Frequency of ash pollen sensitization
The data from this long-term seroepidemiological study in adolescent school children investigated in a nonselective manner reveal the high rate of seroprevalence to ash pollen. As mentioned above, this was often not recorded in epidemiological studies. The frequency of sensitizations to ash pollen is higher with tx15, measured in school children in Grabs (16%), than to birch pollen (15%). More subjects in the cohort reacted to Fraxinus excelsior (t25) in the CAP test than to Fraxinus americana (t15). Therefore, the rate of seroprevalence would have been even higher in the cross-sectional studies in 1983–2007 if allergens from indigenous ash (t25) had been used.
The number of school-age individuals in Grabs is too low to obtain frequency data on subgroups with sensitization to ash pollen. It is nevertheless surprising that, even in this small study, one can discern different sensitization patterns.
Cohort studies in nonselectively investigated school children, including spontaneous follow-up all the way into late adulthood, are rare. This small comparable group (n = 12) followed for over 24 years revealed that the majority have kept the same sensitization pattern (pollen or house dust mites, animal danders) from the time prior to adolescence. This even applies to the subgroup with sensitization to ash pollen. However, one of 12 individuals clearly showed new sensitization to the major allergen nOle e 1.
IgE antibodies to a sum of allergens from the corresponding pollen were investigated in the CAP tests. The molecular structures of some of these ash and olive allergens are known. Determination of rOle e 1, the major allergen in Oleaceae pollen, has become established for the molecular diagnosis of sensitization to ash pollen. Strong cross-reactions between this allergen from ash pollen (nFra e 1) and nOle e 1 from olive pollen have been described . For this reason, they are used as a surrogate for sensitizations to ash pollen.
It remains unclear to what extent the use of olive allergens alone (investigated here: rOle e 1) is relevant in the molecular diagnosis of all sensitizations to ash pollen, even though the molecular similarity (ash: rFra e 1) is extremely strong. After all, CAP tests, which contain numerous molecular allergens, show clear differences. However, there are no recombinant molecular ash pollen allergens available for serology. The differing sensitization pattern to pollen allergens from Fraxinus americana (t15) and Fraxinus excelsior (t25) seen in school children in Grabs demonstrates that different varieties can cause different relevant sensitizations.
As with birch pollen, ash pollen also contains numerous accompanying or minor allergens, such as polcalcins (Fra e 3) and profilins (Fra e 2), which are widespread in nature and also share high molecular similarity. Like the profilins and polcalcins in birch pollen, they are probably of less relevance in terms of respiratory symptoms.
However, from a scientific point of view, it is problematic to use individual molecular allergens as surrogates for sensitization to one pollen species. This also applies to rBet v 1. Although this molecule is important when assessing the efficacy of hyposensitization, it does not exclude sensitization or allergy due to other allergens from these pollen—and even less so sensitization due to all other Fagales pollen.
Accordingly, each molecular selection worsens the sensitivity of a sensitization.
The symptoms to ash pollen can be effectively treated with hyposensitization, much like those to Fagales pollen (major allergen, rBet v 1). Patients sensitized to birch and ash pollen often respond less well to hyposensitization with birch pollen alone . The symptoms to ash pollen become unmasked, given that the simultaneous relevance of ash pollen was previously not taken into account due to the symptoms caused by Fagales pollen. Time-consuming and costly hyposensitization is then inadequately effective not for immunological reasons, but due to the insufficient diagnostic work-up or allergen selection, seeing as extracts without ash pollen allergens were used. As such, the recommendation in the current European guideline  not to use or mix these allergens is incorrect and requires revision in clinical routine. Mixed extracts of relevant pollens are difficult to obtain commercially today (e.g., birch–ash).
The sensitization pattern according to molecular allergens is important in patients from a migrant background. Many children in Spain suffer from a relevant allergy to grass and olive pollen . In Switzerland, a large number of children are polysensitized to grass, birch, and ash pollen.
Although ash pollen is wind-pollinated and ash flowers do not produce any nectar, bees also collect wind pollinated pollen, especially from ash. Among the Oleaceae, pollen from Fraxinus ornus (manna ash) is popular . Depending on the time of year and the location of a beehive, the content of this pollen in honey changes. Peroral immunotherapy uses aeroallergens as an active substance. Local honey is considered an effective phytotherapeutic agent in aeroallergen allergies. The relevance of these aeroallergens in foods in terms of sensitization, adaptation, or pathogenesis in other diseases is unclear, e.g., in eosinophilic esophagitis .
The role of the “major and minor allergens,” e.g., IgE to profilins, polcalcins, and in particular nonspecific lipid transfer proteins (nsLTPs) in most tree pollen (Fagales, Oleaceae, Platanaceae, Ailanthus, Castanea, etc.) with the cross-reactive food allergens is poorly investigated.
Exposure (ash pollen level)
Individuals with ash pollen allergy are often symptom-free in years with low levels. A comparison of their symptoms between years with a low ash pollen count and mast years makes it possible to assess the relevance of ash sensitization, much like a pollen exposure chamber. It is very difficult to judge in polysensitized individuals which pollen levels cause which symptoms, since the most important trees in terms of allergy—birch and ash—bloom almost simultaneously in Switzerland: the ashes usually only for a few days, but sometimes up to 2 weeks before or after birch trees . Therefore, it is virtually impossible to determine pollen thresholds responsible for symtoms in polysensitized individuals (two concomitant allergies). The same problem arises as a result of the simultaneous blooming of olive and grass in Spain [6, 18].
Since annual fluctuations in ash pollen levels are considerable yet unpredictable, standardized pollen data over decades are needed (Fig. 3). Only in this way is it possible to assess secondary phenomena, in particular the effects of climate conditions and harmful organisms, such as the epidemic caused here by an imported mutant fungus Hymenoscyphus fraxineus.
Ashes were problematic in the forest 20 years ago due to their rapid propagation and also due to storm damage; they were considered the “weed of the forest.” Back then, an “ashification” of the forest was feared . The mast years 2003, 2005, 2007, 2009, 2013, 2015, and 2018, which were the same at all measuring stations, likely correspond to the natural rhythm of these trees. The fungus was first recorded in 2008 in Basel, along the Jura, as well as in Zurich. The published forestry data are often subject to regional variation. Damaged ashes were registered in central Switzerland and in particular eastern Switzerland in 2010, in western Switzerland in 2011, in Valais in 2013, and in Ticino in 2015, at first primarily in the Maggia Valley (north of Locarno) and later in southern Ticino (Lugano). This means that the disparate changes in regional peak levels of ash pollen (APIn) occurred approximately 2 years after the tree disease was recorded in forestry data. This paradoxical peak pollen production was identified in Buchs in 2011. Effects of this kind (surges in stress) are known to occur in the case of pollutant exposure in the form of excessive seed and cone production, as seen in forest degradation of the 1980s (forest dieback).
Knowledge of the remarkably synchronous inactive periods every 2–3 years in which ash trees release very little pollen (Fig. 3) are important when assessing clinical relevance.
Thus, the lack of pollen production (emission) in 2014 and 2016 was not an effect of ash dieback, but evidently a natural inactive period.
A large number of sick ash trees were felled in the winter of 2017/2018. In 2018, ash trees at all measuring stations in Switzerland (with the exception of Ticino) once again produced more pollen, despite the epidemic caused by Hymenoscyphus. This is a further indication that not all indigenous ashes (Fraxinus excelsior) simply “die off,” but are also able to recover and adapt (Fig. 1). According to the rhythm of mast years hitherto, an inactive phase would have been more likely. In fact, however, pollen levels in west Switzerland and urban centers were remarkably high in 2018, with a moderate rise in east Switzerland and rural regions. In Ticino, on the other hand, both measuring sites recorded a decline. This trend is difficult to interpret and, as a result, prognostic calculations are becoming ever more speculative. In contrast to the Fagales, the ash influorescences are virtually impossible to assess phenologically prior to flowering.
APIn values above 10,000, as shown in Fig. 3, are extremely high by international standards and have been exceeded at various measuring sites since 2003. In the past, this applied only to 1991 and 1992. Models that predict annual ash pollen levels on the basis of meteorological data [23, 24] are of secondary clinical relevance, since mast years cannot be predicted. Nevertheless, optimal retrospective measurement data are important when assessing an indication for or efficacy of hyposensitization. This information should be made available at the end of a season via open access as meteorological data.
Ash trees in urban areas
Trees are generally extremely important for the health of urban populations, and they improve the climate in urban areas considerably. On the other hand, they cost the taxpayer a lot of money. Due to dense construction, private gardens are becoming smaller and room for large trees is lacking. Local environmental conditions significantly limit the survival time of urban trees.
When planting the ideal tree along an urban road, not only does one need to consider species-specific susceptibility to genetically altered harmful organisms, but also dozens of other mainly site-specific criteria, such as quantitative resistance to frost, road salt, heat, water shortage, etc. Therefore, all nurseries publish data on the suitability of their trees to these conditions. Irrigation systems, fertilizers, protective coatings against heat and parasites, as well as pruning are not feasible for forest trees. Trees in urban areas are less able to withstand storm damage. Ultimately, the survival of an individual tree depends on the sum of these conditions where it is located. Resistant varieties are also important for forestry nurseries . The same applies to specific forest uses (protective forests).
When selecting a tree, landscape architects are concerned with practical and aesthetic criteria, such as shape, color, and leaf color in autumn, rather than with flowers and fruits. An essential aspect is price, which varies depending on the species, variety, and height of the tree. The geographic origin of a tree (the microbiome of the soil with which the tree is delivered) is barely taken into account. In terms of actual planting, a new plant is cultivated nowadays from seeds of international provenance; this plant is raised from cuttings, transported to climatologically and economically favorable regions for faster rearing, transported back, and sometimes “stored temporarily” at a regional nursery. The roots are packed in jute and transported on palettes made from international wood. What remains completely unclear is which microbiomes and insects with known and unknown harmful organisms are transposed in this way and planted in urban areas.
Emissions of molecular allergens from these plants represent the essential criterion of quality for the health of allergy sufferers. The example of Spaeth’s alder (Alnus x spaethii)  very clearly illustrates the relevance of these interdisciplinary networks. The small cross-sectional study on 100 school children in Grabs at a 20-year interval showed a marked increase in sensitization to the molecular PR-10 allergens, in particular the alders (rAln g 1). The search for a new allergen source revealed the extremely high pollen count along the regional promenade between Christmas and New Year due to Spaeth’s alders, 1–2 months before the release of pollen from indigenous alders (Alnus glutinosa, Alnus incana). These trees are aesthetically pleasing, but did not even survive 20 years. They were cultivated and distributed exclusively. They were felled due to the shade they created after growing too rapidly and profusely—allergies were merely a secondary argument. As a result, they are no longer planted in Zurich and Bern, in contrast to Germany.
From an allergy perspective, the damage potential of these ashes is also problematic, since the investigated school children also reacted to the cross-reacting PR-10 allergen of apple (rMal d 1) . This dents confidence in recommendations for a healthy diet (fruit and vegetables). Targeted selection of more resistant and better sustainable plants and livestock in agriculture is essential for food production.
Using the same methods to also ascertain the allergen content of different pollen and fruits would represent the basis of primary allergy prophylaxis.
Allergen exposure in urban areas is of great importance from an epidemiological point of view, but extremely difficult to measure. Tree registers only record public spaces in larger urban areas, and no shrubs. It is impossible to determine how often Alnus viridis or Ligustrum vulgare and other varieties  are planted as hedges or ornamental shrubs. Likewise, these anthropogenically planted trees in urban areas cannot be recorded using individual, distant pollen measuring sites . It is virtually impossible to reliably determine individual trees using current remote sensing data. Individual roads are not always planted with the same tree species, which makes sense. The diversity of species used in urban development, with different varieties of organisms, both indigenous as well as new varieties and neophytes, hinders a standardized flowering forecast. This makes it all the more important for patients to assume responsibility for themselves. They should be able to recognize trees and shrubs in a natural habitat and particularly in their environment. “Pollen Apps” could be helpful here; however, these are no substitute for—and could possibly even hinder—a person’s own observations.
In the case of the ashes, it is important to have more knowledge on the molecular allergen content in the pollen of the different species and genotypes (organisms: subgroup of the same taxonomic unit). Variety-specific differences have also been described in olive pollen . From an allergy perspective, it is not advisable to plant nonindigenous ashes, the allergy potential of which is wholly unclear, in urban areas. It stands to reason that the suffering of patients due to allergy to allergens common to ash and Oleaceae pollen is prolonged when late-flowering species are planted in urban areas. The choice of species or organisms in the context of town planning is even more important in the case of alders (Fagales). From a health policy perspective, it is counterproductive to plant allergens that could be avoided in a selection.
Farm children suffer from allergies less frequently, even though they are the group most exposed to the commonest allergens, e.g., grass pollen. The same is likely to also apply to indigenous tree pollen. They are also more exposed to photochemical oxidants (predominantly composed of ozone) [9, 25]. Children in urban centers grow up under increasing exposure to particulate and chemical industrial pollutants. Their immunological response is different . Due to anthropogenic effects, they are also exposed for longer and more intensively to new allergens from tree pollen.
On the other hand, the risk of allergy must not limit the planting of trees in urban areas in general. Therefore, when selecting trees, it is important to put the risk/benefit ratio into perspective based on the molecular aspects of relevant allergens and to adapt to local conditions. As such, molecular allergens should be accepted as a quality criterion in tree cultivation and trade.
Due to migration and growing mobility, the spectrum of molecular sensitization is becoming ever more important to patients with Oleaceae pollen allergy. Many people travel for business or spend their holidays in Mediterranean countries; others seek and find work in the region. In northern Spain, Fraxinus excelsior flowers as early on as January , whereas other widespread Oleaceae, such as manna ash (Fraxinus ornus) and the olive trees, flower weeks to months later, at the same time as grasses. Patients that have become monovalently sensitized to ash report symptoms in that region in May and June. This creates an unexpected paradoxical situation in terms of time, since relevant allergen exposure in the south occurs later .