12-phase flow (12)

1. 1FRAME
   Frame MCAS as a recurrent multi-organ syndrome requiring ALL THREE consensus criteria (multi-organ symptoms + objective mediator-release + response to MC-directed therapy) — NOT a diagnosis assignable on symptoms alone. Distinguish primary (clonal, KIT D816V) vs secondary (IgE-mediated) vs idiopathic; recognise HαT as a tryptase modifier, not a stand-alone MCAS diagnosis.
   advance: Three-criteria diagnostic frame set; ddx of HαT vs clonal MC disease noted
2. 2ENTRY
   Recognise recurrent episodic multi-organ symptoms (criterion 1) and trigger the diagnostic workup. Do NOT diagnose MCAS based on symptom inventory alone — symptoms are non-specific and overlap with autonomic dysfunction, IBS, anxiety, POTS, hereditary angioedema, paroxysmal autonomic disorder, carcinoid syndrome. Recurrent unexplained anaphylaxis is an entry path (Giannetti 2020 PMID 32276688).
   inputs: episode_symptom_inventory_two_organ_systems
   actions: workup.anaphylaxis
   advance: >=2 organ-system symptom pattern confirmed; criterion-2/3 workup initiated
3. 3CONTEXT
   Capture trigger inventory (heat, exercise, alcohol, stress, NSAIDs, opioids, vancomycin, neuromuscular blockers, Hymenoptera, foods), atopic comorbidities, family history of HαT or systemic mastocytosis, and any prior anaphylaxis grade (drives auto-injector + dose).
   inputs: trigger_inventory, epinephrine_auto_injector_status
   advance: Triggers + comorbidities + family history + auto-injector status documented
4. 4RED_FLAGS
   Active anaphylaxis in progress -> route to allergy.anaphylaxis.v1 for IM epinephrine. Markedly elevated basal tryptase (>20 ng/mL on serial measurement) or unexplained cytopenia / hepatosplenomegaly / lymphadenopathy -> route to haematology for systemic mastocytosis workup (bone marrow biopsy + KIT D816V).
   inputs: basal_tryptase
   actions: workup.anaphylaxis
   advance: Acute anaphylaxis routed; systemic mastocytosis red flags addressed
5. 5INITIAL_WORKUP
   Capture mediator release during events: serum tryptase 1-4h post-symptom-onset + paired basal tryptase >=24h later (or pre-event baseline) — apply the "20+2 rule" (rise >=20% over basal + 2 ng/mL). If tryptase impractical, use 24h urine N-methylhistamine, 11β-PGF2α, or LTE4 (less sensitive). CBC for cytopenias, comprehensive metabolic for organ-specific clues. Skin exam for urticaria pigmentosa (cutaneous mastocytosis lesions). (Valent 2020 PMID 33261124)
   inputs: acute_tryptase_during_or_within_4h_of_event, basal_tryptase
   actions: panel.cbc, panel.lft, panel.renal
   advance: Mediator-rise evidence (criterion 2) sought and documented; cutaneous mastocytosis lesions screened
6. 6BRANCHING_WORKUP
   Etiologic branch: (a) elevated basal tryptase OR cytopenia OR hepatosplenomegaly -> KIT D816V peripheral-blood digital PCR + bone marrow biopsy + tryptase genotyping (TPSAB1) to separate clonal MCAS / systemic mastocytosis from HαT; (b) atopic / IgE-mediated trigger -> route to allergy.food-allergy.core.v1 or aeroallergen workup; (c) recurrent unexplained anaphylaxis with negative clonal + allergic workup -> idiopathic MCAS / idiopathic anaphylaxis (Giannetti 2020 PMID 32276688).
   inputs: kit_d816v_peripheral_blood_or_bone_marrow, tpsab1_genotype_for_hat
   advance: Primary vs secondary vs idiopathic MCAS assigned; HαT genotype interpreted with personalised tryptase reference range
7. 7DIFFERENTIAL
   Terminal differential: MCAS vs systemic mastocytosis (WHO criteria — major: dense MC infiltrates on bone marrow + KIT D816V; minor: atypical MC morphology, tryptase >20, aberrant CD25/CD2/CD30 on MC) vs hereditary alpha-tryptasemia alone vs IgE-mediated allergy with anaphylaxis vs carcinoid syndrome (5-HIAA, neuroendocrine tumour) vs paroxysmal autonomic dysfunction vs hereditary angioedema (C1-INH deficiency, no urticaria, no MC mediator rise) vs phaeochromocytoma vs panic / functional disorder.
   advance: Final etiologic classification assigned
8. 8RISK_STRATIFICATION
   Severity tier: frequent severe anaphylactic-grade events / clonal MCAS / HαT + clonal -> high-risk (anaphylaxis fatality modifier, fast-tracked therapy); recurrent moderate events with cutaneous / GI dominance -> intermediate; sporadic mild events -> baseline therapy + trigger avoidance.
   advance: Severity tier + therapy intensity assigned
9. 9TREATMENT
   Stepwise ladder (Valent 2020 PMID 33261124): (1) trigger avoidance + epinephrine auto-injector x 2 + written action plan; (2) H1 (cetirizine, fexofenadine, loratadine) + H2 (famotidine, ranitidine where available) antihistamines as foundation; (3) oral cromolyn sodium for GI-dominant MCAS; (4) leukotriene receptor antagonist (montelukast) or 5-LO inhibitor (zileuton); (5) ketotifen (mast-cell stabiliser + H1); (6) omalizumab (off-label, durable benefit reported); (7) for clonal MCAS / systemic mastocytosis -> midostaurin (FDA-approved for advanced SM) or avapritinib via haem-onc. Criterion 3 mandates documented improvement on the trial.
   inputs: response_to_mc_directed_therapy_trial, age
   advance: Stepwise therapy started; response documented at 4-8 wk; auto-injector in place
10. 10DISPOSITION
    Entirely outpatient allergy clinic. Haematology referral for elevated basal tryptase >20 ng/mL, KIT D816V positive, cytopenias, hepatosplenomegaly, or refractory disease. Genetic counselling for confirmed HαT family screening. ED only for active anaphylaxis (route to allergy.anaphylaxis.v1).
    advance: Outpatient allergy follow-up + heme referral if indicated; family screening for HαT scheduled
11. 11MONITORING
    Symptom diary correlating triggers, episodes, mediator measurements, and therapy response. Repeat tryptase periodically to detect clonal MC disease progression. Monitor for therapy side-effects: H2 long-term risk (B12, C. difficile with PPIs if co-prescribed), montelukast neuropsych (FDA 2020 boxed warning), midostaurin GI/hepatic AEs. Auto-injector technique + carry every visit.
    actions: panel.cbc
    advance: Diary + serial tryptase + drug-class monitoring on schedule
12. 12FOLLOWUP
    Lifelong chronic-disease maintenance: trigger avoidance + premedication for unavoidable triggers (e.g., contrast studies, surgery, dental procedures — H1 + H2 + cromolyn + corticosteroid premedication regimen), auto-injector + action plan, family screening for HαT, periodic re-evaluation for clonal MC disease emergence.
    inputs: trigger_inventory
    advance: Lifelong plan documented; premedication template ready for procedures