Allergy & Intolerance Drug Sub-project questions

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Open Questions

Scope & Governance

1. How do we present guidance?
   1. False categories (seafood) - may provide frequency but omit value from heuristic list.
      1. If the categories are ambiguous or excessively broad, such as “mold” I would classify them similarly to seafood
      2. Still need to determine whether to include in list
   2. Mislabeled categories (iodine contrast vs. high osmolality contrast) - can't distinguish with the data we have
      1. High osmolality contrast is a subcategory of iodinated contrast
      2. We know osmolality can be an issue; unclear whether iodine can. Either way, we can't distinguish and have zero records for high-osmolality. Default path: list what was reported.
   3. Distinguishing allergies from side effects (e.g., denying azithromycin due to erythromycin sensitivity better managed by contraindications) - can't distinguish with the data we have
      1. Erythromycin sensitivity is almost exclusively gastrointestinal distress and pain; it is a false assumption that azithromycin rarely causes such a reaction; presumed cross-reactivity was on the basis that both are macrolide antibiotics; no such cross reactivity or contraindication exists
      2. Need this sort of info in our guidance, but no actionable way to change our list.
   4. Criticality - to what extent can we prioritize substances based on likelihood that sensitivity may be critical? - can't distinguish with the data we have; see what USP comes up with
      1. Criticality of sensitivities cannot be assigned to substances in the vast majority of cases; many substance can cause reactions by different mechanisms that would have both high and low criticality potential; sulfa drugs, for example, often cause nausea and stomach pain – low criticality, but occasionally they cause Sevens-Johnson Syndrome - high criticality

Specific Questions

1. Need to specify route for certain substances?
   1. See sheet of iodine & media terms here
      1. In all of the cases below the substance is not elemental iodine, it is some other compound which is iodinated
      2. All radiocontrast media is iodinated; the risk of having a serious reaction is lower with low osmolality contrast, but it is not zero; although route of administration does not matter for most sensitivities it does here; the serious reactions are more likely with IV contrast than with arterial contrast
      3. Gadolinium (MRI) media don't contain iodine; numbers are much lower.
   2. Iodine: is povidone always topical? (Can be ophthalmic, but below threshold) Is it ever systemic?
      1. Povidone is an iodinated polymer used as a common skin antiseptic; it is over the counter and is not intended to be used except on the skin; it has toxicity when applied in large amounts; it can cause a reaction called “contact dermatitis” which is by definition a skin reaction
      2. Ophthalmic < 500
   3. aloe vera topical - always?
      1. It is over the counter and not regulated as a pharmaceutical
2. ASPIRIN BUFFERED. Aspirin? Or ASA + Al(OH)3 + CaCO3 + Mg(OH)2?
   1. Buffering with these inorganic compounds would not change the reaction unless it was “upset stomach”; the serious, life threatening reactions known as “Aspirin Related Respiratory Disease” (formerly aspirin sensitive asthma) would not be affected by buffering
3. iodinated glycerol: this substance, or is this about iodine?
   1. Iodinated glycerol was removed from the market by the FDA in 1993
4. Simvastatin, atorvastatin, pravastatin, rosuvastatin: distinct, or cross-reactive "statin"?
   1. Toxicities of statins may cross react, but “allergic/intolerance” reactions are so rare it would be difficult to have any evidence on cross reactivity; some individuals believe they have cognitive changes on statins but since the mechanism of these is unknown, it is impossible to say if there is cross reactivity
5. Tape: How many kinds of tape do we need - plastic, paper, surgical, adhesive, medical, cordran, silk, steristrip, opsite, transparent? Or is this really about adhesive?
   1. it is typically documented as adhesive tape allergy, but it is the adhesive not the tape; the adhesive on traditional “adhesive tape” seems to have a much higher propensity to cause this skin reaction (contact dermatitis) and “paper tape” much lower
   2. Is adhesive one substance or do brands differ?
      1. I am fairly certain they differ; I saw a story a few months ago about the development of band aids and they have tried some that were too sticky and some that were not sticky enough over the years. In addition to adhesive tape, balsam of Peru is often used as an adhesive (I believe it is also used cosmetically to keep bathing suits and bras from slipping); it is a common “sensitizer” and has a high rate of people developing contact dermatitis to it. (balsam of peru N < 500)
   3. 8170008 |Adhesive, device (physical object)|
   4. 418920007 |Adhesive agent (substance)|
6. tegaderm
   1. 400872007 |Hydrocolloid (substance)|
   2. 334582005 |Hydrocolloid dressing (physical object)|
7. Tuberculin Tine Test
   1. 108731003 |Tuberculin purified protein derivative (substance)|
   2. 255688002 |Old tuberculin (substance)| - is this still used?
   3. TTT and PPD are not the same thing; I believe TTT was taken off the market; in either case, if you have immunity to tuberculosis you will react to them; it is not an adverse reaction, it is a positive test and they can be quite dramatic
   4. Does this mean we should not list either?
8. Metal, nickel, trace metals? Top 500 has only nickel sulfate.
   1. Nickel sulfate is used in many metal alloys, particularly costume jewelry and cosmetics like mascara; it leaches out from sweat and in the aqueous state causes a contact dermatitis; the solution is to wear only 21 karat gold and no mascara; it has been suggested that nickel in implants can cause a reaction but there is no evidence of this
9. Do we need acetaminophen, aspirin, naproxen or does NSAIDs do the job?
   1. It is NSAIDs because they inhibit cyclooxygenase-1 and shunt arachidonic acid to the leukotriene pathway; acetaminophen is not an NSAID; some NSAIDs also cause allergic reactions (hives, skin rash) that are unique to that particular drug and do not cross react
   2. I.e., keep them all.
10. Beta Lactamase Inhibitors: no class in SCT
    1. Beta lactamase inhibitors are always given in combination with betalactam antibiotics to keep the antibiotic from being destroyed by the betalactase produced by the bacteria you are trying to kill; I don’t know how in most cases you would distinguish whether a patient reacted to the betalactamase inhibitor or to the antibiotic (penicillin or cephalosporin)
    2. So do we add a 15k entry for 406778007 |Beta-lactam (substance)|?
11. FLUOROQUINOLONES. quinolones?
    1. Sub-group of quinolones; they have been associated with Achilles tendon rupture, can cause prolonged QT interval and Torsades de Pointes but I would consider these side effects, not sensitivity; some individuals may have sensitivity to individual members of this sub-class but I would not assume cross reactivity
    2. So, classify as quinolones or leave out for now? N = 3550
12. IODINATED CASEIN
13. Trace metals
    1. This belongs with mold and seafood; not an actionable term or class; some trace metals cause reactions, selenium causes a a rash in front of your elbows but it is a toxicity not a sensitivity (Selsun shmpoo)
    2. N < 500
14. sulfa topicals
    1. yes, would usually contain one of the sulfa drugs that is also available by mouth and eye drops; not an actionable term though because most of these contain other antimicrobials, as in “triple antibiotic cream”
    2. N = 1500; creams well-represented. redact.
15. Contrast Media Ready-Box
    1. No idea what this is but suspect it is packaging for a radiocontrast media injector (machine used to infuse the radiocontrast media, which would otherwise have the same potential for adverse reaction as the radiocontrast media has)
    2. It's a media warmer. Probably a proxy for ircm, but don't know if it could be double counted or gad; will ignore, as ircm is well-represented.
16. ASA (salicylates)
    1. It is not salicylates that people react to, but specifically acetyl salicylic acid; salicylates do not inhibit cyclooxygenase-1 which is the mechanism of the reaction
    2. classify as ASA. there are also topical salicylate entries; keep separate.
17. BAND-AIDS: see Tape
18. lidocaine topical
    1. lidocaine is a strong sensitizer: it is easy to become allergic to it; it causes a contact dermatitis that is a Type IV cell mediated immune reaction; it is present in many brands of sun-burn cream, insect bite itch relief creams; it would not mean you would have a reaction if you were given intravenous lidocaine for a cardiac arrhythmia or lidocaine as a local anesthetic for a dental procedure (or any other procedure)
    2. Sounds like route is significant here. We don't have an approach for distinguishing; add to list of questions for ballot.
19. fluoride
    1. it is an element; you cannot be sensitive to it, but it is toxic above ppm levels
    2.  : N << 500
20. iron containing compounds
    1. iron is toxic in many forms; ferrous sulfate given as a liquid by mouth for iron deficiency is very irritating to the stomach; you might be sensitive to some of the “compounds” but not to the iron itself
    2. add to guidance. ICC may fall below threshold; Iron will not.
21. A/Fish Oil
    1. Don’t know, except that it would not be related to seafood, iodine, or radiocontrast reactions
22. ANTI-INFLAMMATORY AGENTS OPH/OTIC
    1. See mold, seafood, and trace metals; not an actionable class; this class would include NSAID eye drops, corticosteroid eye drops, eye drops that are mast cell inhibitors, and probably others
    2. N ~ 1100
23. inhalation anesthetics
    1. see mold, seafood, trace metals, ophthalmic anti-inflammatory agents; not an actionable term
24. Prempro
    1. Generic Premarin; Premarin is a consolidation of premenstrual mare’s urine which is how it is made; it is the original estrogen replacement hormone; has all kind of side effects, but I think sensitivity to it would be rare; no, you would not react to it if you were allergic to horses

Closed Questions

Scope

1. How do we confirm quality?
   1. Process
      1. Acquire maps.
      2. If count(maps) > 1 and they agree, status is ok.
      3. If count(maps) < 2, acquire more maps.
      4. If count(maps) > 1 and they disagree, review.
2. Encode and then combine, or combine and then encode?
   1. Encoding is required to combine
3. How do we weight lists?
   1. Use filtered rankings to assess divergence, but no weighting in frequency list.
4. Rank all substances from contributed lists, or only those to a chosen level (97%, 99%, etc.)?
   1. Identified substances with counts > 500 (individually ~0.0017%; aggregate 0.71%)
   2. Actually, 1000. 4/19/17.
   3. Include frequency ratios in resulting list; users may choose their own thresholds.
5. How do we harmonize frequency thresholds for drugs (1000) & food (lower)?
   1. Separate lists.
6. Should we provide a single mapping per code or a multiple mapping table?
   1. Tentatively, one. More later if requested.
7. Should we provide a single value set for substances or multiple sets for drugs, food, other?
   1. In VSAC, the sets have values from a single system, so we are looking at several value sets, possibly with a "grouping" value set to tie them together.
8. Stewardship: who owns and maintains the list? Patient Care? Vocabulary? Someone else?
   1. For now, Patient Care

Domains

1. Include substances only, or also null and negative values?
   1. Use is the criterion: include what is used. Agreed 10/19
   2. Specific negatives are rare; we anticipate two (nka & nkda).
2. Negatives: we have NKA, NKDA, NKFA. Do we need NKEA, NKFDA?
   1. Frequency is the criterion.
3. How do we identify herbals, supplements
   1. As other medications, if in RxNorm
4. How do we identify environmentals
   1. SNOMED CT, which supports classification (e.g., 'wasp venom' vs many species-specific terms in UNII).
5. How do we vaccines
   1. Many vaccines below threshold.
   2. TNF below threshold, and it's a toxin anyway
   3. Vaccines above threshold have many specific RxNorm / CVX values
   4. Use SCT for vaccines for now. E.g.,SCT 396433007 |Pertussis vaccine (substance)|
      1. Tetanus toxoid does have a specific RxNorm IN - ?
   5. Combination vaccines only available in SCT as products (e.g., DPT)
6. Other biologics below threshold

System Choice

1. What system(s) should be used for encoding?
   1. Assumption: do we need to choose, or can we provide a list of substances with all pertinent code assignments?
   2. Criteria
      1. Maximal coverage of identified requirements
      2. Ability to add missing items
      3. Freely available
      4. International
   3. Candidates
      1. SNOMED CT: substances, classes; mixtures only as products. Licensing issue.
      2. RxNorm: substances & mixtures. No license issue, but US realm.
      3. NDF-RT: classes only. Class definitions problematic.
      4. UNII: substances only. US realm. no relationships (e.g., of salts)
      5. ATC: classes only. Class definitions problematic.
      6. INN: no access to list; tbd
      7. Proposal to use whatever G-SRS chooses to use. Will evaluate when available.
   4. Answer: for now, RxNorm (substances - IN & mixtures - MIN) and SNOMED CT (classes) meet our needs. When G-SRS can provide data for comparison and testing, we can confirm whether it also meets our needs and decide whether to map or replace the US realm list.

Details

1. Salt forms of medications are not relevant to the purpose of this list. Incidences recorded as salt forms should be summed to the incidence of the general form (e.g., codeine sulfate as codeine).
   1. Salts in solution have limited effect on the active moiety. This does not mean that an intolerance reaction dependent on a salt is not possible; only that it is not common enough to merit inclusion in this list.
2. Route can be significant.
   1. Enterally administered aspirin does not cross-react with topical salycilates. Topical salycilates should be specified as topical. Similarly, sensitivity to topical iodine preparations is not cross-reactive with intravenously administered iodine.
      1. confirm cross-reactivity. whether iodine can be the problem is a different question.
3. How do we identify supply items (latex, adhesive)
   1. Latex: RxNorm
   2. Adhesive: SCT classifier 418920007 |Adhesive agent (substance)|
4. Food/Drug items: record as both or as one?
   1. Eggs, lactose, fish oil, caffeine, alcohol
   2. Multiple lists. Include question in ballot (RxNorm drug caffeine + SCT food caffeine)
   3. Are Sulfites & Nitrites are food
5. Penicillins
   1. There may be truly cross-reactive subgroups but we don't have the data to identify them.
6. Opioids: synonymous with "narcotic analgesics", "Morphine derivatives"
7. Salicylates: We have Aspirin and Salicylates. "Topical" values below threshold.
8. Estrogens. Class.
9. Iodinated contrast media
   1. Keep 'iodinated contrast media'
   2. Consider describing "high osmolality contrast media" in guidance; no actual instances for list.