omalizumab IgE allergic asthma treatment guidelines

IgE-lowering biologics allergic asthma treatment protocol 2024 2025 omalizumab tezepelumab dupilumab

https://ginasthma.org/wp-content/uploads/2025/11/GINA-Severe…

mkdir -p /home/daytona/workspace/ige-protocol && ls /home/daytona/workspace/

~/ige-protocol/build_protocol.py

from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.units import cm, mm
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, PageBreak, KeepTogether
)
from reportlab.lib.enums import TA_LEFT, TA_CENTER, TA_JUSTIFY
from reportlab.pdfgen import canvas
from datetime import date

OUTPUT = "/home/daytona/workspace/ige-protocol/IgE_Lowering_Therapy_Protocol.pdf"

# ── Colour palette ────────────────────────────────────────────────────────────
NAVY   = colors.HexColor("#1B3A6B")
TEAL   = colors.HexColor("#0D7377")
LTBLUE = colors.HexColor("#EAF4FB")
AMBER  = colors.HexColor("#F5A623")
RED    = colors.HexColor("#C0392B")
LGREY  = colors.HexColor("#F4F6F8")
DGREY  = colors.HexColor("#4A4A4A")
WHITE  = colors.white
BLACK  = colors.black

# ── Styles ────────────────────────────────────────────────────────────────────
styles = getSampleStyleSheet()

def make_style(name, parent="Normal", **kw):
    return ParagraphStyle(name, parent=styles[parent], **kw)

H1 = make_style("H1", "Heading1",
    fontSize=18, textColor=NAVY, spaceAfter=6, spaceBefore=18,
    fontName="Helvetica-Bold", leading=22)

H2 = make_style("H2", "Heading2",
    fontSize=13, textColor=TEAL, spaceAfter=4, spaceBefore=12,
    fontName="Helvetica-Bold", leading=17, borderPad=2)

H3 = make_style("H3", "Heading3",
    fontSize=11, textColor=NAVY, spaceAfter=3, spaceBefore=8,
    fontName="Helvetica-Bold", leading=14)

BODY = make_style("BODY", fontSize=10, textColor=DGREY,
    leading=14, spaceAfter=4, alignment=TA_JUSTIFY)

BODYBOLD = make_style("BODYBOLD", fontSize=10, textColor=DGREY,
    leading=14, spaceAfter=4, fontName="Helvetica-Bold")

SMALL = make_style("SMALL", fontSize=8.5, textColor=colors.HexColor("#666666"),
    leading=12, spaceAfter=3)

BULLET = make_style("BULLET", fontSize=10, textColor=DGREY,
    leading=14, spaceAfter=3, leftIndent=14, bulletIndent=4)

WARN = make_style("WARN", fontSize=10, textColor=RED,
    leading=14, spaceAfter=4, fontName="Helvetica-Bold")

CENTRE = make_style("CENTRE", fontSize=9, textColor=DGREY,
    alignment=TA_CENTER, leading=12)

TH = make_style("TH", fontSize=9, textColor=WHITE,
    fontName="Helvetica-Bold", alignment=TA_CENTER, leading=12)

TD = make_style("TD", fontSize=9, textColor=DGREY, leading=12, alignment=TA_LEFT)

TD_C = make_style("TD_C", fontSize=9, textColor=DGREY, leading=12, alignment=TA_CENTER)

# ── Header / Footer canvas ────────────────────────────────────────────────────
def on_page(canvas_obj, doc):
    w, h = A4
    canvas_obj.saveState()
    # Header bar
    canvas_obj.setFillColor(NAVY)
    canvas_obj.rect(0, h - 28*mm, w, 28*mm, fill=1, stroke=0)
    canvas_obj.setFillColor(AMBER)
    canvas_obj.rect(0, h - 31*mm, w, 3*mm, fill=1, stroke=0)
    canvas_obj.setFillColor(WHITE)
    canvas_obj.setFont("Helvetica-Bold", 13)
    canvas_obj.drawString(18*mm, h - 16*mm,
        "IgE-Lowering Therapy in Allergic Asthma & Atopic Disease")
    canvas_obj.setFont("Helvetica", 9)
    canvas_obj.drawString(18*mm, h - 23*mm, "Treatment Protocol for General Practitioners")
    canvas_obj.drawRightString(w - 18*mm, h - 23*mm, f"Version 1.0 | May 2026")
    # Footer
    canvas_obj.setFillColor(NAVY)
    canvas_obj.rect(0, 0, w, 12*mm, fill=1, stroke=0)
    canvas_obj.setFillColor(WHITE)
    canvas_obj.setFont("Helvetica", 8)
    canvas_obj.drawString(18*mm, 4.5*mm,
        "For GP clinical use | Based on GINA 2025 & current evidence | Review annually")
    canvas_obj.drawRightString(w - 18*mm, 4.5*mm, f"Page {doc.page}")
    canvas_obj.restoreState()

def on_first_page(canvas_obj, doc):
    on_page(canvas_obj, doc)

# ── Helper builders ───────────────────────────────────────────────────────────
def section_rule():
    return HRFlowable(width="100%", thickness=1, color=TEAL, spaceAfter=4, spaceBefore=4)

def info_box(title, lines, bg=LTBLUE, title_color=NAVY):
    """Returns a Table acting as a coloured info box."""
    content = [Paragraph(f"<b>{title}</b>", make_style("BT", fontSize=10,
        textColor=title_color, fontName="Helvetica-Bold", leading=14))]
    for l in lines:
        content.append(Paragraph(f"• {l}", make_style("BL", fontSize=9.5,
            textColor=DGREY, leading=13, leftIndent=8)))
    t = Table([[content]], colWidths=["100%"])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), bg),
        ("LEFTPADDING", (0,0), (-1,-1), 10),
        ("RIGHTPADDING", (0,0), (-1,-1), 10),
        ("TOPPADDING", (0,0), (-1,-1), 8),
        ("BOTTOMPADDING", (0,0), (-1,-1), 8),
        ("ROUNDEDCORNERS", (0,0), (-1,-1), [4,4,4,4]),
    ]))
    return t

def warn_box(text):
    t = Table([[Paragraph(f"⚠ {text}", make_style("WB", fontSize=9.5,
        textColor=RED, fontName="Helvetica-Bold", leading=13))]], colWidths=["100%"])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), colors.HexColor("#FFF3F3")),
        ("BOX", (0,0), (-1,-1), 1, RED),
        ("LEFTPADDING", (0,0), (-1,-1), 10),
        ("RIGHTPADDING", (0,0), (-1,-1), 10),
        ("TOPPADDING", (0,0), (-1,-1), 6),
        ("BOTTOMPADDING", (0,0), (-1,-1), 6),
    ]))
    return t

def drug_table(headers, rows, col_widths):
    data = [[Paragraph(h, TH) for h in headers]]
    for row in rows:
        data.append([Paragraph(cell, TD) for cell in row])
    t = Table(data, colWidths=col_widths, repeatRows=1)
    style = [
        ("BACKGROUND", (0,0), (-1,0), NAVY),
        ("ROWBACKGROUNDS", (0,1), (-1,-1), [WHITE, LGREY]),
        ("GRID", (0,0), (-1,-1), 0.4, colors.HexColor("#CCCCCC")),
        ("VALIGN", (0,0), (-1,-1), "TOP"),
        ("LEFTPADDING", (0,0), (-1,-1), 6),
        ("RIGHTPADDING", (0,0), (-1,-1), 6),
        ("TOPPADDING", (0,0), (-1,-1), 5),
        ("BOTTOMPADDING", (0,0), (-1,-1), 5),
    ]
    t.setStyle(TableStyle(style))
    return t

# ── Document build ────────────────────────────────────────────────────────────
def build():
    doc = SimpleDocTemplate(
        OUTPUT, pagesize=A4,
        topMargin=35*mm, bottomMargin=20*mm,
        leftMargin=18*mm, rightMargin=18*mm,
        title="IgE-Lowering Therapy Protocol",
        author="Clinical Protocols Unit",
    )

    story = []

    # ── SECTION 1: Overview ───────────────────────────────────────────────────
    story.append(Paragraph("1. Overview", H1))
    story.append(section_rule())
    story.append(Paragraph(
        "Elevated immunoglobulin E (IgE) is a hallmark of allergic (atopic) disease. "
        "In allergic asthma, IgE binds high-affinity receptors (FcεRI) on mast cells and basophils, "
        "triggering mediator release upon allergen exposure. IgE-lowering and IgE-pathway biologics "
        "represent a cornerstone of add-on therapy for patients whose disease remains uncontrolled "
        "despite optimised standard treatment.", BODY))
    story.append(Paragraph(
        "This protocol guides general practitioners on patient selection, dosing, monitoring, "
        "and safety of biologic agents targeting the IgE pathway in <b>allergic asthma and "
        "atopic disease</b>, in alignment with GINA 2025 recommendations.", BODY))
    story.append(Spacer(1, 4))

    story.append(info_box("Scope of this Protocol", [
        "Severe allergic (atopic) asthma — uncontrolled despite high-dose ICS/LABA (GINA Step 4–5)",
        "Atopic dermatitis with significant respiratory comorbidity (shared biologics)",
        "Chronic rhinosinusitis with nasal polyposis (CRSwNP) — relevant overlap",
        "Adults and children ≥6 years (biologic eligibility varies by agent and age)",
    ]))
    story.append(Spacer(1, 8))

    # ── SECTION 2: Pathophysiology ───────────────────────────────────────────
    story.append(Paragraph("2. IgE Pathway in Allergic Asthma", H1))
    story.append(section_rule())
    story.append(Paragraph(
        "Allergen exposure activates B lymphocytes (with T-helper 2 cell support via IL-4/IL-13) "
        "to produce IgE antibodies. These IgE molecules bind FcεRI on mast cells and basophils. "
        "Re-exposure to allergen cross-links receptor-bound IgE, causing immediate degranulation "
        "(histamine, leukotrienes, prostaglandins) and a late-phase eosinophilic response.", BODY))
    story.append(Paragraph(
        "Key upstream mediators triggering this cascade include epithelial cell-derived alarmins: "
        "<b>TSLP</b> (thymic stromal lymphopoietin), IL-25, and IL-33. Targeting these alarmins "
        "(e.g., tezepelumab) or downstream effectors (IgE, IL-4Rα) forms the basis of modern "
        "biologic therapy.", BODY))
    story.append(Spacer(1, 6))

    # Pathway summary table
    pathway_rows = [
        ["Allergen sensitisation", "IL-4, IL-13", "IgE production by B cells"],
        ["IgE binding to mast cells", "FcεRI receptor", "Mast cell priming"],
        ["Allergen re-exposure", "IgE cross-linking", "Degranulation → bronchoconstriction"],
        ["Late-phase response", "IL-5, eotaxin", "Eosinophil recruitment & airway remodelling"],
        ["Upstream epithelial alarm", "TSLP, IL-25, IL-33", "Th2 polarisation & amplification"],
    ]
    story.append(Paragraph("Table 1. IgE Inflammatory Pathway Summary", H3))
    story.append(drug_table(
        ["Trigger / Step", "Key Mediator", "Downstream Effect"],
        pathway_rows,
        [5.5*cm, 4.5*cm, 7*cm]
    ))
    story.append(Spacer(1, 8))

    # ── SECTION 3: Patient Selection ─────────────────────────────────────────
    story.append(Paragraph("3. Patient Selection Criteria", H1))
    story.append(section_rule())

    story.append(Paragraph("3.1 General Criteria for Biologic Referral / Initiation", H2))
    story.append(Paragraph(
        "Before considering any biologic therapy, confirm that standard therapy has been optimised:", BODY))

    prereqs = [
        "Correct inhaler technique verified and compliance assessed",
        "Comorbidities treated (rhinitis, GERD, obesity, OSA)",
        "High-dose ICS/LABA at GINA Step 4 (consider LAMA add-on at Step 5)",
        "Two or more severe exacerbations requiring OCS in the past 12 months, OR continuous OCS dependency",
        "Type 2 inflammatory biomarkers assessed: total serum IgE, specific IgE / skin-prick tests, blood eosinophil count, FeNO",
    ]
    for p in prereqs:
        story.append(Paragraph(f"✓  {p}", BULLET))
    story.append(Spacer(1, 6))

    story.append(Paragraph("3.2 Biomarker-Guided Eligibility (GINA 2025 Framework)", H2))
    eligibility_rows = [
        ["<b>Anti-IgE</b>\nOmalizumab",
         "≥6 years",
         "• Allergic sensitisation (positive SPT or specific IgE)\n• Total serum IgE 30–1,500 IU/mL\n• Weight within dosing chart range\n• ≥1 exacerbation in past year",
         "Severe allergic asthma, CRSwNP, chronic spontaneous urticaria"],
        ["<b>Anti-IL-4Rα</b>\nDupilumab",
         "≥6 years",
         "• Blood eosinophils ≥150 cells/µL, OR FeNO ≥25 ppb, OR OCS-dependent\n• ≥1 exacerbation in past year",
         "Severe eosinophilic/T2 asthma, atopic dermatitis, CRSwNP"],
        ["<b>Anti-TSLP</b>\nTezepelumab",
         "≥12 years",
         "• ≥1 exacerbation in past year\n• No biomarker threshold required\n• Useful in T2-low or mixed phenotype",
         "Severe asthma (all phenotypes), including T2-low"],
        ["<b>Anti-IL-5</b>\nMepolizumab\nBenralizumab\nReslizumab",
         "≥6–18 yrs (varies)",
         "• Blood eosinophils ≥150 cells/µL at screening, OR ≥300 cells/µL in past year\n• ≥1 exacerbation in past year",
         "Severe eosinophilic asthma, EGPA, HES"],
    ]
    # Build table with multi-line content
    hdrs = ["Drug Class / Agent", "Min. Age", "Eligibility Criteria", "Approved Indications"]
    col_w = [4*cm, 2*cm, 7*cm, 5.5*cm]
    data = [[Paragraph(h, TH) for h in hdrs]]
    for row in eligibility_rows:
        data.append([Paragraph(cell.replace("\n","<br/>"), TD) for cell in row])
    t = Table(data, colWidths=col_w, repeatRows=1)
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,0), NAVY),
        ("ROWBACKGROUNDS", (0,1), (-1,-1), [WHITE, LGREY]),
        ("GRID", (0,0), (-1,-1), 0.4, colors.HexColor("#CCCCCC")),
        ("VALIGN", (0,0), (-1,-1), "TOP"),
        ("LEFTPADDING", (0,0), (-1,-1), 6),
        ("RIGHTPADDING", (0,0), (-1,-1), 6),
        ("TOPPADDING", (0,0), (-1,-1), 5),
        ("BOTTOMPADDING", (0,0), (-1,-1), 5),
    ]))
    story.append(Paragraph("Table 2. Biologic Agent Eligibility Overview", H3))
    story.append(t)
    story.append(Spacer(1, 6))

    story.append(info_box(
        "Note on Overlapping Eligibility",
        [
            "Patients eligible for multiple biologics should be referred to an allergist/respiratory physician for shared decision-making.",
            "Dupilumab and tezepelumab show superiority over anti-IL-5 agents in reducing exacerbations and improving FEV1 in recent network meta-analyses (Allergy, 2026).",
            "Omalizumab is specifically indicated for allergic (IgE-driven) disease; total IgE and weight must fall within the manufacturer dosing table.",
        ]
    ))
    story.append(Spacer(1, 8))

    # ── SECTION 4: Drug Details ───────────────────────────────────────────────
    story.append(PageBreak())
    story.append(Paragraph("4. Dosing & Administration", H1))
    story.append(section_rule())

    # ── 4.1 Omalizumab ────────────────────────────────────────────────────────
    story.append(Paragraph("4.1 Omalizumab (Xolair®) — Anti-IgE", H2))
    story.append(Paragraph(
        "Omalizumab is a recombinant humanised IgG1 monoclonal antibody that binds the Fc region "
        "of circulating free IgE, blocking its interaction with FcεRI on mast cells, basophils, "
        "dendritic cells, and other inflammatory cells. It reduces both early and late-phase "
        "bronchoconstriction and significantly lowers circulating IgE levels.", BODY))

    oma_rows = [
        ["<b>Mechanism</b>", "Binds free IgE Fc region; blocks FcεRI and FcεRII binding; downregulates FcεRI expression on dendritic cells; enhances type I interferon response to rhinovirus"],
        ["<b>Route &amp; Frequency</b>", "Subcutaneous injection every 2 OR 4 weeks (frequency and dose depend on weight and baseline total IgE — consult dosing chart)"],
        ["<b>Dose Range</b>", "75–600 mg per visit (up to 3 × 150 mg injections per visit); determined by pre-treatment IgE level and body weight"],
        ["<b>IgE Range</b>", "30–1,500 IU/mL. Caution: if IgE >700 IU/mL, dose exceeds limits for heavier patients — check dosing table"],
        ["<b>Weight Limit</b>", "Do not use if baseline IgE >300 IU/mL and body weight >90 kg; or IgE approaching 700 IU/mL at any normal weight"],
        ["<b>Onset of Benefit</b>", "Clinical assessment at 4 months (16 weeks); discontinue if no meaningful response"],
        ["<b>Duration</b>", "Review every 6–12 months; withdrawal may increase exacerbations — taper cautiously"],
        ["<b>Self-administration</b>", "Pre-filled syringe option available; allow to reach room temperature before injection"],
    ]
    data = [[Paragraph(r[0], TD), Paragraph(r[1], TD)] for r in oma_rows]
    t = Table(data, colWidths=[4.5*cm, 13*cm])
    t.setStyle(TableStyle([
        ("ROWBACKGROUNDS", (0,0), (-1,-1), [LTBLUE, WHITE]),
        ("GRID", (0,0), (-1,-1), 0.4, colors.HexColor("#BBDDEE")),
        ("VALIGN", (0,0), (-1,-1), "TOP"),
        ("LEFTPADDING", (0,0), (-1,-1), 6),
        ("RIGHTPADDING", (0,0), (-1,-1), 6),
        ("TOPPADDING", (0,0), (-1,-1), 5),
        ("BOTTOMPADDING", (0,0), (-1,-1), 5),
    ]))
    story.append(t)
    story.append(Spacer(1, 4))
    story.append(info_box("Clinical Outcomes (Omalizumab)", [
        "44% decrease in severe exacerbations in severe allergic asthma (meta-analysis of RCTs, GINA 2025)",
        "59% reduction in exacerbation rate in observational registry data",
        "88% reduction in exacerbations requiring hospitalisation (Katzung's Pharmacology)",
        "Significant ICS and OCS dose reduction; improved quality of life scores",
        "Additional benefit: reduces viral exacerbations via enhanced interferon response",
    ], bg=colors.HexColor("#E8F8F5"), title_color=TEAL))
    story.append(Spacer(1, 10))

    # ── 4.2 Dupilumab ────────────────────────────────────────────────────────
    story.append(Paragraph("4.2 Dupilumab (Dupixent®) — Anti-IL-4Rα", H2))
    story.append(Paragraph(
        "Dupilumab blocks the shared IL-4Rα subunit, thereby inhibiting both IL-4 and IL-13 signalling. "
        "While not a direct anti-IgE agent, it suppresses the upstream drivers of IgE class switching and "
        "is a critical complementary therapy for patients with a T2-high phenotype. It is the preferred "
        "option when atopic dermatitis or CRSwNP coexist with asthma.", BODY))

    dup_rows = [
        ["<b>Mechanism</b>", "Blocks IL-4Rα subunit; inhibits IL-4 and IL-13 signalling; reduces IgE class switching, eosinophilic inflammation, and FeNO"],
        ["<b>Route &amp; Frequency</b>", "Subcutaneous injection every 2 weeks (q2w)"],
        ["<b>Dose</b>", "Adults &amp; adolescents ≥12 years: 200–300 mg q2w (weight-based in children 6–11 yrs). Add-on maintenance therapy"],
        ["<b>Biomarkers</b>", "Blood eosinophils ≥150 cells/µL OR FeNO ≥25 ppb OR OCS-dependent asthma"],
        ["<b>Comorbidities</b>", "Approved for atopic dermatitis, CRSwNP, eosinophilic oesophagitis, prurigo nodularis — ideal when multiple atopic comorbidities present"],
        ["<b>Helminth Risk</b>", "Treat pre-existing helminth infections before initiating; hold if new infection develops"],
        ["<b>Vaccines</b>", "Avoid live attenuated vaccines during therapy"],
    ]
    data = [[Paragraph(r[0], TD), Paragraph(r[1], TD)] for r in dup_rows]
    t = Table(data, colWidths=[4.5*cm, 13*cm])
    t.setStyle(TableStyle([
        ("ROWBACKGROUNDS", (0,0), (-1,-1), [LTBLUE, WHITE]),
        ("GRID", (0,0), (-1,-1), 0.4, colors.HexColor("#BBDDEE")),
        ("VALIGN", (0,0), (-1,-1), "TOP"),
        ("LEFTPADDING", (0,0), (-1,-1), 6),
        ("RIGHTPADDING", (0,0), (-1,-1), 6),
        ("TOPPADDING", (0,0), (-1,-1), 5),
        ("BOTTOMPADDING", (0,0), (-1,-1), 5),
    ]))
    story.append(t)
    story.append(Spacer(1, 10))

    # ── 4.3 Tezepelumab ─────────────────────────────────────────────────────
    story.append(Paragraph("4.3 Tezepelumab (Tezspire®) — Anti-TSLP", H2))
    story.append(Paragraph(
        "Tezepelumab is a fully human IgG2 monoclonal antibody targeting thymic stromal lymphopoietin "
        "(TSLP), an epithelial alarmin. By acting upstream of IgE, IL-5, and IL-4/13 pathways, "
        "it is unique in its efficacy across <i>all asthma phenotypes</i>, including T2-low and "
        "non-eosinophilic disease. It indirectly reduces total serum IgE.", BODY))

    tez_rows = [
        ["<b>Mechanism</b>", "Binds circulating TSLP; blocks downstream Th2, Th17, ILC2 activation; reduces IgE, eosinophils, FeNO, and IL-5/13"],
        ["<b>Route &amp; Frequency</b>", "Subcutaneous injection 210 mg every 4 weeks (q4w)"],
        ["<b>Age</b>", "≥12 years (syringe or auto-injector pen)"],
        ["<b>Biomarker Flexibility</b>", "No minimum IgE or eosinophil threshold required — suitable for T2-low asthma with no elevated biomarkers"],
        ["<b>Exacerbation Requirement</b>", "≥1 severe exacerbation in past 12 months (most payer criteria)"],
        ["<b>Cessation</b>", "Biomarker rebound (IgE, eosinophils) occurs after stopping; extended follow-up from DESTINATION trial (2024) shows IgE and eosinophil levels return to baseline within months"],
    ]
    data = [[Paragraph(r[0], TD), Paragraph(r[1], TD)] for r in tez_rows]
    t = Table(data, colWidths=[4.5*cm, 13*cm])
    t.setStyle(TableStyle([
        ("ROWBACKGROUNDS", (0,0), (-1,-1), [LTBLUE, WHITE]),
        ("GRID", (0,0), (-1,-1), 0.4, colors.HexColor("#BBDDEE")),
        ("VALIGN", (0,0), (-1,-1), "TOP"),
        ("LEFTPADDING", (0,0), (-1,-1), 6),
        ("RIGHTPADDING", (0,0), (-1,-1), 6),
        ("TOPPADDING", (0,0), (-1,-1), 5),
        ("BOTTOMPADDING", (0,0), (-1,-1), 5),
    ]))
    story.append(t)
    story.append(Spacer(1, 6))

    story.append(info_box("Note on Anti-IL-5 Agents (Mepolizumab, Benralizumab, Reslizumab)", [
        "These agents target downstream eosinophilic inflammation rather than IgE directly.",
        "Indicated for severe eosinophilic asthma (blood eosinophils ≥150–300 cells/µL).",
        "Reduce exacerbations by ~50% and enable OCS reduction by ≥50% in appropriate patients.",
        "Refer to specialist for initiation; not covered in full detail within this IgE-pathway protocol.",
    ], bg=LGREY, title_color=DGREY))
    story.append(Spacer(1, 8))

    # ── SECTION 5: Decision Pathway ──────────────────────────────────────────
    story.append(PageBreak())
    story.append(Paragraph("5. GP Decision Pathway", H1))
    story.append(section_rule())

    steps = [
        ("Step 1: Confirm Diagnosis & Severity",
         ["Confirm asthma diagnosis (spirometry with reversibility / bronchial challenge)",
          "Classify as moderate–severe, uncontrolled (ACQ-5 >1.5, ACT <20, or ≥2 OCS courses/year)",
          "Rule out alternative diagnoses: COPD, vocal cord dysfunction, cardiac disease"]),
        ("Step 2: Optimise Standard Therapy",
         ["High-dose ICS/LABA at GINA Steps 4–5",
          "Add LAMA (tiotropium) for uncontrolled symptoms at Step 5",
          "Treat all comorbidities: allergic rhinitis (intranasal corticosteroids), GERD, obesity, OSA",
          "Verify inhaler technique and adherence at every visit"]),
        ("Step 3: Assess Inflammatory Phenotype",
         ["Total serum IgE (IU/mL) + specific IgE panel or skin-prick test (SPT)",
          "Blood eosinophil count (cells/µL) — most recent value in past 12 months",
          "FeNO (fractional exhaled nitric oxide, ppb) — where available",
          "Body weight (for omalizumab dosing chart)"]),
        ("Step 4: Apply Biologic Eligibility Algorithm",
         ["Allergic (positive SPT/specific IgE) + IgE 30–1,500 IU/mL: consider OMALIZUMAB",
          "Eosinophils ≥150 cells/µL or FeNO ≥25 ppb or OCS-dependent: consider DUPILUMAB",
          "No clear T2 phenotype OR eligible for multiple agents: consider TEZEPELUMAB",
          "Predominant eosinophilia ≥300 cells/µL without other T2 markers: consider anti-IL-5 agents",
          "Multiple T2-driven comorbidities (AD, CRSwNP): favour DUPILUMAB"]),
        ("Step 5: Refer to Specialist",
         ["All biologic initiations should involve or be confirmed by an allergist, clinical immunologist, or respiratory physician",
          "Submit prior authorisation / payer documentation with biomarker results",
          "Provide patient education: SC injection technique, recognition of anaphylaxis, avoidance of live vaccines"]),
        ("Step 6: Monitor & Review",
         ["Formal response assessment at 4 months (omalizumab) / 3–6 months (other biologics)",
          "Assess: exacerbation frequency, OCS use, symptom control scores, lung function (FEV1)",
          "If no meaningful response: discontinue and consider switching class",
          "Review every 6–12 months; consider step-down if sustained remission achieved"]),
    ]

    for title, bullets in steps:
        step_content = [Paragraph(f"<b>{title}</b>",
            make_style("SH", fontSize=11, textColor=NAVY, fontName="Helvetica-Bold", leading=15))]
        for b in bullets:
            step_content.append(Paragraph(f"→  {b}",
                make_style("SB", fontSize=9.5, textColor=DGREY, leading=13, leftIndent=10)))
        t = Table([[step_content]], colWidths=["100%"])
        t.setStyle(TableStyle([
            ("BACKGROUND", (0,0), (-1,-1), LGREY),
            ("LEFTPADDING", (0,0), (-1,-1), 12),
            ("RIGHTPADDING", (0,0), (-1,-1), 10),
            ("TOPPADDING", (0,0), (-1,-1), 8),
            ("BOTTOMPADDING", (0,0), (-1,-1), 8),
            ("BOX", (0,0), (-1,-1), 1.5, TEAL),
        ]))
        story.append(KeepTogether([t, Spacer(1, 6)]))

    story.append(Spacer(1, 6))

    # ── SECTION 6: Safety & Monitoring ───────────────────────────────────────
    story.append(PageBreak())
    story.append(Paragraph("6. Safety Considerations & Monitoring", H1))
    story.append(section_rule())

    safety_rows = [
        ["Omalizumab", "Anaphylaxis (<0.1%); local injection-site reactions (~50%); diffuse urticaria (rare); possible association with malignancy (historical concern — not confirmed in large registries)", "Observe patient 30–60 min after first 3 doses; emergency adrenaline available at injection visits; subsequent doses may be home-administered with auto-injector"],
        ["Dupilumab", "Injection-site reactions; transient blood eosinophilia (monitor); conjunctivitis (common in AD patients); rare eosinophilic pneumonia/vasculitis reported", "Monitor eosinophil count at baseline and 3 months; hold and refer if new systemic symptoms develop"],
        ["Tezepelumab", "Injection-site reactions; anaphylaxis (rare); adverse event rates similar to placebo in NAVIGATOR trial", "Standard post-injection monitoring; biomarker rebound on cessation — plan discontinuation with specialist"],
        ["All biologics", "Live attenuated vaccines: avoid during therapy; attenuated vaccines may be given", "Screen for helminth infection in endemic areas before initiating; do not initiate during acute severe asthma exacerbation"],
    ]
    story.append(Paragraph("Table 3. Safety Profile by Biologic Agent", H3))
    story.append(drug_table(
        ["Agent", "Key Adverse Effects", "Monitoring / Risk Mitigation"],
        safety_rows,
        [3.5*cm, 7.5*cm, 7*cm]
    ))
    story.append(Spacer(1, 8))

    story.append(warn_box(
        "Anaphylaxis Risk: All biologic agents carry a risk of anaphylaxis. The first dose should "
        "be administered in a healthcare setting with resuscitation equipment available. "
        "Omalizumab specifically: first-dose observation ≥30–60 minutes is recommended."
    ))
    story.append(Spacer(1, 8))

    # ── SECTION 7: Response Assessment ───────────────────────────────────────
    story.append(Paragraph("7. Assessing Treatment Response", H1))
    story.append(section_rule())
    story.append(Paragraph(
        "A structured response assessment should be completed at 4 months for omalizumab and "
        "within 3–6 months for all other biologics. Both subjective and objective outcomes should "
        "be evaluated:", BODY))

    response_rows = [
        ["Exacerbation rate", "≥50% reduction in severe exacerbations vs. pre-treatment year", "Primary outcome; most reliable indicator"],
        ["OCS dose", "≥50% reduction or complete cessation of maintenance OCS", "Key in OCS-sparing trials"],
        ["Symptom control", "ACQ-5 score ≤0.75 (well-controlled) or ACT ≥20", "Patient-reported outcome"],
        ["Lung function", "FEV1 improvement ≥100–200 mL or ≥10% predicted", "Spirometry at 6-monthly intervals"],
        ["FeNO", "Reduction in FeNO (primarily dupilumab)", "Not reliable for omalizumab monitoring"],
        ["Blood eosinophils", "Reduction to near-zero (benralizumab); modest fall (dupilumab)", "Not primary endpoint for omalizumab"],
        ["Quality of life", "AQLQ or EQ-5D improvement", "Supplement objective measures"],
    ]
    story.append(Paragraph("Table 4. Response Criteria", H3))
    story.append(drug_table(
        ["Parameter", "Target Response", "Notes"],
        response_rows,
        [4.5*cm, 6.5*cm, 7*cm]
    ))
    story.append(Spacer(1, 4))
    story.append(info_box("Discontinuation Guidance", [
        "If no meaningful response at 4 months (omalizumab) or 6 months (others): discontinue and refer back to specialist for reassessment.",
        "Do not reinitiate the same biologic after confirmed non-response.",
        "Switching between biologic classes may be considered for partial responders — specialist decision.",
        "Sustained remission (no exacerbations, normal lung function, low biomarkers): discuss step-down with specialist after ≥12 months of stability.",
    ]))
    story.append(Spacer(1, 8))

    # ── SECTION 8: Special Populations ───────────────────────────────────────
    story.append(Paragraph("8. Special Populations", H1))
    story.append(section_rule())

    sp_rows = [
        ["Children (6–11 yrs)", "Omalizumab and dupilumab approved ≥6 years. Mepolizumab ≥6 years (eosinophilic asthma). Tezepelumab ≥12 years. Dose adjusted by weight in children. Meta-analysis (BMC Pediatrics, 2026) confirms safety and efficacy of omalizumab in children aged 6–11 years."],
        ["Adolescents (12–17 yrs)", "All agents except reslizumab (≥18 yrs). Tezepelumab approved ≥12 yrs. Consider dupilumab if concomitant atopic dermatitis."],
        ["Pregnancy", "Limited RCT data. Observational registry data for omalizumab: no increased risk of major congenital anomalies vs. disease-matched unexposed cohort (Fishman's Pulmonary). Specialist guidance required. Benefits vs. risks to be weighed individually."],
        ["Elderly (≥65 yrs)", "No dose adjustment required for most agents. Monitor for injection-site reactions and falls risk with self-administration."],
        ["Severe obesity", "Check omalizumab dosing chart carefully — weight limits apply at higher IgE levels. Consider dupilumab or tezepelumab without weight-based dosing restrictions."],
        ["Helminth-endemic regions", "Screen and treat helminth infection before initiating any biologic. These agents impair Th2 responses that may be protective against parasitic disease."],
    ]
    story.append(drug_table(
        ["Population", "Guidance"],
        sp_rows,
        [4*cm, 14.5*cm]
    ))
    story.append(Spacer(1, 8))

    # ── SECTION 9: Quick Reference ───────────────────────────────────────────
    story.append(PageBreak())
    story.append(Paragraph("9. Quick Reference Summary", H1))
    story.append(section_rule())

    qr_rows = [
        ["Omalizumab\n(Xolair®)",
         "IgE (FcεRI/II blockade)",
         "SC q2–4 weeks\n75–600 mg\n(weight + IgE chart)",
         "IgE 30–1500 IU/mL\nAllergic sensitisation\n≥6 years",
         "Anaphylaxis <0.1%\nInj. site reactions",
         "Asthma, CSU, CRSwNP, food allergy"],
        ["Dupilumab\n(Dupixent®)",
         "IL-4Rα blockade\n(IL-4 + IL-13)",
         "SC q2 weeks\n200–300 mg adults",
         "Eos ≥150 cells/µL\nOR FeNO ≥25 ppb\nOR OCS-dependent\n≥6 years",
         "Conjunctivitis\nInj. site reactions\nEosinophilia",
         "Asthma, AD, CRSwNP, EoE, PN"],
        ["Tezepelumab\n(Tezspire®)",
         "TSLP blockade\n(upstream alarmin)",
         "SC q4 weeks\n210 mg fixed",
         "≥1 exacerbation/yr\nNo biomarker threshold\n≥12 years",
         "Inj. site reactions\nAnaphylaxis (rare)",
         "Severe asthma\n(all phenotypes incl. T2-low)"],
        ["Mepolizumab\n(Nucala®)",
         "IL-5 blockade",
         "SC q4 weeks\n100 mg",
         "Eos ≥150 cells/µL\n(≥300 cells/µL preferred)\n≥6 years",
         "Inj. site reactions\nHeadache",
         "Severe eosinophilic asthma, EGPA, HES, CRSwNP"],
        ["Benralizumab\n(Fasenra®)",
         "IL-5Rα blockade\n(causes eosinophil apoptosis)",
         "SC 30 mg q4 wks × 3\nthen q8 weeks",
         "Eos ≥150–300 cells/µL\n≥12 years",
         "Inj. site reactions\nAnaphylaxis (rare)",
         "Severe eosinophilic asthma"],
    ]
    hdrs_qr = ["Drug", "Target", "Dose / Route", "Eligibility", "Key AEs", "Indications"]
    col_w_qr = [2.8*cm, 3*cm, 3.5*cm, 3.5*cm, 3.2*cm, 3*cm]
    data = [[Paragraph(h, TH) for h in hdrs_qr]]
    for row in qr_rows:
        data.append([Paragraph(cell.replace("\n","<br/>"), make_style("TDS", fontSize=8.5,
            textColor=DGREY, leading=11)) for cell in row])
    t = Table(data, colWidths=col_w_qr, repeatRows=1)
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,0), NAVY),
        ("ROWBACKGROUNDS", (0,1), (-1,-1), [WHITE, LGREY]),
        ("GRID", (0,0), (-1,-1), 0.4, colors.HexColor("#CCCCCC")),
        ("VALIGN", (0,0), (-1,-1), "TOP"),
        ("LEFTPADDING", (0,0), (-1,-1), 4),
        ("RIGHTPADDING", (0,0), (-1,-1), 4),
        ("TOPPADDING", (0,0), (-1,-1), 5),
        ("BOTTOMPADDING", (0,0), (-1,-1), 5),
    ]))
    story.append(t)
    story.append(Spacer(1, 8))

    # ── SECTION 10: References ────────────────────────────────────────────────
    story.append(Paragraph("10. References & Guidelines", H1))
    story.append(section_rule())

    refs = [
        "GINA. <i>Difficult-to-Treat and Severe Asthma in Adolescent and Adult Patients. A GINA Pocket Guide</i>. GINA 2025 (updated).",
        "Barnes PJ. Biologic Therapies for Severe Asthma. In: <i>Goodman &amp; Gilman's The Pharmacological Basis of Therapeutics</i>, 14th ed. McGraw-Hill, 2023.",
        "Fishman AP, et al. Anti-IgE Therapy. In: <i>Fishman's Pulmonary Diseases and Disorders</i>, 5th ed. McGraw-Hill.",
        "Katzung BG, et al. Anti-IgE Monoclonal Antibodies. In: <i>Katzung's Basic and Clinical Pharmacology</i>, 16th ed. McGraw-Hill, 2021.",
        "Janeway CA, et al. IgE-mediated allergic disease. In: <i>Janeway's Immunobiology</i>, 10th ed. Norton, 2022.",
        "Yang Y, Fang C, Jiang Z. Safety and efficacy of omalizumab in children aged 6–11 years with asthma: a systematic review and meta-analysis of RCTs. <i>BMC Pediatrics</i>. 2026;PMID 41652440.",
        "Zheng Y, Li YC, Li SJ. Patterns and clinical efficacy of biologics switching in patients with severe asthma: a systematic review and meta-analysis. <i>Allergy</i>. 2026 May;PMID 41934326.",
        "Santos AF, et al. EAACI guidelines on the management of IgE-mediated food allergy. <i>Allergy</i>. 2025 Jan;PMID 39473345.",
        "Brightling CE, et al. Biomarkers and clinical outcomes after tezepelumab cessation: extended follow-up from the DESTINATION study. <i>Ann Allergy Asthma Immunol</i>. 2024;133:310–317.",
        "Teach SJ, et al. Preseasonal treatment with omalizumab and exacerbations. <i>N Engl J Med</i>. 2015.",
    ]
    for i, ref in enumerate(refs, 1):
        story.append(Paragraph(f"{i}.  {ref}",
            make_style("REF", fontSize=8.5, textColor=DGREY, leading=13, spaceAfter=3,
                leftIndent=18, firstLineIndent=-18)))
    story.append(Spacer(1, 10))

    # Disclaimer
    disc = Table([[Paragraph(
        "<b>Disclaimer:</b> This protocol is intended as a clinical guidance tool for general "
        "practitioners and does not replace individual clinical judgment or locally approved "
        "formulary decisions. Biologic therapy initiation and oversight should involve specialist "
        "review (allergist / respiratory physician / clinical immunologist). Dosing should always "
        "be verified against the current approved product information and local payer criteria. "
        "Review annually or when new evidence emerges.",
        make_style("DISC", fontSize=8.5, textColor=DGREY, leading=12))]], colWidths=["100%"])
    disc.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), colors.HexColor("#FFFBE6")),
        ("BOX", (0,0), (-1,-1), 1, AMBER),
        ("LEFTPADDING", (0,0), (-1,-1), 10),
        ("RIGHTPADDING", (0,0), (-1,-1), 10),
        ("TOPPADDING", (0,0), (-1,-1), 8),
        ("BOTTOMPADDING", (0,0), (-1,-1), 8),
    ]))
    story.append(disc)

    doc.build(story, onFirstPage=on_first_page, onLaterPages=on_page)
    print(f"PDF generated: {OUTPUT}")

build()

cd /home/daytona/workspace/ige-protocol && python build_protocol.py

ls -lh /home/daytona/workspace/ige-protocol/

chronic urticaria omalizumab treatment guidelines

chronic urticaria IgE biologic therapy protocol 2025 omalizumab dupilumab ligelizumab guidelines

https://pmc.ncbi.nlm.nih.gov/articles/PMC12874352

ls /home/daytona/skills/docx/scripts/office/ 2>/dev/null && ls /home/daytona/wor…

~/ige-protocol/build_urticaria_docx.js

"use strict";
const {
  Document, Packer, Paragraph, TextRun, Table, TableRow, TableCell,
  Header, Footer, AlignmentType, HeadingLevel, BorderStyle, WidthType,
  VerticalAlign, PageNumber, ShadingType, PageBreak,
  convertInchesToTwip, convertMillimetersToTwip
} = require("docx");
const fs = require("fs");

const OUT = "/home/daytona/workspace/ige-protocol/IgE_CU_Treatment_Protocol.docx";

// ── Colour tokens ─────────────────────────────────────────────────────────────
const NAVY    = "1B3A6B";
const TEAL    = "0D7377";
const AMBER   = "F5A623";
const LTBLUE  = "EAF4FB";
const LGREY   = "F4F6F8";
const WHITE   = "FFFFFF";
const DGREY   = "4A4A4A";
const RED     = "C0392B";
const LTRED   = "FFF3F3";
const LTYELL  = "FFFBE6";

// ── Helper: shading ────────────────────────────────────────────────────────────
function shade(fill) { return { type: ShadingType.CLEAR, fill, color: "auto" }; }

// ── Helper: thin border set ────────────────────────────────────────────────────
function thinBorder(color = "CCCCCC") {
  const b = { style: BorderStyle.SINGLE, size: 4, color };
  return { top: b, bottom: b, left: b, right: b };
}

// ── Helper: no border ─────────────────────────────────────────────────────────
function noBorder() {
  const b = { style: BorderStyle.NONE, size: 0, color: "auto" };
  return { top: b, bottom: b, left: b, right: b };
}

// ── Paragraph helpers ─────────────────────────────────────────────────────────
function h1(text) {
  return new Paragraph({
    heading: HeadingLevel.HEADING_1,
    spacing: { before: 320, after: 120 },
    children: [new TextRun({ text, bold: true, color: NAVY, size: 30, font: "Calibri" })],
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}

function h2(text) {
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}

function h3(text) {
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}

function body(text, opts = {}) {
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}

function bullet(text, level = 0) {
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    children: [new TextRun({ text, size: 20, font: "Calibri", color: DGREY })],
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}

function note(label, text) {
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}

function pageBreakPara() {
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}

// ── Table helpers ─────────────────────────────────────────────────────────────
function headerCell(text, widthPct) {
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    verticalAlign: VerticalAlign.CENTER,
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}

function dataCell(text, widthPct, bgColor = WHITE, bold = false, center = false) {
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}

function makeTable(headers, rows, widths) {
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  return new Table({
    width: { size: 100, type: WidthType.PERCENTAGE },
    rows: [headerRow, ...dataRows],
  });
}

// ── Coloured box (single-cell table) ─────────────────────────────────────────
function colorBox(titleText, lines, bg, borderColor, titleColor = NAVY) {
  const paras = [
    new Paragraph({
      spacing: { before: 0, after: 60 },
      children: [new TextRun({ text: titleText, bold: true, size: 20, font: "Calibri", color: titleColor })],
    }),
    ...lines.map(l => new Paragraph({
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        children: [new Paragraph({
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          ],
        })],
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}

function space(pts = 100) {
  return new Paragraph({ spacing: { before: pts, after: 0 }, children: [] });
}

// ── Header & Footer ────────────────────────────────────────────────────────────
function buildHeader() {
  return new Header({
    children: [
      new Table({
        width: { size: 100, type: WidthType.PERCENTAGE },
        rows: [new TableRow({
          children: [
            new TableCell({
              shading: shade(NAVY),
              width: { size: 70, type: WidthType.PERCENTAGE },
              borders: noBorder(),
              margins: { top: 80, bottom: 80, left: 160, right: 80 },
              children: [
                new Paragraph({ children: [new TextRun({ text: "IgE-Lowering Therapies in Chronic Urticaria", bold: true, color: WHITE, size: 22, font: "Calibri" })] }),
                new Paragraph({ children: [new TextRun({ text: "Treatment Protocol for General Practitioners", color: "AACCEE", size: 18, font: "Calibri" })] }),
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              verticalAlign: VerticalAlign.CENTER,
              children: [new Paragraph({
                alignment: AlignmentType.RIGHT,
                children: [new TextRun({ text: "Version 1.0 | May 2026", color: "AACCEE", size: 17, font: "Calibri" })],
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        spacing: { before: 0, after: 80 },
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      new Paragraph({
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        spacing: { before: 60, after: 0 },
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        ],
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    ],
  });
}

// ── DOCUMENT CONTENT ──────────────────────────────────────────────────────────
const children = [];

// ─────────────────────────────────────────────────────────────────────────────
// SECTION 1: Overview
// ─────────────────────────────────────────────────────────────────────────────
children.push(h1("1. Overview & Scope"));
children.push(body(
  "Chronic urticaria (CU) is defined as the recurrent occurrence of wheals, angioedema, or both for more than 6 weeks. " +
  "Immunoglobulin E (IgE) plays a central pathophysiological role: IgE bound to high-affinity FcεRI receptors on mast cells " +
  "triggers mediator release upon allergen exposure, producing the characteristic wheal-and-flare response. " +
  "In chronic spontaneous urticaria (CSU), approximately one third of patients have autoantibodies directed against these IgE receptors."
));
children.push(body(
  "This protocol guides general practitioners on the stepwise management of chronic urticaria, with emphasis on " +
  "IgE-targeted and IgE-pathway biologics. It aligns with the EAACI/GA²LEN/EDF/WAO urticaria guidelines (2022), " +
  "AAAAI/ACAAI practice recommendations, and the most current evidence as of May 2026."
));
children.push(space(80));
children.push(colorBox("Scope of This Protocol", [
  "Chronic spontaneous urticaria (CSU) — lasting >6 weeks without consistent identifiable trigger",
  "Chronic inducible urticaria (CIndU) — symptomatic dermographism, cold, cholinergic, pressure, solar urticaria",
  "Urticaria with concomitant angioedema",
  "Adults and children ≥6 years; specific agent eligibility by age noted throughout",
  "Excludes hereditary angioedema (HAE) — managed under a separate protocol",
], LTBLUE, TEAL));
children.push(space(120));

// ─────────────────────────────────────────────────────────────────────────────
// SECTION 2: Classification & Pathophysiology
// ─────────────────────────────────────────────────────────────────────────────
children.push(h1("2. Classification & Pathophysiology"));
children.push(h2("2.1 Classification"));
children.push(makeTable(
  ["Type", "Subtype", "Key Feature"],
  [
    ["**Chronic Spontaneous**\n(CSU)", "Autoimmune Type IIb\nAutoimmune Type I\nIdiopathic", "Autoantibodies vs FcεRI (IgG → mast cell activation)\nIgE vs self-antigens (e.g. IL-24, thyroid peroxidase)\nNo identifiable immunological trigger"],
    ["**Chronic Inducible**\n(CIndU)", "Symptomatic dermographism\nCold urticaria\nCholinergic\nPressure, solar, aquagenic", "Physical or environmental trigger reproducibly elicits wheals"],
  ],
  [22, 35, 43]
));
children.push(space(100));
children.push(h2("2.2 IgE Pathway in Chronic Urticaria"));
children.push(body(
  "Allergen or autoantibody binding → IgE/FcεRI cross-linking on mast cells → degranulation → histamine, " +
  "prostaglandins, leukotrienes, cytokines → vasodilatation, plasma extravasation, neural sensitisation → wheal and flare. " +
  "Sustained IgE production is driven by IL-4 and IL-13 (via IL-4Rα signalling) and upstream epithelial alarmins (TSLP, IL-33, IL-25). " +
  "Blocking free IgE (omalizumab) or its upstream drivers (dupilumab) interrupts this cascade."
));
children.push(space(120));

// ─────────────────────────────────────────────────────────────────────────────
// SECTION 3: Diagnosis
// ─────────────────────────────────────────────────────────────────────────────
children.push(h1("3. Diagnosis & Initial Assessment"));
children.push(h2("3.1 Clinical Diagnosis"));
children.push(body(
  "Diagnosis is clinical. Wheals are transient (<24 h), migratory, pruritic, and leave no residual skin change. " +
  "Angioedema involves deeper dermis/subcutaneous tissue and resolves within 72 hours. " +
  "Lesions lasting >36 hours, burning rather than itching, or leaving pigmentation warrant skin biopsy to exclude urticarial vasculitis."
));
children.push(h2("3.2 Recommended Investigations"));
children.push(makeTable(
  ["Investigation", "Indication", "Notes"],
  [
    ["CBC with differential", "All patients at baseline", "Screen for eosinophilia, haematological causes"],
    ["ESR or CRP", "All patients at baseline", "Elevated in vasculitic or autoinflammatory urticaria"],
    ["Thyroid function (TSH, anti-TPO)", "Suspected autoimmune association", "Thyroid autoimmunity in ~10–30% of CSU"],
    ["Specific IgE / skin-prick test", "History suggesting allergen trigger", "Most CSU is not truly allergen-driven"],
    ["Total serum IgE", "Before biologic initiation", "Not a threshold for omalizumab in CSU — used for monitoring"],
    ["C4 level", "Isolated angioedema without wheals", "Low C4 suggests HAE or acquired C1INH deficiency"],
    ["Skin biopsy", "Lesions >36 h, burning, non-pruritic", "Exclude urticarial vasculitis (fibrinoid necrosis)"],
    ["Autologous serum skin test (ASST)", "Research/specialist setting", "Indicates autoimmune subtype; not routine"],
  ],
  [28, 30, 42]
));
children.push(space(80));
children.push(note("Note:", "Extensive laboratory investigation is not recommended routinely. ~95% of CSU has no identifiable systemic cause. Testing should be directed by clinical findings."));
children.push(space(80));
children.push(h2("3.3 Disease Activity Scoring"));
children.push(makeTable(
  ["Tool", "What It Measures", "Interpretation"],
  [
    ["**UAS7** (Urticaria Activity Score — 7 days)", "Weekly sum of wheal count + itch intensity (0–6/day)", "0 = urticaria-free; 1–6 = well-controlled; 7–15 = moderate; 16–27 = severe; 28–42 = very severe"],
    ["**UCT** (Urticaria Control Test)", "4-item retrospective 4-week symptom control", "Score ≥12 = well-controlled; <12 = inadequately controlled"],
    ["**CU-Q2oL**", "Quality of life impact", "Higher score = worse QoL"],
    ["**AAS7** (Angioedema Activity Score)", "Angioedema burden over 7 days", "Weekly score 0–35"],
  ],
  [28, 35, 37]
));
children.push(space(120));

// ─────────────────────────────────────────────────────────────────────────────
// SECTION 4: Stepwise Treatment Algorithm
// ─────────────────────────────────────────────────────────────────────────────
children.push(pageBreakPara());
children.push(h1("4. Stepwise Treatment Algorithm"));
children.push(body("Therapy follows a stepwise escalation model. Advance to the next step only when the current step has been adequately trialled (minimum 2–4 weeks per step, except where indicated)."));
children.push(space(80));

const steps = [
  {
    step: "Step 1 (First-Line) — Second-Generation H1-Antihistamines",
    color: TEAL,
    items: [
      "Cetirizine 10 mg once daily, OR levocetirizine 5 mg once daily, OR fexofenadine 180 mg once daily, OR loratadine 10 mg once daily, OR desloratadine 5 mg once daily",
      "Duration: trial for at least 2–4 weeks before escalating",
      "Avoid first-generation antihistamines (diphenhydramine, chlorphenamine) as first-line — sedation, psychomotor impairment, anticholinergic effects (especially in elderly)",
      "Avoid NSAIDs and opioids — exacerbate urticaria in up to 30% of patients",
    ],
  },
  {
    step: "Step 2 — Up-Dose Antihistamine",
    color: TEAL,
    items: [
      "If Step 1 is insufficient after 2 weeks: increase to up to 4× the standard daily dose",
      "Titrate upward gradually: add second tablet in evening → third in morning → fourth (2 morning, 2 evening)",
      "Note: fexofenadine has limited evidence of benefit with up-dosing; switch if no response at standard dose",
      "Optional adjuncts (limited evidence): H2-blocker (famotidine), leukotriene receptor antagonist (montelukast 10 mg daily), or bedtime first-generation antihistamine",
      "Topical corticosteroids, antihistamines, and anaesthetics have no role in CU management",
    ],
  },
  {
    step: "Step 3 (Second-Line) — Add Omalizumab",
    color: NAVY,
    items: [
      "Initiate omalizumab 300 mg SC every 4 weeks when Step 2 fails",
      "Continue background second-generation antihistamine (taper as tolerated as symptoms improve)",
      "No pre-treatment IgE threshold required for CSU (unlike in asthma): IgE level does not determine eligibility",
      "Response assessment at 3 months: UAS7 reduction ≥75% from baseline = good response",
      "If no or partial response at 3 months: consider dose increase to 300 mg every 2 weeks (off-label) or switch agent",
      "Prescribe epinephrine autoinjector and counsel on anaphylaxis recognition (rare but reported)",
    ],
  },
  {
    step: "Step 4 — Dupilumab (if Omalizumab Insufficient or Contraindicated)",
    color: NAVY,
    items: [
      "Dupilumab 300 mg SC every 2 weeks — approved April 2025 (FDA) for CSU in patients ≥12 years failing H1-antihistamines",
      "Indicated for antihistamine-refractory CSU regardless of prior omalizumab status",
      "CUPID A trial (omalizumab-naïve): UAS7 reduction −20.5 vs −12.0 (placebo); p=0.0003",
      "Note: CUPID B (omalizumab-refractory patients) did not demonstrate superiority over placebo — dupilumab may not rescue omalizumab failures",
      "Avoid live attenuated vaccines; treat helminth infections before initiation",
    ],
  },
  {
    step: "Step 5 (Third-Line) — Cyclosporine or Specialist Referral",
    color: "8B0000",
    items: [
      "Cyclosporine 3–5 mg/kg/day (in divided doses) — for severe, refractory CSU unresponsive to omalizumab",
      "Monitor: renal function (creatinine, eGFR), blood pressure, serum potassium at baseline and every 2 weeks for 3 months, then monthly",
      "Limit treatment duration to minimum required; taper when remission achieved",
      "Alternative immunomodulators (specialist-supervised): hydroxychloroquine, mycophenolate mofetil, dapsone, sulfasalazine, tacrolimus",
      "Short-course oral corticosteroids only for acute flare control (5–10 days); avoid long-term use",
      "Emerging: Remibrutinib (BTK inhibitor) — Phase III data promising for antihistamine-refractory CSU (PMID 41005705)",
    ],
  },
];

for (const s of steps) {
  children.push(colorBox(s.step, s.items, LGREY, s.color, s.color));
  children.push(space(80));
}

children.push(warnBox("Important: Do not initiate omalizumab or dupilumab during an acute severe urticaria flare. Ensure baseline disease activity is documented with UAS7 before starting."));
children.push(space(120));

// ─────────────────────────────────────────────────────────────────────────────
// SECTION 5: Drug Reference — Omalizumab
// ─────────────────────────────────────────────────────────────────────────────
children.push(pageBreakPara());
children.push(h1("5. Drug Reference: IgE-Pathway Biologics"));
children.push(h2("5.1 Omalizumab (Xolair®) — Anti-IgE"));
children.push(body(
  "Omalizumab is a recombinant humanised IgG1 monoclonal antibody that binds the Fc region of free circulating IgE, " +
  "preventing its interaction with FcεRI and FcεRII receptors on mast cells and basophils. It does not bind receptor-bound IgE " +
  "and therefore does not trigger mast cell degranulation. It reduces both early and late-phase urticarial reactions and " +
  "lowers FcεRI expression on mast cells over time."
));
children.push(space(60));
children.push(makeTable(
  ["Parameter", "Details"],
  [
    ["**Mechanism**", "Binds free IgE Fc region → blocks FcεRI/FcεRII; reduces circulating IgE levels; downregulates FcεRI surface expression"],
    ["**Approved Indication (CU)**", "Chronic spontaneous urticaria (CSU) in adults and adolescents ≥12 years who remain symptomatic despite H1-antihistamine therapy"],
    ["**Off-label use (younger children)**", "Case series and systematic review (PMID 40545961, Pediatric Allergy Immunol 2025) support use in children <12 years; specialist oversight required"],
    ["**Dose**", "300 mg SC every 4 weeks (standard). A 150 mg dose may be trialled in mild-moderate CSU but 300 mg is preferred per evidence base"],
    ["**Route & Administration**", "Subcutaneous injection; single-use pre-filled syringe or auto-injector pen; allow to reach room temperature before injection"],
    ["**IgE eligibility**", "No IgE threshold required for CSU (unlike asthma). IgE level does not determine dose in urticaria — fixed 300 mg regimen"],
    ["**Onset of Action**", "Rapid in many patients: itch reduction within 1–2 weeks; wheal resolution by 3 months in responders"],
    ["**Response Rate**", "~60–70% achieve complete or near-complete response (UAS7 = 0); ~30% partial response; ~10–15% non-responders"],
    ["**Duration of Therapy**", "Reassess every 3–6 months; consider discontinuation trial after 6–12 months of disease control; disease often recurs after stopping"],
    ["**Pregnancy**", "Observational registry data: no increased risk of major congenital anomalies vs. disease-matched unexposed cohort; preferred over cyclosporine in refractory CU during pregnancy"],
    ["**Co-prescriptions**", "Continue H1-antihistamine during initiation; taper antihistamine as control is achieved"],
  ],
  [30, 70]
));
children.push(space(120));

children.push(h2("5.2 Dupilumab (Dupixent®) — Anti-IL-4Rα"));
children.push(body(
  "Dupilumab blocks the shared IL-4Rα subunit, inhibiting both IL-4 and IL-13 signalling. " +
  "Although not a direct anti-IgE antibody, IL-4 drives IgE class-switching in B cells; " +
  "blockade of IL-4Rα therefore reduces IgE production upstream and modulates mast cell priming and inflammatory amplification. " +
  "FDA-approved for CSU in April 2025."
));
children.push(space(60));
children.push(makeTable(
  ["Parameter", "Details"],
  [
    ["**Mechanism**", "Blocks IL-4Rα → inhibits IL-4 and IL-13 signalling → reduces IgE class switching, mast cell priming, and Th2 amplification"],
    ["**Approved Indication (CU)**", "CSU in adults and adolescents ≥12 years who remain symptomatic despite H1-antihistamine therapy (FDA approval April 2025)"],
    ["**Dose**", "300 mg SC every 2 weeks"],
    ["**Route**", "Subcutaneous injection; pre-filled syringe or pen"],
    ["**Clinical Evidence**", "CUPID A (omalizumab-naïve): UAS7 −20.5 vs −12.0 placebo (p=0.0003). CUPID B (omalizumab-refractory): did not meet primary endpoint — dupilumab unlikely to rescue omalizumab failures"],
    ["**Best use case**", "Antihistamine-refractory CSU in patients who are omalizumab-naïve OR who have type 2 inflammatory comorbidities (atopic dermatitis, eosinophilic oesophagitis, CRSwNP)"],
    ["**Precautions**", "Treat helminth infections before initiation; avoid live attenuated vaccines during treatment; monitor for eosinophilia"],
    ["**Adverse Effects**", "Injection-site reactions; conjunctivitis (common in atopic dermatitis patients); transient eosinophilia"],
  ],
  [30, 70]
));
children.push(space(120));

children.push(h2("5.3 Emerging & Investigational IgE-Pathway Agents"));
children.push(makeTable(
  ["Agent", "Target / Mechanism", "Status (2025–2026)", "Notes"],
  [
    ["**Ligelizumab**", "Anti-IgE (40–50× higher affinity than omalizumab)", "Development terminated", "PEARL1/2 trials showed superiority over placebo (UAS7 −19–20 points) but failed to demonstrate superiority over omalizumab; development stopped"],
    ["**Omalizumab biosimilars** (e.g. CT-P39)", "Anti-IgE (identical mechanism)", "FDA-approved (CT-P39)", "Equivalent efficacy; potential cost benefit"],
    ["**Tezepelumab**", "Anti-TSLP (upstream epithelial alarmin)", "Phase 2b (INCEPTION trial)", "Phase 2b in CSU: did not meet primary endpoint in overall population; sustained post-treatment effect in anti-IgE-naïve subgroup; lower baseline IgE subgroup showed promise"],
    ["**Remibrutinib** (BTK inhibitor)", "Bruton tyrosine kinase — mast cell activation", "Phase 3 completed (FDA submission expected)", "Phase 3 data promising for antihistamine-refractory CSU; PMID 41005705"],
    ["**Barzolvolimab**", "Anti-KIT (c-Kit / CD117) — mast cell depletion", "Phase 2 — positive results", "Significantly reduces CSU activity; mast cell depletion approach"],
  ],
  [18, 28, 22, 32]
));
children.push(space(120));

// ─────────────────────────────────────────────────────────────────────────────
// SECTION 6: Safety & Monitoring
// ─────────────────────────────────────────────────────────────────────────────
children.push(pageBreakPara());
children.push(h1("6. Safety Monitoring"));
children.push(makeTable(
  ["Agent", "Key Adverse Effects", "Monitoring Requirements"],
  [
    ["**Omalizumab**", "Anaphylaxis (<0.1%); injection-site reactions (local swelling, erythema ~50%); diffuse urticaria (rare); historical malignancy signal not confirmed in registries", "Observe 30–60 min post-injection for first 3 doses in clinical setting. Prescribe epinephrine autoinjector. Subsequent doses may be home-administered. Review every 3–6 months."],
    ["**Dupilumab**", "Injection-site reactions; conjunctivitis; transient blood eosinophilia; rare eosinophilic pneumonia", "CBC with eosinophil count at baseline and 3 months. Ophthalmic review if persistent conjunctivitis develops. Avoid live vaccines."],
    ["**Cyclosporine**", "Nephrotoxicity, hypertension, dyslipidaemia, infections, gingival hyperplasia, hirsutism, drug interactions (CYP3A4)", "Serum creatinine, eGFR, BP, potassium at baseline; fortnightly for 3 months, then monthly. Lipid profile 3-monthly."],
    ["**All biologics**", "Live vaccine contraindication; helminth risk in endemic regions; potential masking of symptoms on discontinuation", "Screen for helminth infection in endemic areas before starting. Do not give live vaccines during therapy. Do not initiate during acute severe exacerbation."],
  ],
  [18, 40, 42]
));
children.push(space(80));
children.push(warnBox("Anaphylaxis Protocol: All patients initiating omalizumab must be observed for a minimum of 30–60 minutes after the first three injections in a clinical setting with resuscitation equipment. An epinephrine autoinjector (e.g. EpiPen 0.3 mg) must be prescribed and patient education on use provided at the first visit."));
children.push(space(120));

// ─────────────────────────────────────────────────────────────────────────────
// SECTION 7: Response Assessment & Follow-Up
// ─────────────────────────────────────────────────────────────────────────────
children.push(h1("7. Response Assessment & Follow-Up"));
children.push(makeTable(
  ["Timepoint", "Actions"],
  [
    ["**Baseline (before biologic)**", "Document UAS7, UCT score. Review and document antihistamine failure. Record weight, renal function (if cyclosporine planned). Educate on injection technique and anaphylaxis."],
    ["**4–6 weeks (early check)**", "Assess tolerability. Check for injection-site reactions. Confirm correct technique. Patient-reported UAS7 diary review."],
    ["**3 months (formal assessment)**", "UAS7, UCT, AAS7 (if angioedema). Compare to baseline. Good response: UAS7 reduction ≥75% or UAS7 ≤6. Partial response: ≥50% but <75% reduction. Non-response: <50% reduction."],
    ["**6 months**", "Continue if good response. Consider antihistamine dose reduction. Plan discontinuation trial if sustained remission (UAS7 = 0 for ≥3 months)."],
    ["**12 months**", "Review for disease remission. In spontaneous remission or well-controlled disease: consider structured biologic withdrawal with close monitoring. Restart if relapse."],
    ["**Ongoing**", "6-monthly review. Recheck renal function (if on cyclosporine). Reassess need for continuing therapy annually."],
  ],
  [22, 78]
));
children.push(space(80));
children.push(colorBox("Response Definitions", [
  "Complete response: UAS7 = 0 (urticaria-free) for ≥4 consecutive weeks",
  "Well-controlled: UAS7 1–6 with minimal impact on daily life",
  "Partial response: UAS7 reduction ≥50% from baseline",
  "Non-response / treatment failure: UAS7 reduction <50% at 3 months — reassess diagnosis, advance therapy, refer to specialist",
], LTBLUE, TEAL));
children.push(space(120));

// ─────────────────────────────────────────────────────────────────────────────
// SECTION 8: Special Populations
// ─────────────────────────────────────────────────────────────────────────────
children.push(h1("8. Special Populations"));
children.push(makeTable(
  ["Population", "Guidance"],
  [
    ["**Children <12 years**", "Omalizumab approved ≥12 years for CSU; systematic review (Pediatric Allergy Immunol 2025, PMID 40545961) supports off-label use in younger children with good efficacy and safety data. Requires specialist oversight. Standard dose 300 mg q4w regardless of weight (unlike asthma)."],
    ["**Adolescents (12–17 years)**", "Omalizumab and dupilumab both approved ≥12 years. Consider dupilumab if concomitant atopic dermatitis or other type 2 comorbidities."],
    ["**Pregnancy**", "Omalizumab preferred over cyclosporine for refractory CSU in pregnancy. Registry data shows no increased major congenital anomaly risk. Dupilumab: insufficient data — specialist guidance required. Avoid cyclosporine and systemic immunosuppressants where possible."],
    ["**Elderly (≥65 years)**", "Avoid first-generation antihistamines (falls risk, anticholinergic toxicity). Omalizumab well-tolerated; no dose adjustment required. Use cyclosporine cautiously — higher risk of renal impairment and hypertension."],
    ["**Autoimmune urticaria (Type IIb)**", "Patients with anti-FcεRI antibodies may have attenuated response to omalizumab. Cyclosporine may be more effective in this subgroup. Consider earlier specialist referral."],
    ["**Inducible urticaria (CIndU)**", "Omalizumab approved for chronic inducible urticaria (symptomatic dermographism, cold, cholinergic). Same dose and regimen as CSU. Response rates slightly lower than in CSU."],
  ],
  [22, 78]
));
children.push(space(120));

// ─────────────────────────────────────────────────────────────────────────────
// SECTION 9: GP Quick Reference
// ─────────────────────────────────────────────────────────────────────────────
children.push(pageBreakPara());
children.push(h1("9. GP Quick Reference Summary"));
children.push(makeTable(
  ["Drug", "Target", "Dose", "Eligibility", "Key AEs", "Key Notes"],
  [
    ["**Omalizumab**\n(Xolair®)", "Free IgE (FcεRI/II blockade)", "300 mg SC\nevery 4 weeks", "≥12 yrs (off-label <12)\nCSU failing antihistamines\nNo IgE threshold", "Anaphylaxis <0.1%\nInj. site reactions", "First biologic of choice.\nObserve 30–60 min first 3 doses."],
    ["**Dupilumab**\n(Dupixent®)", "IL-4Rα (IL-4 + IL-13 blockade)", "300 mg SC\nevery 2 weeks", "≥12 yrs\nCSU failing antihistamines (FDA 2025)", "Conjunctivitis\nInj. site reactions\nEosinophilia", "FDA approved Apr 2025.\nPreferred if type-2 comorbidities.\nNot shown to rescue omalizumab failures."],
    ["**Cyclosporine**\n(Neoral®)", "Calcineurin inhibitor (T-cell suppressor)", "3–5 mg/kg/day\norally (divided)", "Refractory CSU\nFailing omalizumab", "Nephrotoxicity\nHypertension\nInfections", "Intensive monitoring required.\nSpecialist supervision.\nLimit duration."],
    ["**Remibrutinib**\n(investigational)", "BTK (mast cell signalling)", "Oral (dose TBC)", "Antihistamine-refractory CSU", "GI effects, infections (early data)", "Phase 3 data positive.\nRegulatory submission expected 2025–2026."],
  ],
  [16, 18, 18, 20, 16, 22]
));
children.push(space(120));

// ─────────────────────────────────────────────────────────────────────────────
// SECTION 10: References
// ─────────────────────────────────────────────────────────────────────────────
children.push(h1("10. References"));
const refs = [
  "Zuberbier T, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy. 2022;73:1393–1414.",
  "Goldman-Cecil Medicine, 26th ed (International). Chronic Urticaria. Elsevier, 2023.",
  "Harrison's Principles of Internal Medicine, 22nd ed (2025). Urticaria and Angioedema. McGraw-Hill.",
  "Andrews' Diseases of the Skin: Clinical Dermatology, 13th ed. Chronic Urticaria. Elsevier.",
  "Katzung BG, et al. Anti-IgE Monoclonal Antibodies. Katzung's Basic and Clinical Pharmacology, 16th ed. McGraw-Hill, 2021.",
  "Chronic Urticaria. StatPearls [Internet]. NCBI Bookshelf. NBK555910. Accessed May 2026.",
  "Khan AA, Riaz AA, Naseer F. Efficacy, Safety, and QoL outcomes of remibrutinib in CSU: systematic review and meta-analysis. J Allergy Clin Immunol Pract. 2025. PMID: 41005705.",
  "Alomari O, Ozceker D, Mokresh ME. Omalizumab in pediatric CSU: systematic review and meta-analysis. Pediatr Allergy Immunol. 2025 Jun. PMID: 40545961.",
  "Chu AWL, et al. Comparative efficacy and safety of biologics and systemic immunomodulatory treatments for chronic urticaria: network meta-analysis. J Allergy Clin Immunol. 2025 Oct. PMID: 40663028.",
  "Emerging IgE and non-IgE targeted therapies for chronic urticaria. PMC12874352. 2025.",
  "Dermatology Times. 2025 Year in Review: Chronic Spontaneous Urticaria. Dupilumab and remibrutinib FDA approvals.",
  "National Consensus on Diagnosis and Treatment of Chronic Urticaria (2025). Rev Med Chil. 2026 Feb. PMID: 42024696.",
];
for (let i = 0; i < refs.length; i++) {
  children.push(new Paragraph({
    spacing: { before: 40, after: 40 },
    indent: { left: convertInchesToTwip(0.3), hanging: convertInchesToTwip(0.3) },
    children: [
      new TextRun({ text: `${i + 1}.  `, bold: true, size: 17, font: "Calibri", color: DGREY }),
      new TextRun({ text: refs[i], size: 17, font: "Calibri", color: DGREY }),
    ],
  }));
}
children.push(space(120));

// Disclaimer
children.push(colorBox(
  "Disclaimer",
  [
    "This protocol is a clinical guidance tool for general practitioners and does not replace individual clinical judgement.",
    "Biologic therapy initiation and oversight should involve specialist review (allergist/clinical immunologist/dermatologist).",
    "Check current approved product information and local formulary/payer criteria before prescribing.",
    "Review annually or when updated guidelines are published.",
  ],
  LTYELL, AMBER, "856404"
));

// ── Build Document ─────────────────────────────────────────────────────────────
const doc = new Document({
  styles: {
    default: {
      document: {
        run: { font: "Calibri", size: 20, color: DGREY },
      },
    },
  },
  sections: [
    {
      properties: {
        page: {
          margin: {
            top: convertMillimetersToTwip(38),
            bottom: convertMillimetersToTwip(22),
            left: convertMillimetersToTwip(20),
            right: convertMillimetersToTwip(20),
          },
        },
      },
      headers: { default: buildHeader() },
      footers: { default: buildFooter() },
      children,
    },
  ],
});

Packer.toBuffer(doc).then(buf => {
  fs.writeFileSync(OUT, buf);
  console.log("DOCX written:", OUT);
}).catch(err => { console.error(err); process.exit(1); });

cd /home/daytona/workspace/ige-protocol && node build_urticaria_docx.js 2>&1

~/ige-protocol/build_urticaria_docx.js

Successfully replaced 1 instance(s) of the string in '/home/daytona/workspace/ige-protocol/build_urticaria_docx.js'

cd /home/daytona/workspace/ige-protocol && node build_urticaria_docx.js 2>&1

cd /home/daytona/workspace/ige-protocol && python /home/daytona/skills/docx/scri…

cd /home/daytona/workspace/ige-protocol && python3 -c " import zipfile, sys try:…

ls -lh /home/daytona/workspace/ige-protocol/IgE_CU_Treatment_Protocol.docx