clinical sensitivity (CCS) and cross-reactivity
Concomitant clinical sensitivity (CCS) and cross-reactivity.
(Allergy & Clinical Immunology International - January
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
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
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.
I. Associative Mechanisms resulting in CCS.
proteins, similar or related species
Rye grass and Timothy grass
Explanation: Family relationship, may contain identical allergens
Similar proteins, dissimilar or unrelated species
Olive, privet, ryegrass
Explanation: Cross-reactivity demonstrated but pan-allergen
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
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
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.
Similar proteins, dissimilar or unrelated species
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.
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 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.
Bet v 1-homologues
c. Lipid Transfer Proteins (LTP)
g. Thaumatin-like proteins (TLP)
h. Isoflavone Reductase (IFR)
i. Glutathione-S-transferase (GST)
k. 2S albumins
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.
of allergens will be specific for certain locations, occupations
or groups of people, beyond what is explained by known CCS
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
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
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
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.