Allergenic Pollen in Europe and in the Mediterranean Area



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Other relevant allergens
There are sometimes IgE binding carbohydrates of the antigenic molecule, which can explain some other cross-reacting phenomena, due to the fucose and xylose residues not present in mammalian molecules, although their clinical relevance remains still unknown (13).

Bibliography
1.- Barber D. Gramíneas: alergenos y reactividad cruzada. Alergología e Inmunología Clínica 2003; 18: 12-16.

2.- Taylor PE, Flagan RC, Valenta R et al. Release of allergens as respirable aerosols: Alind between grass pollen and asthma. J Allergy Clin Immunol 2002; 109: 51-56.

3.- Andersson K, Lidholm J. Characteristics and immunobiology of grass pollen allergens. Int Arch Allergy Immunol 2003; 130: 87-107.

4.- Van Ree R., Van Leeuwen WA, Aalberse RC. How far can we simplify in vitro diagnostics for grass pollen allergy?: A study with 17 whole pollen extracts and purified natural and recombinant major allergens. J Allergy Clin Immunol 1998; 102: 184-190.

5.- Grobe K, Becker WM, Schlaak M et al. Grass group I allergens (β- expansins) are novel, papain-related proteinases. Eur J Biochem 1999; 263: 33-40.

6.- Cosgrove DJ. Cell wall loosening by expansins. Plant Physiol 1998; 118: 333-339.

7.- Bufe A, Schramm G, Keown MB et al. Major allergen Phl p Vb in timothy grass is a novel Rnase. FEBS Lett 1995: 363: 6-12.

8.- Würtzen P, Wissenbach M, Ipsen H et al. Highly heterogeneous Phl p 5- specific T cells from patients with allergic rhinitis differentially recognize recombinant Phl p 5 isoallergens. J Allergy Clin Immunol 1999; 104: 115-122.

9.- Tinghino R, Twarsdosz A, Barletta B et al. Molecular, structural and immunologic relationships between different families of recombinant calcium-binding pollen allergens. J Allergy Clin Immunol 2002; 109: 314-320.

10.- Valenta R, Natter S, Seiberler S et al. Isolation of cDNAs coding for IgE autoantigens: a link between atopy and autoimmunity. Int Arch Allergy Immunol 1997; 113: 209-212.

11.- Rothkegel M, Mayboroda O, Rohde M et al. Plant and animal profilins are functionally equivalent and stabilize microfilaments in living animal cells. Journal of Cell Science 1996; 109: 83-90.

12.- Vidali L, McKenna ST, Hepler PK. Actin polymerisation is essential for pollen tube growth. Mol Biol Cell 2001; 12: 2534-2545.



13.- Van Ree R. Carbohydrate epitopes and their relevance for the diagnosis and treatment of allergic diseases. Int Arch allergy Immunol 2002; 129: 189-197.
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Oral Allergy Syndrome (OAS)

Philippe GEVAERT, MD PhD
Oral Allergy syndrome (OAS; also known as pollen-food allergy syndrome) is a symptom complex almost exclusively localized to the oropharynx and is a “mucosal equivalent of urticaria. The syndrome is usually caused by certain fresh fruits and vegetables in individuals who are sensitive to pollens, but also occurs in subjects allergic to shell-fish and eggs. Typical symptoms of OAS include itching of the mouth and/or throat, and swelling of the lips. Rarely, oedema of the glottis and systemic anaphylaxis may occur. 

Prevalence


In an initial report, Amlot1 reported about 80 adult food-allergic patients who were experiencing frequent symptoms of oral irritation and throat tightness. One fifth of the patients experienced other symptoms of food allergy (gastro-intestinal, respiratory, or cutaneous) immediately following the initial oral symptoms on at least one occasion. Another study reported that approximately 35% of patients with pollen allergy were also sensitive to fresh fruits and vegetables2. Subsequently, Ortolani3 described 262 patients with OAS, most of whom had allergic rhinitis. Foods most commonly implicated were fruits, nuts and vegetables (i.e. apple 53%, peach 40%, hazelnut 37%).

Pathogenesis


Currently, it is believed that the local oral symptoms in OAS are caused by a high concentration of mast cells in the oropharyngeal mucosa. Interaction between specific IgE found on the surface of these cells and allergens rapidly released from the offending food or fruit might explain the early onset of OAS symptoms. 

Cross-reactivity


OAS is an IgE-mediated allergy caused by homologous proteins and cross-reacting antigenic determinants in pollen and various fruits, vegetables, and nuts. Birch sensitive patients frequently react to fresh apple, hazelnuts, cherry, celery, and carrot, whereas ragweed-sensitive patients might react to banana, kiwi, and melons. On the one hand, synthesis of IgE stimulated by a cross-reactive allergen in pollen can result in a diverse pattern of sensitisations against various foods. On the other hand, even anaphylactic reactions may occur after consumption of a food containing a cross-reactive allergen for the first time. Frequent cross-reactivity was observed within botanical families (e.g. apple and pear; melon, apricot, peach and plum), and with certain aeroallergens, especially birch and grass pollens.

Table I.   Clusters of hypersensitivity


  • Hazelnut, walnut, brazil nut, and almond reciprocally, and even nuts combined with apple and stone fruits.

  • Apple and pear

  • Kiwi fruit and avocado

  • Potato-and carrot

  • Parsley and celery

  • Celery, mugwort and spices

  • Apple, carrot and potato

  • Cherry and apple

  • Melon, watermelon and tomato

  • Lettuce and carrot

  • Tomato and peanut

  • Celery, cucumber, carrot and watermelon

Molecular biology-based approaches have also improved knowledge about cross-reactivity among allergens4. The identification of allergens in fruits and vegetables showed IgE cross-reactivities with the important birch pollen allergens, Bet v 1 and Bet v 2 (birch profilin). Many other cross-reactive antigens have also been identified and characterised. Depending on the main cross-reactive allergen, different symptoms may be observed. Bet v 1 in apples, cherries, peaches and plums primarily causes mild symptoms such as the oral allergy syndrome. However, Bet v 1 associated with other allergens may cause generalised symptoms. Sensitisation to Bet v 2 is more often associated with generalized symptoms, in particular urticaria and angioedema. Lipid-transfer proteins are relevant apple and peach allergens and, considering their ubiquitous distribution in tissues of many plant species, could be a novel pan-allergen of fruits and vegetables.


Diagnosis


Evaluation of a patient with pollen-food allergy syndrome should include a careful history to determine the triggering foods and characteristics of the reactions, diagnostic tests that might include skin prick testing with fresh, raw, or both fruits (although this is not standardized), and possibly oral food challenges5;6.

Management


For patients with mild pollen-food allergy syndrome, treatment should be individualized with understanding that the risk of progression to a severe reaction is not known. As with other manifestations of food allergy, the mainstay of treatment in OAS is strict avoidance of the offending food. Elimination need not be lifelong as the natural history of food allergy, especially in children, is gradual loss of sensitivity to most food including fruit and vegetables.  As tolerance seldom develops to fish and nuts, it is recommended that these foods be avoided permanently if implicated in OAS. Drug therapy (antihistamines, adrenaline) may be necessary to treat angioedema or anaphylaxis. Treatment of atopic problems due to the associated pollen allergy (e.g. allergic rhinitis, asthma is also necessary. A few open studies have demonstrated the therapeutic potential in pollen-related food allergy: in at least 50 % of the cases, tree pollen immunotherapy led to an improvement of associated food allergies. However, these results have to be confirmed in placebo-controlled studies. Further studies to define clinical features and the natural course of pollen-food allergy syndrome and the development of improved diagnostic tests will be necessary to develop a more specific approach for the diagnosis and management of these patients.

As we are facing an increase of pollen allergies, a shift in sensitisation patterns and changes in nutritional habits, the occurrence new, unknown cross-reactions is expected.


References


1. Amlot PL, Kemeny DM, Zachary C, Parkes P, Lessof MH. Oral allergy syndrome (OAS): symptoms of IgE-mediated hypersensitivity to foods. Clin Allergy 1987; 17(1):33-42.

2. Bircher AJ, Van Melle G, Haller E, Curty B, Frei PC. IgE to food allergens are highly prevalent in patients allergic to pollens, with and without symptoms of food allergy. Clin Exp Allergy 1994; 24(4):367-374.

3. Ortolani C, Ispano M, Pastorello E, Bigi A, Ansaloni R. The oral allergy syndrome. Ann Allergy 1988; 61(6 Pt 2):47-52.

4. Bousquet J, van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001; 108(5 Suppl):S147-S334.

5. Ma S, Sicherer SH, Nowak-Wegrzyn A. A survey on the management of pollen-food allergy syndrome in allergy practices. J Allergy Clin Immunol 2003; 112(4):784-788.

6. Osterballe M, Scheller R, Stahl SP, Andersen KE, Bindslev-Jensen C. Diagnostic value of scratch-chamber test, skin prick test, histamine release and specific IgE in birch-allergic patients with oral allergy syndrome to apple. Allergy 2003; 58(9):950-953.


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SAMPLING TECHNIQUES FOR BIOAEROSOLS
Rui Brandao
Universidade de Évora, Portugal

Bioaerosols consists of particles of biological origin or activity finely divided and suspended in the air or other gaseous environment. Particle sizes may range from aerodynamic diameters of ca.0.5 to 100 m and they may affect living things through infectivity, allergenicity, toxicity, pharmacological or other processes [Cox et al., 1995].

In general, the first aim of sampling bioaerosols is to determine which species within some selected group are present and how their atmospheric concentration changes. Some sampling strategies include surveys over space, time, or both and often complex processes are required to identify the collected material.

Many devices are in use for sampling airborne particles and they differ according to several sampling principles (gravitational settling, filtration, electrostatic precipitation, etc). There is no universal sampler and each field of application has developed its own sampling methods. Therefore a sampling device or method should be selected only after the purpose of sampling has been established, the characteristics of the particles are known, and the methods for handling the samples chosen.

The athmospheric physicist and aerobiologist P. Mandrioli had systematized recently, in a clear and practical way, the diversity of equipments and sampling devices according to 2 main classes[Mandrioli et al., 1998]:

1) Deposition Samplers: based on simple methods of collecting bioaerosols through an exposure of a horizontal surface for particle gravitational settling. Particles settle at their terminal velocity and are retained by an adhesive on the sampling surface. Ex: Durham and Tauber traps and Petri dishes



2) Impaction Samplers: includes a wide spectrum of devises that have in common a impaction sampling on a solid surface. There are several classes namely:

  • Suction samplers in which air containing the material to be sampled is drawn through an orifice usually by suction from a vacuum pump. Examples: 1 to 7 Day Recording Volumetric Spore Trap; Airborne Bacterial Sampler MK-ll; Surface Air System SAS; Slit-to-agar impactor sampler;

  • Cascade impactors are suction samplers composed of one or more deposition surfaces. In the most widely utilised device, particles are deposited on Petri dishes with nutrient media for culture of the viable fraction. In other models, particles are impacted on glass or stainless steel collection plates allowing observation and analysis. Examples: Andersen Microbial Air Sampler; Marple Personal Cascade Impactor; Marple 290 Personal Cascade Impactor; Burkard personal sampler.

  • Filter samplers: Filtration is the commonest method for removing particles from the air drawn in by suction. The air passes through a fibrous or porous medium that impacts or sieves the particles. They have the advantage of a high particle retention capability both on the surface and inside the filtration mass, and the disadvantage of an undefined pore diameter and retention of particles within the filter depth. Examples: Filter cassettes made by several manufacturers; Cour Samplers used in some mediterranean countries namely at the Portuguse Aerobiology Network in the year of 1999-2000;




  • Inertial samplers: In these devices the impaction surface is in motion rather than the particles. The most famous is the Rotorod Sampler developed at the Stanford Research Institute;




  • Cyclone Samplers in which particle discrimination is carried out thanks to the centrifugal force generated either by the rotating air mass or by the spiral trajectory in which they are forced to move. Example: Cyclone sampler manufactured by Burkard Manufacturing Co., Ltd, Hertfordshire, U.K. ;




  • Liquid impingers operate by drawing a stream of air into the bottom of a container of liquid and allowing it to rise through the liquid as buoyant bubbles. During the process particles are transferred to the liquid and retained. These instruments have been recommended for sampling delicate organisms such as algae. Examples: The All Glass Impinger (AGI-30) sold by Ace Glass; The Burkard Multi-stage liquid impinger by Burkard Manufacturing Co., Ltd, Hertfordshire, U.K.

SAMPLING TECHNIQUES FOR AIRBORNE POLLEN


The Hirst spore trap (Hirst, 1952) is the standard sampler to record the atmospheric concentration of pollen grains and fungal spores. It is a suction sampler based on the basic principle of the impaction, with a 2x14 mm intake orifice through which the sampled air is impacted onto a collection surface moving at 2 mm h-1.

The most used commercial models available at the present time are the Burkard Volumetric Spore Trap designed by Burkard Manufacturing Company Limited UK and the VPPS 2000 Volumetric Spore Trap designed by Lanzoni S.R.L. Italy. These samplers have the possibility to run for a week or to incorporate a daily mechanism. The air flow exhaled is 10 litres per minute.

Recently, some portable personal sampling devices have been designed to do samples in any place without power supply. The most used commercial models are those designed by Burkard Manufacturing Co. with the Personal trap, by Lanzoni S.R.L. Italy with the VPPS 1000 model, and by Coppa S.R.L. Italy, with the Partrap FA52. The air flow is the same as the Hirst type sampler.

The Hirst sampler designed by Burkard Co. or Lanzoni S.R.L. (they have the same sampling features) and in use at the Portuguese Aerobiological Network or other European networks consists of a impaction unit which consists of an adhesive-coated transparent tape (a Melinex tape) placed on a drum rotating once every 7 days, a wind-vane mounting unit and the motor housing unit (figure 1). A vane tail keeps the cylindrical housing facing the wind. The motor housing contains a vacuum pump and equipment for measuring the rate of suction.


Adhesive coatings
Currently a wide variety of adhesives exist which are used in different places for aerobiological sampling with such samplers: vaseline, petrolatum white, silicone fluid, and a mixture of vaseline and parafine. Moreover, other adhesives in use are glycerol, glycerol jelly and gum resins.

It is very important to use an adhesive that does not vary with different meteorological conditions. Some comparative studies have already been done using different media in order to evaluate the efficiency and the possible standardization of their use, (Kapyla, 1989; Galan and Dominguez-Vilches, 1997).

It could be inferred from the results of these studies that the differences which exist between the efficiency of one adhesive or another are normally small and depend on the local climatic conditions (Galan and Dominguez-Vilches, 1997).
Drum preparation
In weekly samplers the Melinex tape is mounted on a drum (figure 1). The Melinex tape is 336 mm long which correspond with the seven days of a week. Ones the tape is on the drum then the adhesive must be applied with the aid of a brush. If a vaseline is used the person who is mounting the tape apply it by slightly and continuously turning the drum without stopping ensuring that a very fine and uniformed layer is obtained. In the case of silicone fluid let the brush slide slowly only once and exclusively in one direction. It does not matter the thickness of the layer of silicone because within 30 sec the tape dries and it is ready to be used.

Lid Assembly


Rotation lock
Build-in Motor


Wind vane



Trapping surface


Lid
Start reference pointer

Figure 1: The Burkard 7-Day Volumetric Spore Trap (left) with Lid Assembly with drum (right) [adapted from “A Guide to Trapping and Counting, The British Aerobiological Federation]


Slide mounting

As the drum rotes at a 2 mm per hour, and the Melinex tape is 336 mm long, the operator must cut in the laboratory seven 48 mm pieces (each one corresponds to one day) with the aid of a transparent ruler. These pieces of tape are mounted on the slides with a mounting media (a diagram of this process can be visualized at http://www.rpa.uevora.pt). The most frequent mounting media are: glycerol jelly, polyvinyl alcohol, polyvinyl lactophenol. It is important to add phenol to this media to avoid microbial growth [Galán, 2001]. In the case of pollen grain collection, basic fucsin is often used to stain the samples.



Site location

Three main criteria should be considered when one choose the sampling site: 1) it should be representative, 2) accessible and 3) within reach of a power supply. The sampler should be positioned on a site where local air circulation is not influenced by nearby obstacles, preferably in the middle of a roof terrace at a height of 15-20 m above ground level and far from walls and rails [Mandrioli, 1998].

Site specifications and its surrounding vegetation should be taken into due account in the interpretation of aerobiological results, because some particular situations could lead to pollen overload. Since aerobiological studies have been traditionally applied to allergy, most of the samplers are placed under urban conditions, on the top of hospitals or other public buildings. However, the urban climate features special temperature regimes and air flows in cities that we must take into account when a sampler is installed

The terrain nature will have a great influence on the air flow. Solid obstacles projected into the wind cause eddies which may break away from the surface and travel down wind. The roughness of the ground produces a certain amount of turbulence in the lowest layer of the atmosphere which promotes the mixing and dispersion of particles. This effect will be greater for a city with lot of buildings than for an open ground with few obstructions in a rural area [Galán, 2001].

Another factor is the location of the sampler in respect to the particle source. A sampler closer to ground level detects higher concentrations of pollen from plants close to the sampling site, while a sampler situated higher above ground level detects pollen grains from a wider ranging area.

In a rural area, the researchers must consider the topographic wind effects. The sampler must be installed in an open place and the interpretation of the sampler results depends on the topography of the site: the coast, with land and sea breezes, the mountains and valleys with local wind systems, etc




REFERENCES

British Aerobiology Federation (1999) – Airborne Pollen and Spores: A Guide to Trapping and Counting. Edit. by National Pollen and Hayfever Bureau, Rotherham, U.K.

Cox, C.; Wathes, C. (1995) – Bioaerosols Handbook. CRC Press Inc., 621 p.

Galán, C.(2001) – The Use of the Hirst Volumetric Trap: operation, adhesive coatings, drum preparation, slide mounting and Site location (printed material for didactical purpose), Universidad de Córdoba, Cordoba.

Galán, C.; Domínguez-Vilches, E.(1997) – The capture media in Aerobiological Sampling. Aerobiologia, 3(3)

Käpilä, M.(1989) – Adhesives and mounting media in aerobiological sampling. Grana 28:215-218

Mandrioli, P.; Comtois, P.; Levizzani, V.(1998) – Methods in Aerobiology. Pitagora Edit. Bologna, 262p.

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MOULD SPORE COUNTS IN FUNCHAL

2003-2004 YEARS STUDY


Sofia Camacho1, Irene Câmara1, Rita Câmara2, Susana Oliveira2, Miguel Pinheiro de Carvalho1, Fernando Drummond Borges2.
1Centro de Estudos da Macaronésia (CEM), Universidade da Madeira.

2Unidade de Imunoalergologia, Hospital Central do Funchal.
Background: Aerobiological and epidemiological research has been made in Funchal till now in order to detect pollen and fungi airborne and the prevalence of allergic disease.

Purpose: Analysis of airborne fungal spores observed in Funchal city during one-year study.

Methods: Aerobiological records of mould spores were conducted by a Burkard sampler between April 2003 and March 2004. Parallel records of meteorological parameters were obtained at Meteorology Institute and correlated with aerobiological data.

Results: The fungal counts obtained during the study were equalled 11.862 spores/m3/year. Three main classes were identified: Deuteromycetes (55,4%), Ascomycetes: (23,0%) and Basidiomycetes: (20,6%). Cladosporium, Torula, Fusarium and Alternaria were the most prevalent Deuteromycetes, whereas Leptosphaeria (Ascomycete) and Coprinus (Basidiomycete) were the most frequent types within their class. Despite the maximum number recorded being during springtime, there is a continuous presence of sporomorphs in the atmosphere all the year round. The relation between airborne fungi variation and daily climatic factors, namely temperature and relative humidity was shown.

Conclusion: The tendency to an increasing number of airborne fungi every year could be explained by meteorological and outdoor conditions. An integrative analysis of aerobiological data, epidemiological studies and the influence of environment should provide a better approach of the allergic disease.
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ENVIRONMENTAL CHARACTERIZATION AND ALLERGIC DISEASE

IN MADEIRA ISLAND


Susana Oliveira1, Rita Câmara1, Irene Câmara2, Mariana Rodrigues3, Mário Morais Almeida4, José Rosado Pinto4 Fernando Drummond Borges1.

1Immunoallergy Unit 3Statistic and Research Department – Funchal Hospital (HCF), 2Biology Department – UMa, 4Immunoallergy Department – Dona Estefânia Hospital.
Background: Interaction between meteorology, outdoor / indoor characteristics and genetics predisposition for the allergic disease condition the disease prevalence. Purpose: Environmental characterization: meteorology, aerobiology, airborne pollution and indoor conditions in order to find an explanation to the atopy and allergic disease prevalence. Methods: Analysis of thirty-year meteorology, airborne pollen and mould sampling (Burkard), airborne pollution studied on the context of ISAAC and indoor conditions studied during PAC-Study. Results: Madeira has a subtropical climate with low temperature amplitude; mean annual temperature – 19,5ºC (maximum mean temperature – 22ºC and minimum mean temperature – 17ºC) and a moderate rainfall. Year round there’s high mean relative humidity of 67%. The airborne level spores mould varies between 6584 to 11925 spores/m3/year. Deuteromycetes is the most prevalent class, and in this class Cladosporium type is the most prevalent. Highest incidence of mould spores occurs on springtime. The most prevalent pollen families are Urticaceae and Pteridophyta with a mean grain pollen/m3/year = 1246. The highest pollen concentration occurs on springtime and autumn. Regarding pollution we have mean NO2 level = 22,5 g/m2 air. Indoors conditions characterization: mean temperature = 21ºC, mean relative humidity = 74% and house dust mite concentration shows Der p1 higher than Der f1. Mean of house dust mite concentration found was for mattress Der p1 = 19,76 g/g of dust, Der f1 = 0,30 g/g of dust; and for floor: Der p1 = 2,11 g/g of dust, Der f1 = 0,08 g/g of dust. Conclusion: The outdoor conditions, namely subtropical climate, significant level of pollen, mould spores and NO2, corroborated by indoor conditions, like high relative humidity and dust mites concentration, enhance the 1genetic predisposition supposed by the frequency of HLADr B1*7 found in this population, for house dust mites atopy (general population = 50% and asthmatic population = 80%) and allergic disease prevalence (asthma = 14% and rhinitis = 20% - ISAAC – 1st phase).
1Spínola H, Brehm A, Williams F, Jesus J, Middleton D (2002). "Distribution of HLA alleles in Portugal and Cabo Verde. Relationships with the slave trade route". Annals Hum. Genet. 66: 285-296.

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INDOOR CHARACTERIZATION – AEROALLERGENS SENSITIZATION



Susana Oliveira1, Rita Câmara1, Maria João Castro1, Mariana Rodrigues2 Fernanda Vila3, Cátia Cardoso3; Ana Carvalho Marques3; Fernando Drummond Borges1.

1Unidade de Imunoalergologia, 2Serviço de Estatística e Apoio à Investigação, 3Serviço de Pediatria – Hospital Central do Funchal.
Background: Indoor home conditions of allergic patients associated with an increased sedentary life style, could be a trigger for allergic illness. Purpose: Indoor characterization from Immunoallergy outpatients and correlation with their atopy incidence. Methods: Questionnaire systematic application in order to characterize indoors conditions of Immunoallergy outpatients. Skin Prick Test (SPT) with commercial extracts (dust mites, moulds and cockroach). Statistic analysis and correlation between indoor conditions and sensitization was done. Results: Patients population: n=193. Male – 47,7% and female – 52,3%. Mean age = 15 years old (8 months – 80 years). Home place: urban, suburban and rural, equitable distribution. Basic sanitation inexistent in 10% (n=20) of the population. House floor was predominantly: wood (44%) and mosaic (40,4%). Only 4,1% (n=8) of the individuals bedroom have carpet. The majority of the houses has 2 or 3 sleeping rooms and almost of the population shares the room with one more person. In average the mattress has 5 years, it is predominantly springs (90,2%) and is not shared in 81,1% of cases. Pillow is used by 89,6% of patients, whose average age is 3 years, and being scum in 51,8% of cases. The eider down is used by 61,7% of the population. In almost half of patient room there are soft toys (n=90) in number >=5 (47,8 %). Indoor humidity is present in 57,9% and cockroach in 48,2 % of houses. In studied population 75% have SPT positive to at least one tested allergen. Positive sensitization was: house dust mite 77,2% cockroach 26,2% and mould 23,4%. For allergens like house dust mite the only significant Pearson correlation founded was for >=5 soft toys (<0,001) indoor. There were not found other significant correlation to this allergen or between indoor humidity and mould sensibilization. Pearson correlation was significant (<0,001) for home occurrence cockroach and positive SPT to this aeroallergen. Conclusion: Incidence for sensitization to the tested aeroallergens was similar to that found in PAC-study. The reason for no significant Pearson correlation between other indoor conditions beside soft toys >5 and house dust mite sensitization could be explained by some previous environment control already done. Finally, the inexistence of significant correlation between indoor humidity and moulds atopy could be explained by the lacking of moulds standardized extracts for prick test and regional variation. The correlation found for indoor cockroach and sensitization for this specific allergen could be justified, in one hand by high prevalence of indoor cockroach and in another hand, by extermination difficulties.
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MOLD SPORE COUNTS IN FUNCHAL

2003-2004 YEARS STUDY

Sofia Camacho1, Irene Câmara1, Rita Câmara2, Susana Oliveira2, Miguel Pinheiro de Carvalho1, Fernando Drummond Borges2.
1Centro de Estudos da Macaronésia (CEM), Universidade da Madeira.

2Unidade de Imunoalergologia, Hospital Central do Funchal.
Background: Aerobiological and epidemiological research has been made in Funchal till now in order to detect pollen and fungi airborne and the prevalence of allergic disease.

Purpose: Analysis of airborne fungal spores observed in Funchal city during one year study.

Methods: Aerobiological records of spores were conducted by a Burkard sampler between April 2003 and March 2004. Parallel records of meteorological parameters were obtained at Meteorological Institute and correlated with aerobiological data.

Results: The fungal counts obtained during the study were equalled 11.862.126 spores/m3/year. Three classes were identified: Deuteromycetes 55,44%, Ascomycetes: 23,05% and Basidiomycetes: 20,63%. Cladosporium, Torula, Fusarium and Alternaria were the most prevalent Deuteromycetes, whereas Leptosphaeria (Ascomycete) and Coprinus (Basidiomycete) the most frequent types within their class. Despite the maximum number recorded being during springtime, there is a continuous presence of sporomorphs in the atmosphere all around the year. The relation between increasing airborne fungi and daily climatic factors, namely temperature and humidity was shown.

Conclusion: The tendency of the increasing number in airborne fungi every year could be explained by meteorological and outdoor conditions. An integrative analysis of aerobiological data, epidemiological studies and the influence of environment should provide a better approach of the allergic disease.

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Respiratory Allergy to Moulds
A.C. Loureiro

Immunoallergogy Service

Coimbra-Portugal
Respiratory repercussions caused by exposure to fungal allergens are varied and can commonly trigger asthma, rhinitis, hypersensitivity pneumonitis and allergic bronchopulmonary aspergillosis. In 1982 a new clinical entity was established - allergic fungal sinusitis.

Fungi are uni or multicellular organisms that live in organic materials in decomposition. They are dispersed, as spores or fragments of mycelia, both outdoor and indoor, and form a kingdom of living organisms which is relatively unknown.

It was only in 1966, with Whittaker, that an independent fungus kingdom was established, due to the identification of the characteristic and distinct means of reproduction and nourishment, which differ from the ones observed in plants and animals1. The classification of fungi and its knowledge is not totally established, particularly in the lower taxonomic categories. Four subgroups in the fungus kingdom are recognised under the general designations of Ascomycota, Basidiomycota, Zygomycota and Mitosporic fungi. This classification is based in the characteristics of their reproductive organs – teleomorph or perfect form, with the division by meiosis – corresponding to the first three subgroups. The fourth subgroup includes all those whose the perfect form is not known – the anamorph or imperfect fungi– in which multiplication is made by mitosis. However, many perfect fungi are currently known by the most common names of their imperfect forms2.

About 250,000 species of fungi are known today, being about 100 species related to the allergic pathology documented by hypersensitivity skin prick tests and/or bronchial or nasal provocative tests. The first description that associates fungi with allergic pathology was reported by Maimonides in the 12th century, but it was only in 1873 that Blackley established a relationship between allergic disease and the inhalation of Penicillium spores 3.

The concentration of fungus spores in the air depends on factors related to their growth, being the temperature, the humidity and the presence of organic substratum the most relevant ones, and factors related to their dispersion like the wind, the rain and the turn over of the soils.

The knowledge in fungal allergy has improved as more advanced methods of spores counts and standardization of allergen extracts had been developed. Furthermore, the implementation of epidemiological studies has contributed to a more correct clarification of their clinical relevance.

Aerobiological studies have shown that spores can be in the air virtually all year-round. In countries with temperate climate the number of spores reaches a peak in the months of July and October, being Cladosporium more predominant during the day, and Sporobolomyces during the night, with a decline in the winter months. Some fungi as Fusarium and Phoma betae, are easily dispersed by humidity and rain, or by dry and windy weather, as Cladosporium, Alternaria Epicoccum or Helminthosporium 4.

The spores of Cladosporium and Alternaria are more frequent. The Cladosporium ones can reach 24000/m3 having, nevertheless, the daily average counts of 5000/m3. The counts of Alternaria spores are lower, with an average counts of 150/m3 5.

Generally fungi species found indoors are correlated with the ones found outdoors, though in lower quantities. The most frequently identified are Cladosporium, Aspergillus and Penicillium6.

There are various methods for fungi identification. The collection of air samples based on volumetric or gravimetrical methods can be directly processed for microscopic identification or for culture media and further analysis. The morphologic differences of the spores of varied genera are often so insignificant that they cannot be characterized correctly, such as Penicillium and Aspergillus. In this case, culture is nedeed to identify them. Sporulation characteristics are better analysed in the culture, but this technique is time consuming and the diversity of the culture media used is another disadvantage.

The more frequent fungi identified through culture in the homes of asthmatic patients living in the Central Region of Portugal were Rhizopus nigricans (42,3%), Aspergillus níger and Mucor racemosus (15,4%), Penicillium notatum (13,4%) and Fusarium culmorum (5,7%)7.

The use of inquiries has been carried out in epidemiological studies in order to get an indirect characterization of fungus presence. However, some studies did not point out a significant correlation between asthma prevalence and its seriousness and the presence of visible colonies of fungi, seepage and mould smell8.

In spite of the fact that fungi are associated with allergic diseases, their clinical relevance is difficult to establish. In fact, though the concentration of spores in the environment is generally superior to the pollen spores, only some fungi like Alternaria alternata, Aspergillus fumigatus and oryzae, Cladosporium herbarum, Penicillium notatum and citrinum, Candida albicans and Cryphonectira parasitica can trigger allergy and have a characterization of their allergens, although an incomplete one9.

The prevalence of sensitisation to fungi determined by skin tests of allergy is not well known. According to the population studied and the allergen extract used, the prevalence of sensitisation to fungus can vary from 3 to 91%10. In fact, even in the same population the use of different extracts of Cladosporium herbarum can lead to variations of prevalence from 12 to 65%. In Portugal, studies pointed out values of allergy prevalence to fungi in the general population from 2% to 3%, and 21% in an atopic population, being bronchial asthma the predominant allergic pathology 11. In the central region, in a population aged 20 to 44 years, we observed a prevalence of sensitisation to Alternaria alternata and to Cladosporium herbarum of 1%, determined by allergy skin prick tests and by RAST 7. It was observed a prevalence of 8,1% to Alternaria alternata and of 6,9% to Cladosporium herbarum in a student population12. An adult allergic population showed a sensitising prevalence from 1% to 4,2% to Alternaria alternata and from 1,8% to 3,8% to Cladosporium herbarum13.

These variations in the prevalence values of allergy to fungi seem to be also influenced by the age of the studied population. In fact, it often occurs in children and bronchial asthma seems to be the most frequent clinical expression of fungus exposure especially to Alternaria and Cladosporium14.

Allergic bronchopulmonary aspergillosis is a clinical entity associated to exposure to Aspergillus fumigatus.

The Pathophysiology is not still full clarified, but it can be characterized by bronchial colonization of asthmatic patients, with subsequent release of mycotoxins and proteolytic enzymes which cause eosinophilic inflammation, depending on the activation of CD4 lymphocytes, restricted to antigens HLA – DR2 e DR5 – and increase of interleukins concentrations IL4, IL5, of IgE and IgG115.

There is no correlation between the intensity of exposure to the spores of Aspergillus fumigatus and the prevalence of sensitivity to this fungus determined by skin prick tests 16. In addition to Aspergillus (fumigatus, terreus, oryzaeochraceus) other species have been reported in clinical cases similar to APBA, like Curvularia lunata, Dreschlera hawiiensis, Geotrichum candidum and Stemphylium lanuginosum, belonging to allergic bronchopulmonary mycoses.17

A set of criteria, major and minor, has been proposed to evaluate the diagnosis. Under these criteria it is possible to establish subcategories that could have implications either in the diagnosis or in the prognostic. The presence of bronchial asthma is considered one of the major criteria for the diagnosis. In some series positive skin tests to Aspergillus is from 20% to 30%. The valorisation of this association (bronchial asthma and positive skin prick tests to Aspergillus) may open the way to further studies, particularly in CT scan, in order to establish an early diagnosis 18.

Frequent inhalation of organic particles can cause a group of lung diseases known as hypersensitivity pneumonitis or extrinsic allergic alveolitis. Presently there are an increasing number of etiologic agents. They are generally present in the descriptions of isolated clinical cases or in small series and need a better characterization 19,20.

Hypersensitivity is a complex syndrome with clinical presentation, seriousness and diverse evolutions, according to the responsible etiologic agent, the time, and the degree of exposure. Bird fancier´disease and farmer lung have been deeply studied and thus provided a better knowledge of this clinical entities 21.

Fungi found in diverse environments have also been considered as etiologic agents. It was clearly demonstrated that fungi found in working environments have implications in some diseases.

Pathophysiology seems to be focused on the release of pro-inflammatory cytokines (TNT, IL1, IL2, IL3, IL12, IF  and GM-CSF) influenced by T lymphocyte and on the formation of immune complexes likely to cause a constant release of these cytokines. In more evolutional forms to fibrosis, IL8 will have a significant contribution. On the other hand, the conteregulation of granuloma formation will have a participation of IL10 and of IL6.The diagnosis is established by the conjugation of clinical, laboratorial radiographic, and histological criteria. Provocative tests, specially those made in the working environment have a diagnostic interest.

The prognostic seems to be different, depending on the causal agent22. Extrinsic allergic alveolitis among pigeon breeders seems to have a more serious prognosis. It was demonstrated that there is a decrease in FEF50 and in FEV1 in the exposed subjects, when compared to the general population 23.

Allergic fungal sinusitis was first described by Katzenstein in 1983 and characterized as an inflammatory response to the colonies set in the paranasal sinusis24. The presence of mechanical factors like polyps and septal deviation, or inflammatory factors like chronic sinusitis, lead to the obstruction of the paranasal sinuses and create optimal conditions for fungal growth. The most important fungi associated with this pathology belong to Bipolaris, Curvularia, Drechslera, Exserohilum and Alternaria species. Aspergillus species are also frequently present with a frequence varying from 10% to 20%. Fungal allergic sinusitis seems to be more frequent in hot climates with high air humidity. It is commonly found in young atopic subjects with chronic sinusitis and polyps25.

Several diagnostic criteria have been proposed. However, the demonstration of sinusitis image and the presence of allergic mucin and hyphae, in the absence of immunodeficiency, are essential. Fungus culture or the demonstration of other fungal elements in the nasal lavage is not relevant for most authors 26.


References


  1. Whittaker RH. New Concepts of Kingdoms of Organisms. Science. 1969; 163:150-60.

  2. Sutton DA, Fothergill AW and Rinaldi MG. 1998. Introduction, p 3-11. In Mitchell CW (Ed). Guide to Clinically Significant Fungi. The Williams & Wilkins Co. Baltimore, Md.

  3. Blackley CH. Experimental Researchs on the Causes and Nature of Catarrhus Aestivus (Hay Fever or Hay Asthma). Ballière. Tindall and Cox. London. (Rep: Dawson, London 1959).

  4. Solomon W, Platts-Mills T. 1998. Aerobiology and Inhalant allergens, p 367-403. In Midleton E Jr, Reed CE, Ellis EF, Adkinson NF Jr, Yunginger JW, Busse WW (Ed Allergy Principles and Pratice. 5th. Mosby.

  5. Lacey J. 1997. Fungi and Actynomycetes as Allergens, .858-87. In Kay AB (Ed.). Allergy and Allergic Diseases. Blackwell Science.

  6. Takahashi T. Airborne Fungalcolony-Forming units in Outdoor and Indoor Environments in Yokohama, Japan. Mycopathology. 1997;139:23-33.

  7. Chieira C, Loureiro AC, Paiva J, Todo Bom A, Pereira AC, Faria E, Ribeiro H, Gertrudes Almeida M, Baptista-Ferreira JL, Robalo Cordeiro AJA. Fungos e Alergia Respiratória. Via Pneumológica. 1990; 2: 103-10.

  8. Garret MH, Rayment PR, Hooper Ma, Abranson MJ and Hooper BM. Indoor Fungal Spores, House Dampness and Associations with Environmental Factors and Respiratory Health in Children. Clin Exp Allergy. 1998; 28: 459-67.

  9. Philip JT, Geoffrey AS and Jonathan MS. 2001. Allergens and Pollutants, p 213-42. In Stephen Holgate, Martin K Church, Lawrence M Lichtenstein (Ed). Allergy. Mosby.

  10. Horner WE, Helbling A, Salvaggio JE, Lehrer SB. Fungal Allergens. Clin Microbiol Rev, 1995; 40: 161-79.

  11. Palma Carlos AG, Sousa Uva A. 1984. Mould Allergy in Portugal, p 105. In Knud Wilken-Jensen and Suzanne Gravesen (Ed) Atlas of Moulds in Europe Causing Respiratory Allergy. Foudation for Allergy Research in Europe. ASK Publishing.

  12. AC Loureiro, Graça Loureiro, B Tavares, I Carrapatoso, C Chieira. Sensibilização a Fungos. Rev Port Imunoalergol, 1999; 7 (2):120.

  13. Loureiro AC, Chieira C, Pereira AC, Todo Bom A, Faria E, Alendouro P, Tavares B, Victor L Rodrigues, Salvador M Cardoso, Robalo Cordeiro AJA. Estudos Epidemiológicos da Asma Brônquica numa População Adulta. Rev Port Imunoalergol, 1996; 4 (1):35-54.

  14. Tariq SM, Mathews SM, Stevens M and Hakin EA. Sensitization to Alternaria and Cladosporium by age of 4 years. Clin Exp Allergy, 1996; 26:794-8.

  15. Chauhan B, Knutsen AP, Hutcheson PS, Slavin RG, Bellone CJ. T Cell Subsets, Epitope Mapping, and HLA- Restrction in Patiennts with Allergic Bronchopulmonary Aspergillosis. J Clin Invest, 1996; 97 (10): 2324-31.

  16. Beaumont F, Kauffman HF, DeMonchy JGR, Sluiter HJ and DeVries K. Volumetric Aerobiological Survey of Conidial Fungi in the North-East Netherlands II. Comparison of Aerobiological Data and Skin tests with Mold Extracts in an Asthmatic Population. Allergy, 1985; 40: 181-6.

  17. Elliot MW and Newman Taylor AJ. Allergic Bronchopulmonary Aspergillosis. Clin Exp Allergy, 1997; 27 (S1): 55-9.

  18. Angus RM, Davies ML, Cowan MD, McSharry C, Thomson NC. Computed Tomografic Scanning of the Lung in Patients with Allergic Bronchopulmonary Aspergillosis and in Asthmatic Patients with a Positive Skin Test to Aspergillus fumigatus. Thorax, 1994; 49 (6): 586-9.

  19. Winck JC, Delgado L, Murta R, Lopez M, Marques JA. Antigen Characterization of Major Cork Moulds in Suberosis (Cork Worker´pneumonitis) by Immunobloting. Allergy, 2004;59:739-45.

  20. Morais A, Winck JC, Delgado L, Palmares MC, Fonseca J, Moura e Sa J, Marques JA. Suberosis and Bird Fancier´s Disease: A Comparative Study of Radiological, Functional and Bronchoalveolar Profiles. J Invest Allergol Clin Immunol, 2004;14:26-33.

  21. John E Salvaggio and David J Hendrik. 2001. Extrinsic Allergic Alveolitis, p 37-53. In Stephen Holgate, Martin K Church, Lawrence M Lichtenstein (Ed). Allergy. Mosby.

  22. Grammar LC, Roberts M, Lerner C, Patterson R. Clinical and Serologic Follow-Up of Four Children and Five Adults with Bird-Fancier’s Lung. J Allergy Clin Immunol, 1990; 85 (3): 655-60.

  23. Segorbe Luís A, Franco A, Pereira C, Robalo Cordeiro C, Fernandes A, Loureiro C, Todo Bom A, Fava Abreu, Morais T, Garção F, Paiva Carvalho J, Oliveira LC, Robalo cordeiro AJ. Estudo da Repercussão Ventilatória no Criador de Pombos Assintomático. Archivos Bronconeumologia, 1993; 29 (S1):7.

  24. Katzenstein AL, Sale SR, Greenberger PA. Pathologic Findings in Allergic Aspergillus Sinusitis: A Newly Recognized Form of Sinusitis. Am J Surg Pathol, 1983; 7: 439-43.

  25. DeShazo RD, Chapin K, Swain RE. Fungal Sinusitis. N Engl J Med, 1997; 337: 254-9.

  26. DeShazo RD, Swain RE. Diagnostic Criteria for Allergic Fungal Sinusitis. J Allergy Clin Immunol, 1995; 96: 24-35.

*****



Mite allergen characterization and monitoring

Ronald van Ree, PhD
House dust mites were identified as a cause of allergy and asthma in the mid-sixties by Voorhorst and Spieksma(1,2). The major allergenic species in temperate climates are Dermatophagoides pteronyssinus and Dematophagoides farinae. In tropical environments Blomia tropicalis has been identified as an important species(3). The first allergens identified in Dermatophagoides pteronyssinus house dust mites were at that time called P1 and Dpx(4,5). At present these allergens are designated Der p 1 and Der p 2, respectively, following the guidelines of the IUIS Allergen Nomenclature Committee (www.allergen.org).Their homologues in Dermatophagoides farinae are Der f 1 and Der f 2. Although almost 20 different allergens have been identified in both mite species since, group 1 and group 2 allergens are still regarded as the most important allergens(6-8). Several other allergens have been reported to be “major allergens”, like group 5, group 7, group 10 and group 14 allergens (www.allergome.org). So far, stable consensus about the importance of the broad spectrum of house dust mite allergens exists for group 1 and group 2. The third allergen for which consensus can probably be reached that it is a true major allergen is the group 7 allergen(8). For most of the other allergens identified so far, reported prevalence of recognition have been less consistent. Most likely, these are explained by the different areas where studies were performed and/or the size of the group of patients that were studied.
Biological function of mite allergens

Group 1 mite allergens were shown to share homology with the family of cystein proteases(9). The major house dust mite allergen has indeed been shown to possess cystein protease activity(10). Enzymatic activity of Der p 1 has been proposed as a pro-inflammatory activity contributing to its allergenicity. Cleavage of CD25 (IL2 receptor), CD23 (low-affinity IgE receptor), and permeabilization of tight junctions have all been implicated to favour a role of Der p 1 as a major allergen(11-17). Group 1 house dust mite allergens are secreted and are highly abundant in mite faecal particles. In contrast, Der p 2 is a body protein of which the exact function has not yet been elucidated, although homology has been found with human epididymous protein(18). In general, IgE titres against Der p 2 tend to be slightly stronger than those observed against Der p 1(8). The reason for this apparent higher allergenicity is not clear. Der p 3, 6 and 9 all are active serine proteases: trypsine, chymotrypsine and elastase (www.allergome.org). Their importance as mite allergens is not well established yet but it certainly is thought to be less than of Der p 1 and 2. Der p 4 is again an enzyme, i.e. an amylase(19). Der p 5 and Der p 7 do not share homology with any known proteins and their function is therefore still unknown. Der p 8 again is an enzyme, i.e. glutathion-S-transferase(20). Group 10 and group 11 are both structural proteins, i.e. tropomyosin(21)and paramyosin (www.allergome.org), respectively. Over recent years, new molecular biology techniques have resulted in identification of many new allergens from house dust mite. Here it suffices to state that it is not yet really clear what their importance for mite allergy will turn out to be.


Cross reactivity to foods

It is well-established that IgE antibodies to pollen frequently cross-react to plant foods. The best example of a cross-reactive allergen in pollen is Bet v 1. Cross-reactivity of IgE antibodies results in allergy to fruits like apple, cherry and peach and to hazelnut and some vegetables like carrot and celery. Also for IgE antibodies against house dust mites cross-reactivity to foods has been reported on several occasions. The muscle protein tropomyosin (group 10 in mites) is instrumental in cross-reactivity between house dust mites and foods from invertebrate animal origin like shrimps, molluscs, lobster, crab and snails(22-28). Tropomyosin is the major allergen of shrimp and of several the other listed sea foods(29). It is not always clear what the primary sensitizer is, but most likely both seafood tropomyosin and house dust mite tropomyosin can act as such. As an inhalant allergen however, tropomyosin most likely plays a minor role. It has been claimed that mite immunotherapy can cause snail and shrimp allergy by induction of cross-reactive IgE antibodies to allergens like tropomyosin(30). This however still waits for confirmation in double-blind clinical trials.


Diagnosis and therapy using major mite allergens

At present routine diagnosis and immunotherapy are carried out with house dust mite extracts. Depending on the company, purified mite-body extracts or whole-culture extracts are used. It is important to realise that these different approaches will result in different ratios between secreted allergens (like Der p 1) and non-secreted allergens (like Der p 2). This can influence the performance of diagnostic tests and the efficacy of immunotherapy. It is therefore important to monitor the major allergen levels. To better control the major allergen content of house dust mite diagnostics and therapeutics, the application of recombinant mite allergens has been proposed. Most major allergens have been cloned and expressed in several different expression systems. Of course the feasibility of such approaches will depend on the quality of recombinant allergens and on the number of allergens needed to replace extracts. Several studies have been carried out to compare the sensitivity of diagnostics based on extracts and on combinations of recombinant major allergens. It has been claimed that the combination of Der p 1, 2 and 7 will result in sensitivity over 95% compared to extract(8). Although these results look very promising, some reservation is still needed. Diagnostics based on house dust mite extracts do not always reach saturation for all allergens. The sensitivity of major allergen combinations compared to extracts might therefore be overestimated.

Pittner et al. have proposed that component-resolved diagnosis (as they have designated diagnosis with multiple individual major allergens) can be used to distinguish patients with a good prognosis for immunotherapy from those that can better not be treated by immunotherapy(31). It was suggested that patients with IgE antibodies to mite allergens with a broad spectrum of cross-reactivity (e.g. to tropomyosin) are less likely to benefit from immunotherapy than those who only recognize mite allergens like Der p 1 and Der p 2. This hypothesis is in line with the concept that immunotherapy is most successful in mono-sensitized patients. Nevertheless it needs to be confirmed by well-controlled clinical trials.

So far, no attempts have been made to replace mite extracts for immunotherapy. Whether Der p 1 and Der p 2 will be sufficient to replace mite extracts or allergens like Der p 7 need to be included will have to be established in clinical trials. Another interesting aspect of the application of recombinant allergens is the possible absence of naturally occurring adjuvant activity in extracts. Again, only well-controlled trials with recombinant allergens can demonstrate whether they will be an efficient replacement of current extract-based products.


Monitoring of mite allergens

As long as diagnosis and immunotherapy are carried out with extracts, measurement of major allergens like Der p 1 and Der p 2 will be of great importance. At present several different assays for their measurement are available. An EU-funded project is currently comparing these assays and developing candidate certified references based on recombinant versions of Der p 1 and Der p 2(32). This project will provide the tools to reliably standardize extract-based products for diagnosis and immunotherapy.



References
(1) Voorhorst R, Elias RW, Spieksma FT. [Housedust, a source of allergens and of misunderstanding]. Ned Tijdschr Geneeskd 1966; 110(1):46-8.

(2) Voorhorst R, SPIEKSMA-BOEZEMAN MI, Spieksma FT. IS A MITE (DERMATOPHAGOIDES SP.) THE PRODUCER OF THE HOUSE-DUST ALLERGEN? Allerg Asthma (Leipz ) 1964; 10:329-34.

(3) Thomas WR, Hales BJ, Smith W. Blomia tropicalis: more than just another source of mite allergens. Clin Exp Allergy 2003; 33(4):416-8.

(4) Chapman MD, Platts-Mills TA. Purification and characterization of the major allergen from Dermatophagoides pteronyssinus-antigen P1. J Immunol 1980; 125(2):587-92.

(5) Lind P. Purification and partial characterization of two major allergens from the house dust mite Dermatophagoides pteronyssinus. J Allergy Clin Immunol 1985; 76(5):753-61.

(6) Thomas WR, Smith WA, Hales BJ, Mills KL, O'Brien RM. Characterization and immunobiology of house dust mite allergens. Int Arch Allergy Immunol 2002; 129(1):1-18.

(7) Thomas WR, Smith W. Towards defining the full spectrum of important house dust mite allergens. Clin Exp Allergy 1999; 29(12):1583-7.

(8) van Ree R, van Leeuwen WA, Bulder I, van Oort E, Kramer M, Shen HD et al. Recombinant allergens for the diagnosis and treatment of house dust mite allergy. Which allergens are essential? In: Bienenstock J, Ring J, Togias AG, editors. Allergy Frontiers and Futures. Cambridge, MA: Hogrefe & Huber, 2004: 55-9.

(9) Chua KY, Stewart GA, Thomas WR, Simpson RJ, Dilworth RJ, Plozza TM et al. Sequence analysis of cDNA coding for a major house dust mite allergen, Der p 1. Homology with cysteine proteases. J Exp Med 1988; 167(1):175-82.

(10) Schulz O, Sewell HF, Shakib F. A sensitive fluorescent assay for measuring the cysteine protease activity of Der p 1, a major allergen from the dust mite Dermatophagoides pteronyssinus. Mol Pathol 1998; 51(4):222-4.

(11) Gough L, Schulz O, Sewell HF, Shakib F. The cysteine protease activity of the major dust mite allergen Der p 1 selectively enhances the immunoglobulin E antibody response. J Exp Med 1999; 190(12):1897-902.

(12) Wan H, Winton HL, Soeller C, Tovey ER, Gruenert DC, Thompson PJ et al. Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions. J Clin Invest 1999; 104(1):123-33.

(13) King C, Brennan S, Thompson PJ, Stewart GA. Dust mite proteolytic allergens induce cytokine release from cultured airway epithelium. J Immunol 1998; 161(7):3645-51.

(14) Comoy EE, Pestel J, Duez C, Stewart GA, Vendeville C, Fournier C et al. The house dust mite allergen, Dermatophagoides pteronyssinus, promotes type 2 responses by modulating the balance between IL-4 and IFN-gamma. J Immunol 1998; 160(5):2456-62.

(15) Schulz O, Sewell HF, Shakib F. Proteolytic cleavage of CD25, the alpha subunit of the human T cell interleukin 2 receptor, by Der p 1, a major mite allergen with cysteine protease activity. J Exp Med 1998; 187(2):271-5.

(16) Asokananthan N, Graham PT, Stewart DJ, Bakker AJ, Eidne KA, Thompson PJ et al. House dust mite allergens induce proinflammatory cytokines from respiratory epithelial cells: the cysteine protease allergen, Der p 1, activates protease-activated receptor (PAR)-2 and inactivates PAR-1. J Immunol 2002; 169(8):4572-8.

(17) Gough L, Sewell HF, Shakib F. The proteolytic activity of the major dust mite allergen Der p 1 enhances the IgE antibody response to a bystander antigen. Clin Exp Allergy 2001; 31(10):1594-8.

(18) Thomas WR, Chua KY. The major mite allergen Der p 2--a secretion of the male mite reproductive tract? Clin Exp Allergy 1995; 25(7):667-9.

(19) Mills KL, Hart BJ, Lynch NR, Thomas WR, Smith W. Molecular characterization of the group 4 house dust mite allergen from Dermatophagoides pteronyssinus and its amylase homologue from Euroglyphus maynei. Int Arch Allergy Immunol 1999; 120(2):100-7.

(20) O'Neill GM, Donovan GR, Baldo BA. Cloning and characterization of a major allergen of the house dust mite, Dermatophagoides pteronyssinus, homologous with glutathione S-transferase. Biochim Biophys Acta 1994; 1219(2):521-8.

(21) Asturias JA, Arilla MC, Gomez-Bayon N, Martinez A, Martinez J, Palacios R. Sequencing and high level expression in Escherichia coli of the tropomyosin allergen (Der p 10) from Dermatophagoides pteronyssinus. Biochim Biophys Acta 1998; 1397(1):27-30.

(22) Ayuso R, Reese G, Leong-Kee S, Plante M, Lehrer SB. Molecular basis of arthropod cross-reactivity: IgE-binding cross-reactive epitopes of shrimp, house dust mite and cockroach tropomyosins. Int Arch Allergy Immunol 2002; 129(1):38-48.

(23) Aalberse RC, Akkerdaas J, van Ree R. Cross-reactivity of IgE antibodies to allergens. Allergy 2001; 56(6):478-90.

(24) Leung PS, Chen YC, Mykles DL, Chow WK, Li CP, Chu KH. Molecular identification of the lobster muscle protein tropomyosin as a seafood allergen. Mol Mar Biol Biotechnol 1998; 7(1):12-20.

(25) Guilloux L, Vuitton DA, Delbourg M, Lagier A, Adessi B, Marchand CR et al. Cross-reactivity between terrestrial snails (Helix species) and house-dust mite (Dermatophagoides pteronyssinus). II. In vitro study. Allergy 1998; 53(2):151-8.

(26) Martinez A, Martinez J, Palacios R, Panzani R. Importance of tropomyosin in the allergy to household arthropods. Cross-reactivity with other invertebrate extracts. Allergol Immunopathol (Madr ) 1997; 25(3):118-26.

(27) Leung PS, Chow WK, Duffey S, Kwan HS, Gershwin ME, Chu KH. IgE reactivity against a cross-reactive allergen in crustacea and mollusca: evidence for tropomyosin as the common allergen. J Allergy Clin Immunol 1996; 98(5 Pt 1):954-61.

(28) Witteman AM, Akkerdaas JH, Van Leeuwen J, van der Zee JS, Aalberse RC. Identification of a cross-reactive allergen (presumably tropomyosin) in shrimp, mite and insects. Int Arch Allergy Immunol 1994; 105(1):56-61.

(29) Shanti KN, Martin BM, Nagpal S, Metcalfe DD, Rao PV. Identification of tropomyosin as the major shrimp allergen and characterization of its IgE-binding epitopes. J Immunol 1993; 151(10):5354-63.

(30) van Ree R, Antonicelli L, Akkerdaas JH, Garritani MS, Aalberse RC, Bonifazi F. Possible induction of food allergy during mite immunotherapy. Allergy 1996; 51(2):108-13.

(31) Pittner G, Vrtala S, Thomas WR, Weghofer M, Kundi M, Horak F et al. Component-resolved diagnosis of house-dust mite allergy with purified natural and recombinant mite allergens. Clin Exp Allergy 2004; 34(4):597-603.

(32) van Ree R. The CREATE project: EU support for the improvement of allergen standardization in Europe. Allergy 2004; 59(6):571-4.


*****
INDOOR POLLUTION AND IMMUNOLOGIC CHANGES



Mário Morais‑Almeida MD

Immunoallergy Department, Dona Estefânia Hospital, Lisbon, Portugal



(mmoraisalmeida@netcabo.pt)
The development and phenotypic expression of allergic disease depends on a complex interaction between genetic and several environmental factors, such as exposure to food and inhalant allergens and also to non-specific adjuvant factors (e.g. tobacco smoke, air pollution and infections). The first year of life seems to be a particularly vulnerable period and there is evidence that sensitisation is related to the level of allergen exposure during early life. At present, atopic heredity seems to result in the best predictive discrimination as regards development of allergic disease at birth.1 Early sensitisation, either to aeroallergens as to foods, atopic dermatitis and allergic rhinitis are predictors for later development of allergic lower airway disease. Various environmental factors, pollutants, that may enhance sensitisation include tobacco smoke, NO2, SO2, ozone, and diesel particles; within them, at an indoor perspective, passive smoking is by far the best-established risk factor, particularly in early childhood.2 The indoor environment probably plays a larger role than outdoor air pollution in the development of allergic disease, and are usually considered as a major risk factor for asthma prevalence increase.3 Expanding the concept, the mother is not only a source of genetic information, but also an "environmental factor", as there is a very close continuous immune interaction between her and the offspring.2 Intrauterine environment may play a significant role, particularly tobacco smoke during pregnancy, and its respiratory effects on infant. Maternal allergenic exposure during pregnancy is also an important factor because of materno-fetal immunologic interactions.4,5
Outdoor pollution acts by enhancing bronchial responsiveness, allergenic sensitisation and worsening respiratory diseases.6 Its effect is probably less important in infants and small children who are living indoor most of the time. Infection seems to have a complex action: some respiratory virus act to induce asthma or sensitisation; other kind of infections (viral, microbial, parasites) can have a protector effect. Exposure to tobacco smoke, particularly maternal smoking, is identified in all studies, as one of the most important factors to be considered in childhood asthma.4,5
Bronchial asthma represents a major health problem. Last decades increase in the prevalence and severity of this disease is widely accepted, particularly at paediatric age, leading to a high rate of school absenteeism, emergency room visits and hospital admissions.7 Asthma is the main cause of hospital admission in children with chronic disease and, parallel to a decrease in the global number of admissions at paediatric age, studies showed an increase in asthma admissions.9,10 The reasons that justify this fact are yet to be determined. Some studies report not only an increase in the number of admissions, but also mainly an increase in readmissions to hospital, suggesting that the increase in asthma severity is more important than the increase in incidence.8,10

There are few studies evaluating risk factors associated with hospital admission for childhood asthma, but in the majority of them identified: age under 4 years, male gender, black race, low socio-economic status, absence of specialised medical care, prior asthma hospitalisation, environmental tobacco‑smoke exposure and indoor allergen sensitisation.7-13


From our own experience, in a case-control study, performed in a sample of children admitted to hospital for acute asthma, comparing with a group of asthmatic outpatients (matched by age, gender and socio-economic status), by logistic regression analysis, we identified as significant and independent risk factors for hospital admission: prior asthma hospitalisation and last‑year admission, environmental tobacco‑smoke exposure, allergen sensitisation, maternal asthma and onset of symptoms before 12 months of age. As it was found by others, attendance at day‑care or kindergarten and large family size were identified as protective factors.14
Environmental tobacco‑smoke exposure adversely affects asthmatic children in several ways, including increase total IgE and specific IgE antibody responses, eosinophilia, decrease in lung function, increase in bronchial hyperreactivity, increase in attack number and emergency‑room visits.11,12,15-18 Chilmonczyk et al,17 in a retrospective study including 199 asthmatic children, found a relationship between tobacco‑smoke exposure and asthma morbidity, through measurement of urine cotinine levels. Other authors have tried to correlate passive smoking to asthma morbidity. Azizi et al,11 in a study performed in Kuala Lumpur, with 158 hospitalised children, found a relative risk of 1.9 for passive smoking. Macarthur et al,12 also identified passive tobacco‑smoke as a risk for asthma readmission to hospital.
The mechanisms by which passive smoking is associated with an increase in the severity of childhood asthma are still unclear. A possible mechanism could be the direct effect on bronchial mucosa, triggering the inflammatory process, as tobacco smoke had two main effects on the respiratory tract: 1) induction of inflammation, and 2) mutagenic / carcinogenic effects.19 It also could enhance allergenic sensitisation, by the disruption of the bronchial epithelium, increasing the permeability to antigens. Another hypothesis could be that this disruption of bronchial epithelium promotes the appearance of respiratory infections, common triggers of asthma exacerbations.
It has been demonstrated that cigarette smoking affects the immune system. Impairment of alveolar mononuclear cell function, may contribute to the higher rate of respiratory infections; however, increased susceptibility of smokers to infections of other origin (e.g. wound-related) implies that tobacco effect is not restricted to the respiratory immune competent cells. Cigarette smokers with no chronic obstructive pulmonary disease, exhibit impaired NK cytotoxic activity in peripheral blood and unbalanced systemic production of pro- and anti-inflammatory cytokines.20
Epidemiologic studies have suggested that tobacco passive exposure increases the prevalence and severity of allergic diseases, as bronchial asthma, but also atopic dermatitis.21 It was proved that, even in healthy non-atopic children, exposure to ETS causes changes in cellular infiltrates which partly resemble those seen in the nasal mucosa of allergic children.22 Seymour et al, in a murine model, that included generation of and exposure to environmental tobacco smoke (ETS) followed by aerosolised allergen challenge, showed that "second-hand smoke" up-regulates the allergic response to inhaled allergen.23 Rumold et al,24 found that ETS, in mice, can induce allergic sensitisation to a normally harmless antigen, and that may explain why second-hand smoke is a major risk factor for the development of allergy in children.25
Despite all the understanding related with the effect of ETS on allergic disease expression, there is scarce information about the immunological effects of maternal smoking on the fetus. Noakes et al, compared, for the first time, cord blood mononuclear cell cytokine responses to ovalbumin or house dust mite and mitogens in neonates whose mothers smoked throughout pregnancy, controlled with responses of neonates never exposed to maternal smoke, concluding that maternal cigarette smoking can modify aspects of fetal immune function and highlight the need for further studies in this area.26

The importance of tobacco‑smoke exposure lies in the fact that it is potentially avoidable. In a prospective study including 807 asthmatic children, Murray et al16 found a decrease in the severity of asthma and an improvement in functional respiratory parameters with reduction of smoke exposure. This study allows us to enhance the importance of establishing preventive anti-smoking campaigns, aiming mainly at asthmatic children’s parents. The identification of severity risk factors for asthma, related to hospital admission, allows the establishment of preventive measures, namely in high‑risk children, with emphasis on medication planning and the establishment of education programs such as environmental tobacco‑smoke avoidance and limitation of aeroallergen exposure.

Given the documented health risks to the mother and infant and the significant number of women who continue to smoke in the postpartum period, it is imperative that health care providers continue to assess smoking status and provide smoking-cessation counselling at every consultation.

Among many as ETS, other significant indoor pollutants / irritants are associated with the allergic respiratory symptoms occurrence and severity, namely to asthma current symptoms: wood-smoke pollution related to cooking,27 new surface materials in the home (linoleum flooring, synthetic carpeting, particleboard, wall coverings, furniture, paint),28,29 building quality,30 formaldehyde,31 …



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The central role of IgE in allergic disease – but what is around?
A phenotype-tailored therapy for allergic diseases



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