initial Th2 profile toward a Th1 just not to favor atopy development.
Ten years ago the hygiene hypothesis was suggested, an extensive analysis was done to determine its current relevance, and the conclusions were:
 (a) atopic diseases, but not necessarily asthma, are highly prevalent in smaller and more affluent families;
(b) the postulate of protective infections against atopy is immunologically plausible; the reversal is inconclusive;
(c) the modulating effects of antibiotic therapy and diet influencing intestinal flora need to be evaluated extensively;
(d) The inverse association of family size and allergic sensitization could potentially help to discern underlying causes of the increasing prevalence of atopic diseases.
However, the Th1/Th2 paradigm and how it fits in the hygiene hypothesis must be analyzed. Table 1 considers how all these factors affect both Th2 and Th1 illnesses, and its scheme outlines factors influencing immune system development at different time points.
In this context, genetically inheritance should be the beginning, while the attributable genetic risk ranges from 30% to 80% depending on the disease considered.
Then, susceptibility to multiple exposures will determine if “western and industrialized world” affects the development of atopic diseases in these individuals.
There, developing countries with the objective of reaching a better quality of life increase their risk as shown by the increased atopic prevalence in people who migrated to developed regions and in urban cities when compared to rural.
As a conclusion, we do not need to go back in evolution, we must maintain the control over infections, but need to clarify the role of each microbial stimulus (especially at the gastrointestinal tract), in parallel with genetic background and every co-factor. Large longitudinal birth cohort studies, getting representative
biological and environmental samples, will help us in the future.

Work Exposure

With an obvious gap in concentration, some same outdoor pollutants could be found at working places. But time and dose exposure could promote the starting of irritant asthma, like sulfite mill workers in whom sulfur dioxide established a risk of four to six times greater for new-onset medical-diagnosed asthma. Not only
pollutants are capable of inducing asthma, instruments and surface cleaners, adhesives and latex particles have been implicated in that process within healthcare workers. The list of demonstrated provoking agents, as well as mechanism involved, goes beyond the present analysis.

What About Environmental Pollution and Work Exposure?

The effects of air pollution have been described some years ago as significantly harmful in children with elevated IgE and bronchial hyper-responsiveness. Airborne particulate of a size of less than 10 μm (PM10), sulfur dioxide, black smoke, and nitrogen dioxide provoked lower airways symptoms in these patients (wheezing
and dyspnea), as well as a decrease in peak expiratory flow greater than 10% while
particulate amounts increased.
PM10, nitrogen dioxide, and carbon monoxide showed a considerable correlation with emergency assistance in children, but not in adults. In children under 5 years, peak carbon monoxide level was predictive of hospitalization because of asthma attack.
Going from an epidemiological to a bio-immunological approach, one of the risk factors that could explain the increasing prevalence of atopic diseases in industrialized countries has been the exposure to diesel exhaust particles, recognized as enhancer of IgE-dependent allergic inflammation, and the consequent
symptoms of asthma and rhinitis. Once again, a recent revision cannot be conclusive in considering these particles as a significant risk factor for having atopic diseases.
About indoor pollution, there is no doubt that tobacco smoke constitutes the key factor to be considered, since it has been implicated in the development of asthma in children and non-smoking adults exposed. About those smoking actively, the RR for incidental asthma was reported as high as 3.9 (95% CI 1.7–8.5).

Could Diet Effect Be Related to Overweight?

As atopy, asthma, and obesity increased in the last decades, it was reasonable to speculate that maybe they are linked. When evaluating the effect of the Mediterranean diet, it was reported that obesity was a risk factor for current severe asthma in girls. A practical measurement of total body fat is the estimation of body mass index (BMI)–weight/height ratio.
However, controversies about the relationship of BMI with the presence of atopy and asthma is shown by a report from Australia, which states that increased BMI was a risk factor for cough, ever wheezing and atopy (predominantly in girls), but not for diagnosed asthma or bronchial hyper-responsiveness. Without these last
two conditions, it is difficult to be conclusive, as gastro-esophageal reflux, sleep disorders, being unfit, or altered mechanical ventilation could explain symptoms, and all are associated with overweight.

So some meta-analysis was required to elucidate the real impact of overweight in the incidence of asthma, and 1 with a sample larger than 300,000, evidenced a dose–response increasing odds for incident asthma: odds ratio (OR) 1.38 for normal versus overweight comparison, and OR 1.92 for obesity; none of them was
affected by sex. These odds have a huge impact on populations like the USA, where more than 60% of adults are overweight/obese, and in consequence at risk of developing asthma.

Also considering a meta-analysis in children, the same evidence was reported. The relative risk (RR) of high birth weight on developing asthma later was RR = 1.2 (95% confidence interval (CI) 1.1–1.3), while the effect of overweight in middle childhood was RR = 1.5 (95% CI 1.2–1.8) [31]. Misclassification, diagnostic
bias, and individual confounders are always doubts emerging from meta-analysis; however, the results from an enormous cohort study, from childhood to adulthood, are the only possibility to corroborate or contradict this evidence.

Let us analyze the risk factors that could help to explain these phenomena:

Sex
In childhood, male sex has been considered to be a risk factor for having atopic diseases and asthma. Some years ago, this predominance was partially explained by an increased sensitivity to inhalant allergens.
However, we mentioned earlier that the increasing prevalence among girls equalized the male to female ratio
recently, even being more prevalent when considering eczema.
By the age of 11, male sex is still stronger when considering current wheezing. As the age of the sample evaluated increases, the predominance reverses. In a cohort evaluation, male in childhood declined by adolescence and early adulthood, considering female sex as one of the major risk factors for having asthma. It was also a predictive factor for persistence of asthma symptoms from childhood, but this conclusion needs to be reinforced in larger populations because the odds obtained revealed evidence of a wide confidence
interval.
Not only the former but also allergic rhinitis shows similar transition from male in childhood to female in adolescence. Having those repeated observations reinforced by evaluations in large population samples, the fact that estrogen has pro-inflammatory and testosterone anti-inflammatory effects could explain this trend.

Diet
Recently, Garcia-Marcos  evaluated the relationship of the Mediterranean diet (vegetables, pulses, cereals, potatoes, pasta, and rice) with asthma and rhinoconjunctivitis in more than 20,000 children, adjusting for exercise and obesity, finding its protective effect against current severe asthma in girls. Also, seafood and
fruit were protective against having rhinoconjunctivitis.
In the same direction, Wickens  corroborated that fast food intake was related with asthma symptoms in a frequency-dependent manner. Takeaway consumption greater than once a week showed an increased (although not significant) bronchial hyper-responsiveness, but had no effect on atopy.

Not only animal fat consumption was implicated as a risk factor for atopic diseases expressions. Vegetable oils contain linoleic acid, an Omega 6 polyunsaturated fatty acid (PUFA) precursor of arachidonic acid and consequently of eicosanoid metabolites, promoting the Th2 imbalance while decreasing interferong (IFNg); omega 3 PUFA found in fish oil inhibits PGE2 formation, modulating the production of immunoglobulin E (IgE) indirectly. However, the clinical relevance of adding fish oil in pregnancy diet demonstrated just a decrease in the severity of eczema in infants at high risk of atopy.
Feeding habits in the UK over the last decades, where atopic expressions grew, evidenced diminished saturated fat consumption. This growing could then be attributed to a reduction of antioxidants in the diet, since only the fatty acids deregulations could oversimplify the frame. Anyway, more studies are needed in
this field as interventional strategies have been disappointing as of date.

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.