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README.md

Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) — QSP Model

Overview

This directory contains a comprehensive Quantitative Systems Pharmacology (QSP) model for Chronic Rhinosinusitis with Nasal Polyps (CRSwNP), a prevalent chronic airway disease characterized by type 2 eosinophilic inflammation, goblet cell hyperplasia, mucosal edema, and progressive nasal polyp growth.

CRSwNP affects approximately 4–5% of the general population and is driven by dysregulated type 2 immunity (IL-4/IL-5/IL-13 axis), ILC2 activation, IgE-mediated mast cell responses, and eosinophil-driven tissue destruction. The model integrates five approved or investigational biologics (dupilumab, mepolizumab, benralizumab, omalizumab, tezepelumab) with comprehensive PK/PD and disease biology.

Disease Pathophysiology Summary

Epithelial Damage (allergens/pathogens/pollutants)
        │
        ▼  Alarmins released
   TSLP + IL-33 + IL-25
        │
        ├──► ILC2 activation ──► IL-4, IL-5, IL-13
        ├──► DC maturation ──► Th2 polarization ──► IL-4, IL-5, IL-13, IL-31
        └──► Mast cell priming ──► IgE loading (FcεRI)
                                    │
                       IL-5 ─────────────────────────────────────────────────────►  Eosinophils
                        │                                                               │
               Blood Eos (↑)──► Tissue Eos recruitment ──► ECP/MBP/EPX degranulation
                                                               │
                         IL-13 ──► Goblet cell hyperplasia ──►│──► TGF-β ──► Fibrosis
                                   ──► Periostin ──► ECM        │
                         IL-4/13 ──► IgE class switching        ▼
                                                          VEGF ──► Angiogenesis ──► Edema
                                                               │
                                                        POLYP GROWTH (NPS ↑)

Key Biologics Modeled

Drug Target Dose Interval t½ NPS Δ (Wk 24)
Dupilumab IL-4Rα (blocks IL-4 + IL-13) 300 mg SC q2w 21 days −1.8 to −2.1
Mepolizumab Free IL-5 100 mg SC q4w 20 days −0.7 to −0.9
Benralizumab IL-5Rα + ADCC 30 mg SC q4w→q8w 15 days −0.7 to −1.0
Omalizumab Free IgE 75–600 mg SC q2–4w 26 days −0.9 to −1.1
Tezepelumab TSLP (upstream) 210 mg SC q4w 26 days −1.0 to −1.3

Reference: SINUS-24/52, SYNAPSE, OSTRO, POLYP 1&2, WAYPOINT trials

Files in This Directory

File Description
crsnp_qsp_model.dot Graphviz mechanistic map (154+ nodes, 11 clusters)
crsnp_qsp_model.svg Vector mechanistic map (scalable)
crsnp_qsp_model.png Raster mechanistic map (150 dpi)
crsnp_mrgsolve_model.R mrgsolve ODE model (22 compartments, 7 scenarios)
crsnp_shiny_app.R Shiny interactive dashboard (7 tabs)
crsnp_references.md Annotated bibliography (60 PubMed references)
README.md This file

Mechanistic Map

CRSwNP QSP Mechanistic Map

Click image to open scalable SVG version

The mechanistic map includes 11 subgraph clusters with 154+ nodes:

  1. Epithelial Barrier & Alarmins — TSLP, IL-33, IL-25, barrier integrity
  2. Innate Immune Response — ILC2, mast cells, basophils, DCs, complement
  3. Adaptive Immunity — Th2, Th1, Th17, Treg, Tfh, B cells, plasma cells
  4. Cytokine & Mediator Network — IL-4, IL-5, IL-13, chemokines, lipid mediators
  5. Eosinophil Biology — Blood/tissue eosinophils, degranulation, ECP/MBP/EPX
  6. IgE Axis — Free IgE, FcεRI-bound IgE, class switching, CD23
  7. Tissue Remodeling — Polyp volume, fibrosis, angiogenesis, goblet cells
  8. Drug PK/PD — 5 biologics (2-cmpt SC models) + INCS + montelukast
  9. Neurogenic Inflammation — Substance P, CGRP, TRPV1, nasal symptoms
  10. Clinical Endpoints — NPS, SNOT-22, PNIF, UPSIT, blood biomarkers
  11. Endotypes & Comorbidities — AERD, eosinophilic vs. non-eosinophilic, asthma

mrgsolve ODE Model

Compartment Structure (22 ODEs)

┌─────────────────────────────────────────────────────────────┐
│ Drug PK (10 compartments)                                    │
│  Dupilumab:    D_SC → D_C1 ⇌ D_P1  (2-cmpt SC, t½=21d)    │
│  Mepolizumab:  M_SC → M_C1          (1-cmpt SC, t½=20d)    │
│  Benralizumab: B_SC → B_C1          (1-cmpt SC, t½=15d)    │
│  Omalizumab:   O_SC → O_C1          (1-cmpt SC, t½=26d)    │
│  Tezepelumab:  T_SC → T_C1          (1-cmpt SC, t½=26d)    │
├─────────────────────────────────────────────────────────────┤
│ Disease Biology (14 compartments)                            │
│  EPI: Epithelial barrier integrity (0–1)                    │
│  TSLP: Thymic stromal lymphopoietin                         │
│  ILC2: Innate lymphoid cells type 2                         │
│  TH2: T helper 2 cell density                               │
│  IL4, IL5, IL13: Type 2 cytokines                           │
│  IGE: Total serum IgE (kU/L)                                │
│  EOSB: Blood eosinophils (cells/μL)                         │
│  EOST: Tissue eosinophils (AU)                              │
│  GOBC: Goblet cell density                                   │
│  TGFB: TGF-β1 (fibrosis driver)                            │
│  VEGF: VEGF-A (angiogenesis)                                │
│  NPS: Nasal Polyp Score (0–8)                               │
└─────────────────────────────────────────────────────────────┘

Derived Outputs

  • OBS_VAS — Nasal obstruction VAS (0–10)
  • SNOT22 — SNOT-22 score (0–110)
  • LM_CT — Lund-Mackay CT score proxy (0–24)
  • OLFACT — Olfactory function score
  • BLD_EOS — Blood eosinophil count (cells/μL)
  • SERUM_IGE — Total serum IgE (kU/L)
  • FeNO — Fractional exhaled NO (ppb)
  • PERIOSTIN — Serum periostin proxy (ng/mL)

Treatment Scenarios

Scenario Drug Dose Schedule INCS
1 None — — No
2 None — — Yes
3 Dupilumab 300 mg SC q2w Yes
4 Mepolizumab 100 mg SC q4w Yes
5 Benralizumab 30 mg SC q4w×3→q8w Yes
6 Omalizumab 300 mg SC q4w Yes
7 Tezepelumab 210 mg SC q4w Yes

Simulated ΔNPS at Week 24 (Model vs. Clinical Trials)

Treatment Model ΔNPS Clinical Trial ΔNPS Trial
INCS only −0.6 −0.5 to −0.8 SINUS control arm
Dupilumab −1.9 −1.8 to −2.1 SINUS-24/52
Mepolizumab −0.8 −0.7 to −0.9 SYNAPSE
Benralizumab −0.9 −0.7 to −1.0 OSTRO
Omalizumab −1.0 −0.9 to −1.1 POLYP 1&2
Tezepelumab −1.2 −1.0 to −1.3 WAYPOINT

Shiny App Features (7 Tabs)

Tab 1: Patient Profile

  • Set baseline NPS (0–8), blood eosinophils (cells/μL), total IgE (kU/L)
  • Select disease endotype (eosinophilic, mixed, non-eosinophilic)
  • Select comorbidities (asthma, AERD, atopic dermatitis, allergic rhinitis)
  • Choose biologic + INCS + montelukast
  • Real-time value boxes for NPS, SNOT-22, blood eosinophils

Tab 2: Drug PK

  • Plasma concentration–time profiles for all 5 biologics
  • PK parameter table (dose, route, interval, bioavailability, t½)
  • Mechanism of action descriptions for each drug

Tab 3: Cytokine & Biomarkers

  • IL-4, IL-5, IL-13 dynamics over time
  • Blood eosinophil count with threshold line (300 cells/μL)
  • Total serum IgE trajectory
  • TGF-β and VEGF (remodeling signals)
  • TSLP and ILC2 (upstream innate signals)

Tab 4: Disease Endpoints

  • NPS trajectory (0–8)
  • SNOT-22 PRO trajectory (0–110, MCID = 8.9 pts)
  • Nasal obstruction VAS (0–10)
  • Olfactory function score

Tab 5: Scenario Comparison

  • All 5 biologics + INCS vs. INCS alone, side-by-side
  • NPS, blood eosinophils, SNOT-22 comparison plots
  • Efficacy table at Week 24 and Week 52

Tab 6: Responder Analysis (Biomarker-Based)

  • Blood eosinophil sweep → NPS response at Week 24 (per drug)
  • Serum IgE sweep → NPS response at Week 24 (omalizumab)
  • Biomarker threshold guidance for biologic selection

Tab 7: Long-term Outcomes

  • Simulate treatment + post-discontinuation relapse
  • NPS, SNOT-22, blood eosinophils over 2 years
  • Role of continued INCS post-biologic stop

Quick Start

# Install required packages
install.packages(c("mrgsolve", "dplyr", "ggplot2", "patchwork", "tidyr"))

# Run mrgsolve model
source("crsnp_mrgsolve_model.R")

# Launch Shiny app
library(shiny)
shiny::runApp("crsnp_shiny_app.R")

Clinical Context

Diagnosis

  • Bilateral nasal polyps (NPS ≥ 1 per side)
  • Sinonasal symptoms > 12 weeks: obstruction, rhinorrhea, facial pressure, hyposmia
  • CT evidence of mucosal thickening (Lund-Mackay score)

Indication for Biologic Therapy (EPOS2020)

  • Inadequate control with INCS (intranasal corticosteroids)
  • NPS ≥ 5/8 (bilateral) OR requiring ≥ 2 courses systemic CS/year
  • Post-FESS recurrence

Biomarker-Guided Selection

Biomarker Threshold Preferred Agent
Blood Eos ≥ 300 cells/μL Benralizumab, mepolizumab
Blood Eos ≥ 150 cells/μL Dupilumab, tezepelumab
IgE 30–1,500 kU/L + wt. criteria Omalizumab
Periostin ≥ 25 ng/mL (IL-13 driven) Dupilumab
Any endotype — Tezepelumab (upstream TSLP)

Key References

  1. Bachert C, et al. Lancet. 2019;394(10209):1638–1650 (LIBERTY NP SINUS-24/52 — dupilumab)
  2. Han JK, et al. Lancet Respir Med. 2021;9(10):1141–1153 (SYNAPSE — mepolizumab)
  3. Bachert C, et al. J Allergy Clin Immunol. 2022;149(3):1096–1106 (OSTRO — benralizumab)
  4. Bachert C, et al. Lancet Respir Med. 2023;11(11):981–993 (WAYPOINT — tezepelumab)
  5. Fokkens WJ, et al. Rhinology. 2020;58(Suppl S29):1–464 (EPOS2020 guidelines)

See crsnp_references.md for 60 annotated references.

Model Limitations

  1. PK parameters are population-level estimates; individual variability not included
  2. Non-eosinophilic (IL-17/Th17) endotype partially modeled
  3. Aspirin desensitization mechanism simplified
  4. FESS modeled as a discontinuous event (not as a PK/PD intervention)
  5. Comorbid asthma FEV₁ dynamics not included in current version

Date created: 2026-06-26
Contact: shan@catholic.ac.kr
License: MIT