Representation of Hypersensitivity and Allergy in SNOMED CT

Current state of allergy hierarchies in SNOMED CT July 2013 release

Definitions-Hypersensitivity Term Current definition Proposed definition Hypersensitivity condition The disposition to develop an allergic or pseudoallergic reaction, the reaction itself or its consequences. N/A Hypersensitivity disposition The disposition to develop hypersensitivity. The disposition to develop an allergic or pseudoallergic reaction Hypersensitivity reaction A pathological process initiated by exposure to a defined stimulus at a dose tolerated by normal persons. It is the realization of the disposition to hypersensitivity.

Definitions-Allergy Term Current definition Proposed definition Allergic condition The disposition to develop an allergic reaction, the allergic reaction itself or its consequences N/A Allergic disposition The disposition to develop an allergic reaction Allergic reaction A pathological immune process generally directed towards a foreign antigen, which results in tissue injury, which is usually transient. It is the realization of the allergic disposition. It is most often applied to type I hypersensitivity but other hypersensitivity types especially type IV (e.g. allergic contact dermatitis) may be involved

Definitions-Allergic sensitization Term Current definition Proposed definition Allergic sensitization A process characterized by a humoral or cell-mediated immune response to a foreign antigen resulting in the production of specific antibodies and/or immune cells which may then lead to an allergic disposition. N/A

Definitions-Pseudoallergy Term Current definition Proposed definition Pseudoallergic condition The disposition to develop a pseudoallergic reaction, the pseudoallergic reaction itself or its consequences N/A Pseudoallergic disposition The disposition to develop a pseudoallergic reaction Pseudoallergic reaction A nonimmune hypersensitivity reaction directed towards a foreign substance, which results in tissue injury, which is usually transient. It is the manifestation of the pseudoallergic state. A pathological nonimmune process generally directed towards a foreign substance, which results in tissue injury, which is usually transient. It is the realization of the pseudoallergic disposition. A variety of mechanisms such as direct histamine release, complement activation, cyclooxygenase activation and bradykinin generation may be involved

Pseudoallergy The revised model for 419199007, allergy to substance (disorder) involves a role group, linking after allergic sensitization (disorder) with causative agent substance (substance). As pseudoallergies are not preceded by a sensitization phase (they may occur upon initial exposure), this model would not hold for pseudoallergic dispositions.

Proposed revisions to Concept Model of Pseudoallergy to substance Current model is just Pseudoallergy to substance |Pseudoallergic disposition| With pseudoallergy to specific substances modeled using causative agent Option #1 |associated with|=|substance (substance)| In this case, as substances don’t directly cause dispositions, the uncertainty of how the substance relates to the disposition may be best expressed using associated with rather than the more specific due to role.

Option #2* Pseudoallergy to substance |causative agent|=|substance|} |Pseudoallergic disposition| RG: {|after|=|pseudoallergic reaction| |causative agent|=|substance|}   It might be argued that a pseudoallergic disposition cannot follow a pseudoallergic reaction as the disposition must have existed first in order for the reaction to have occurred. On the other hand, the disposition to develop a pseudoallergic reaction could only be discerned by the presence of a prior reaction as there is no other way to predict such reactivity. * This option was approved by the group

Option #3 Pseudoallergy to substance |Pseudoallergic disposition| |Agent of realization|=|substance|   This approach would require introducing a new attribute. The utility of such an attribute outside of this domain will need to be determined

Option #4 Pseudoallergy to substance |Pseudoallergic disposition| |Causative agent|=|substance|   This option essentially leaves the current concept model unchanged. Although this is technically incorrect for the same reason that allergic disposition to substance can’t be defined with causative agent substance (dispositions can’t have causative agents, only their realizations (processes) can), at least retrieval of the associated substances would not be disrupted.

Agents that can act as allergens or pseudoallergens There are some substances that may be able to elicit allergic as well as pseudoallergic reactions Examples Include NSAIDs, protamine and perhaps radiocontrast agents and opiates

NSAID hypersensitivity I A classification scheme for NSAID hypersensitivity taking into account allergy and pseudoallergy has been developed NSAID pseudo allergy Type 1: NSAID-induced asthma and rhinosinusitis Type 2: NSAID-induced urticaria/angioedema in patients with chronic urticaria Type 3: NSAID-induced urticaria/angioedema in otherwise asymptomatic individuals - Type 4: Blended reactions in otherwise asymptomatic individuals NSAID allergy Type 5: Urticaria/angioedema to a single NSAID - urticaria and/or angioedema within minutes to one hour of taking a particular NSAID or ASA. These patients generally do not have underlying chronic urticaria. Type 6: Anaphylaxis to a single NSAID (not ASA) Type 6 reactions are distinguished from type 5 reactions based only upon severity. Typical symptoms of anaphylaxis include shortness of breath/wheezing due to bronchospasm or laryngeal edema and hypotension due to vascular collapse.

NSAID hypersensitivity II Consideration might be given to reproducing this content in SNOMED CT as shown below. Note end users would need to be educated to search under NSAID hypersensitivity in order to retrieve all types of reactions

Review of allergy use cases I Representation of Allergy to X i.e the disposition to developing an allergic reaction after exposure to allergen X Fit with IHTSDO strategy 1B Problem list diagnosis 1D Allergy list 2A Medication / allergy management Use case 2 Representation of specific allergic/immunologic disorders such as allergic rhinits 1B Problem list Diagnosis There are 29 diagnoses on the SNOMED CT core problem list that refer to allergy, anaphylaxis or hypersensitivity. Allergic rhinitis is the top 11th diagnosis. Relevant for decision support algorithms involving medication management in allergic individuals. An example would be an alert regarding use of radiocontrast agents in those with a history of an atopic disorder.

Review of allergy use cases II Representation of specific allergic disorders caused by allergen X e.g. Allergic rhinitis due to pollen Fit with IHTSDO strategy 1B Problem list diagnosis 1D Allergy list 2A Medication / allergy management Use Case 4 Representation of Non-specified allergic reactions to allergen X such as allergic reaction to penicillin There is a need to distinguish an episode of an allergic reaction to a particular substance occurring at the time of an encounter from a disposition to an allergic reaction to a particular substance

Review of allergy use cases III Representation of specific types of allergic reactions to allergen x such as anaphylactic reaction to penicillin Fit with IHTSDO strategy 1B Problem list diagnosis

Modeling Allergy to Combination Drug Products

Definition A medicinal product containing 2 or more active ingredients Example Amoxicillin + clavulanate potassium (Augmentin®)

Issues Current SNOMED model contains causative agent roles pointing to each of the active ingredients of the preparation:

Issues II The previous example would seem to indicate that the allergy (disposition) is to both amoxicillin and to clavulanate potassium but in reality the allergic disposition would be to one or the other (almost always to amoxicillin but allergy to clavulanic acid has been reported)

Issues III Invoking the new model for allergic disposition in which causative agent=substance x and after=allergic sensitization are role grouped, one would infer that the disposition to allergy x follows allergic sensitization to both amoxicillin + clavulanate potassium which is unlikely to ever be true

Possible solutions I Use product as the value for causative agent* Current amoxicillin + clavulanate potassium allergy (disorder) |combined penicillin preparation allergy (disorder)| |causative agent|=|amoxicillin (substance)| |causative agent|=|clavulanate potassium (substance)| Proposed |causative agent|=|amoxicillin with clavulanate potassium (product)| *Response from Bob Dolin re. medication and allergy value sets for HL-7: "As for using the Product as the value of the causative agent, our initial Allergy/Intolerance value sets were comprised of RxNorm Semantic Clinical Drugs, which are kinda like products. Folks complained that they didn’t align with the way allergies are captured in the EHR, that documentation is generally at the ingredient level, which led us to abandon the semantic clinical drugs and move to ingredients".

Possible solutions II Reorganize Allergy to combined substances as shown below: Current Allergy to penicillin (disorder) Combined penicillin preparation allergy (disorder) broad spectrum penicillins allergy (disorder) Amoxicillin allergy (disorder) Amoxicillin + clavulanate potassium allergy (disorder) In the current view, someone with allergy to amoxicillin + clavulanate potassium would be considered allergic to amoxicillin and penicillin which although may have some practical import is not necessarily true (see example at end)

Possible solution II Proposed hierarchy Antibacterial drug allergy (disorder) Combined penicillin preparation allergy Amoxicillin or clavulanate potassium allergy (disorder) Amoxicillin allergy (disorder) Clavulanic acid allergy (disorder) In this case, an individual considered to be allergic to amoxicillin would be considered to be allergic to amoxicillin or clavulanate potassium and an individual considered to be allergic to clavulanate potassium (or clavulanic acid) would also be considered to be allergic to amoxicillin or clavulanate potassium. This would appear to be more correct than the preceding model although admittedly it would not capture the case where an individual allergic to amoxicillin or clavulanate potassium is indeed allergic to amoxicillin (or clavulanic acid).

Possible solution III Retain allergy to individual ingredients but not to combination agents Capture allergy to combination agents in the EHR information model.

Real world example 57 year old female developed diffuse urticaria and angioedema 2 days after completing a 10 day course of Augmentin for a URI

Allergy testing Interpretation: Penicillin skin test negative. Tolerated oral challenge to Amoxicillin

Allergy documentation in EHR

Ordering medication in EHR In this patient for whom Augmentin allergy was documented in the EHR but amoxicillin allergy was ruled out, an alert is generated when amoxicillin is ordered.

Decision was to defer above pending further development and collaboration with SHRD group

Allergic disposition vs. History of allergy

Clinical usage of history of x (situation) X in remission X resolved X disposition

Meaning of history of x (situation) in SNOMED Concept model |finding with explicit context| |associated finding|=|x| |finding context|=|known present| |subject relationship context|=|subject of record| |temporal context|=|past| Thus history of x (situation) in SNOMED really means X resolved

Dispositions A disposition is the propensity or tendency to develop a pathological process under the proper circumstances The only clear example of a disposition currently in SNOMED is propensity to adverse reactions and it’s descendants most notably allergic disposition (formerly allergic state, syn. allergy) which is now the parent for various allergy to x terms. History of allergy to x in common usage is most often meant to represent the disposition i.e. the tendency to develop an allergic reaction to x if exposed to x Allergies may completely disappear with time and avoidance (e.g. egg and milk allergies in children, penicillin allergy) and thus truly represent history of allergy to x, but since allergy to x is more commonly used to represent the disposition, documenting history of allergy to x in someone whose penicillin allergy has disappeared because they have not been exposed to penicillin for many years may confuse providers into thinking that the allergy still exists. It is best not to document an allergy that no longer exists Thus, one might consider retiring history of allergy to x (situation) maybe A allergy to x (disorder)

Impact of retiring history of allergy concepts Total concepts = 56 48/56 (86%) concepts modeled with associated finding of the corresponding allergy to x term 8/56 (14%) concepts not modeled with associated finding of the corresponding allergy to x term 2 terms , history of bee sting allergy and history of - angiotensin II receptor antagonist allergy do have suitable corresponding allergic/pseudoallergic disposition replacements (allergy to bee venom and Pseudoallergy to angiotensin II receptor antagonist) 1 term, history of - non-drug allergy is a non-specific grouper subsuming history of allergy to latex, history of allergy to seafood and history of bee sting allergy which can possibly be retired without a replacement The following 5 terms will require creation of new corresponding allergic disposition concepts history of - combined calcium and vitamin D3 preparation allergy history of - selective estrogen receptor modulator allergy history of allergy to opiate agonist history of - strontium ranelate allergy history of - serum allergy

Modeling of pollen allergens Paul

Aspirational (formal ontologic) model of Allergy - Stefan

Original model

Revised model with clinical situations

Changest to original model - Stefan new btl2 (BioTopLite) namings of some relations for all classes distinguished between “general” and “related to Allergen X” added situation concepts

Changes to original model – details I hasLocus: in btl2 „is included in“ (renamed for better understandability) Allergen-specific IGE: is not always included in an immune system structure, because it can be isolated from it: therefore, btl2 compatible: 'at some time' some ('is included in' some ImmuneSystemStructure) Allergen-specific IgE is related to “X”, therefore introduction of subclass AllergenXspecific IGE Allergic reaction and Allergic disorder: If you mean that for every Allergic reaction there is some Allergic Disorder as an outcome and vice versa, then there should be used the quantifier “some”

Changes to original model – details II Allergic reaction / allergic sensitization: Subclasses introduced: Allergic reaction to X / allergic sensitization to X (in order to distinguish the general classes from the specific ones) Sensitization: has outcome “some” (not “only”) – because there is always some IgE as outcome (and I would not exclude that there is any other outcome) Allergic dispositionAllergyToX: I added the definitional condition “AllergicDispositionAllergy and 'has realization' only AllergicReactionToX” This cannot be expressed by the current SNOMED CT syntax, which explains the additional relation with “hasAgentOfRealization”