Concomitant clinical sensitivity (CCS) and cross-reactivity
Steinman Harris A.
Concomitant clinical sensitivity (CCS) and cross-reactivity.
(Allergy & Clinical Immunology International - January 2002)

Removal of allergenic substances is the treatment of choice in allergy, and may be the only effective management tool with food allergies. Many patients are sensitised to more than one allergen, and "hidden" allergens render it unlikely that the removal of the easily identified allergens will be sufficient in any given case. To apply this principle, a more systematic understanding of the interactions of different allergens and allergies is necessary.

Many biological factors are involved in cross-reactivity and clinical tolerance or hypersensitivity. In particular, complete absence of cross-reactivity cannot be proven, but a theoretical scale of cross-reactivity could be developed ranging from highly cross-reactive to probably non-cross-reactive. An allergen amino acid homology of less than 35% is unlikely to result in high-affinity cross-reactivity.
Plants and pollen usually contain more than one protein allergen. For example, allergy to zucchini can occur as a result of primary sensitisation to zucchini, as well as of cross-reactions to the panallergen profilin and cross-reacting carbohydrate determinants.

In developing Allergy Advisor, I recognised 5 patterns/mechanisms that will influence a patient's allergen load or clinical expression of allergic disease. These 5 patterns/mechanisms have been designated 'Concomitant Clinical Sensitivity' (CCS). CCS is the propensity for a patient to be allergic to other allergens due to one or more of five associative mechanisms. These are listed in table I.

Table I. Associative Mechanisms resulting in CCS.
1. Similar proteins, similar or related species
Examples: Rye grass and Timothy grass
Explanation: Family relationship, may contain identical allergens

2. Similar proteins, dissimilar or unrelated species
Examples: Olive, privet, ryegrass
Explanation: Cross-reactivity demonstrated but pan-allergen not identified

3. Panallergens
Examples: Peach, peanut, apple
Explanation: Cross-reactivity demonstrated, panallergen identified, e.g., LTPs, chitinases, profilin

4. Proximal occurrence
Examples: Apparent feather pillow allergy actually caused by house dust mite
Explanation: Allergen in same location, e.g., mites in feather pillows

5. Co-sensitization
Examples: The most common foods associated with melon allergy were avocado, banana, kiwi and peach
Explanation: Statistical event with no known clinical or biochemical basis, and with no associations such as listed above

1. Similar proteins, similar or related species
The family relationship of plants has been long recognised as the basis for cross-reactivity. The closer the botanical relationship between two plants, the greater the degree of structural and immunological similarity of the allergens. More-recent research has demonstrated that the clinical significance of cross-reactivity in fact differs among families; therefore, for example, although cross-reactivity between members of the legume family (peanut, soybean, green bean, pea, and lima bean) can be established in the laboratory, clinical hypersensitivity to one legume does not warrant dietary elimination of all legumes.

2. Similar proteins, dissimilar or unrelated species
Cross-reactivity between two or more dissimilar taxonomical species has been recognised for over 3 decades. In this CCS associative mechanism, the main cross-reactivity is due to one or more allergens that appear to be similar, but occur in dissimilar species, yet have not been identified as a panallergen (see below). In time the cross-reactivity may be shown by applied analytical tests and techniques to be a panallergen.

Cross-reactivity in the "celery-spice-carrot-mugwort syndrome" is an example of this mechanism. Components of this cross-reactivity complex are pollen from mugwort, ragweed, birch pollen, members of the family Asteraceae and food of the Apiaceae family: celery, carrot, parsley, anise, fennel, caraway, and the spices pepper and paprika. Despite extensive investigation, no molecular basis for this association has been determined.

3. Panallergens
Sensitisation to multiple pollen species occurs frequently. Several allergenic molecules with a high level of homology have been identified in the pollen of divergent plant families and named panallergens.

Panallergens are not equally relevant to the various clinical allergic diseases seen in practise. For example, panallergens are more frequently implicated in Oral Allergy Syndrome than in asthma.
In many instances, panallergens are pathogenesis-related proteins (PRs). These are proteins that are induced by pathogens, wounding, or certain environmental stresses. PRs have been classified into 14 groups. Seven of these groups contain proteins with allergenic properties and six contain food allergens. Examples of allergens homologous to PRs include chitinases (PR-3 group) from avocado, banana, and chestnut; antifungal proteins such as the thaumatin-like proteins (PR-5) from cherry and apple; proteins homologous to the major birch pollen allergen Bet v 1 (PR-10) from vegetables and fruits; and Lipid Transfer Proteins (PR-14) from fruits and cereals.
Panallergens other than PR homologs can be assigned to other well-known protein families such as inhibitors of alpha-amylases and trypsin from cereal seeds; profilins from fruits and vegetables; seed storage proteins from nuts and mustard seeds (2S albumins); and proteases from fruits.
Stress may derive from plant infection, changes in environment and weather, storage conditions, or biotechnology aimed at creating transgenic plants with enhanced pathogen resistance. For example, ethylene used in storage of apples induces the expression of plant class I chitinases.

Examples of panallergens.
a. Bet v 1-homologues
b. Profilin
c. Lipid Transfer Proteins (LTP)
d. Chitinases
e. Tropomyosin
f. Cyclophilins
g. Thaumatin-like proteins (TLP)
h. Isoflavone Reductase (IFR)
i. Glutathione-S-transferase (GST)
j. Lipocalin
k. 2S albumins
L. Enolase

4. Proximal occurrence
CCS due to a proximal occurrence mechanism is important to consider and occurs when an adverse effect is caused not by the apparent allergen, but by another allergen proximal or physically associated with it. Examples are Baker's Asthma and hidden allergens in food, medications and cosmetics.

Globalisation and the adoption of other cultures' practises contribute to unusual associations and unexpected allergens. Buckwheat allergy, a frequent allergen in Asian countries because of the substance's widespread use in food and in bed furniture, may be the cause of exacerbation of allergy following contact with pillows filled with buckwheat, although pillows are traditionally associated in the West with feather and mite allergy. Individuals working in tomato greenhouses may be allergic to red spider mite found on the tomato surface and not to the tomato itself. Allergic reactions credited to fish without compatible in vivo or in vitro evidence may be attributable to the parasitic worm, Anisakis (Cod worm), rather than the actual fish. Apparent allergy latex condoms may be an allergy to seminal fluid, or both may occur concurrently.

5. Co-sensitization
The co-sensitization of allergens will be specific for certain locations, occupations or groups of people, beyond what is explained by known CCS mechanisms.

Cross-reactivity co-sensitization may vary widely depending on the route of exposure of the allergen: oral, parenteral, skin or airways. Within a food, allergens involved may differ. This is particularly evident in exposure to latex and soy allergens. For example, the allergens involved in occupational asthma caused by soybean flour are predominantly high-MW proteins that are present both in soybean hull and flour, whereas the soybean allergens causing asthma outbreaks are mainly low-MW proteins concentrated in the hull.

Co-sensitization nevertheless constitutes valuable clinical knowledge. For example, knowing that atopic sensitisation to inhaled allergens in a specific group of children living near a citrus orchard are to the following allergens, Dermatophagoides pteronyssinus (26.6%), D. farinae (22.7%), Panonychus citri (14.2%), cockroach (11.3%), and Japanese cedar pollen (9.7%), enables the clinician to assess a patient for unusual or unexplored allergens.

Use of CCS
The importance of CCS is relevant for the following:
Implications for patient interview. For the doctor to enquire whether the patient exhibits any allergic symptoms to associated allergens.
Implications for testing. For further investigation if appropriate.
Implications for treatment. For the doctor to advise the patient to avoid exposure to the associated allergens.

Quality care requires a reduction of symptoms with minimal use of medication. This necessitates reducing the number of allergens that the individual is affected by, and for this CCS is a tool that may be of great benefit.

The challenge of CCS is to use the most appropriate algorithm in determining the most relevant CCS allergen affecting a specific patient. For example, it may be more appropriate to review CCS mechanism 1, 2 or 3 in a patient affected by ingesting tomato, whereas the proximal association mechanism may be more relevant in a patient affected while working with tomato.
Clinically, it is important to identify the primary sensitising allergen, as this covers the widest spectrum of specificities.

Identifying CCS allergens can simplify diagnostic procedures and therapeutic regimes. The practical benefits of this knowledge are too numerous for detailed coverage here, but a couple of examples may be suggestive. If two allergens are very similar, it does not increase the diagnostic accuracy to include both in a diagnostic panel; hence a savings of time and money. Similarly, successful desensitisation with one allergen is likely to relieve the symptoms of other very similar allergens.

The basic premise of CCS is the synthesis of laboratory with clinical experience and the presentation of both in a form that is practically useful for the clinician.