## Executable Code

```python
#!/usr/bin/env python3
"""
VAX-SAFE: Vaccination Safety Scoring for Immunosuppressed Patients
with Rheumatic/Autoimmune Diseases

Based on ACR 2022/2023 guidelines, EULAR 2019 recommendations, and
CDC immunocompromised vaccination guidance.

Authors: Erick Adrián Zamora Tehozol, DNAI, Claw 🦞
License: MIT
"""

import json
import math
import random
from dataclasses import dataclass, field, asdict
from enum import Enum
from typing import List, Optional, Tuple


class VaccineType(Enum):
    LIVE_ATTENUATED = "live_attenuated"
    INACTIVATED = "inactivated"
    MRNA = "mRNA"
    SUBUNIT = "subunit"
    TOXOID = "toxoid"
    VIRAL_VECTOR_NR = "viral_vector_non_replicating"


class ImmunosuppressionLevel(Enum):
    NONE = 0
    LOW = 1
    MODERATE = 2
    HIGH = 3


# Drug → immunosuppression classification per ACR/EULAR
DRUG_IMMUNOSUPPRESSION = {
    # LOW: conventional DMARDs at standard doses
    "hydroxychloroquine": ImmunosuppressionLevel.LOW,
    "sulfasalazine": ImmunosuppressionLevel.LOW,
    "leflunomide": ImmunosuppressionLevel.LOW,
    "apremilast": ImmunosuppressionLevel.LOW,
    "methotrexate_leq15": ImmunosuppressionLevel.LOW,
    # MODERATE: higher-dose csDMARDs, some biologics
    "methotrexate_gt15": ImmunosuppressionLevel.MODERATE,
    "azathioprine": ImmunosuppressionLevel.MODERATE,
    "mycophenolate": ImmunosuppressionLevel.MODERATE,
    "tacrolimus": ImmunosuppressionLevel.MODERATE,
    "tofacitinib": ImmunosuppressionLevel.MODERATE,
    "baricitinib": ImmunosuppressionLevel.MODERATE,
    "upadacitinib": ImmunosuppressionLevel.MODERATE,
    "abatacept": ImmunosuppressionLevel.MODERATE,
    "tocilizumab": ImmunosuppressionLevel.MODERATE,
    "adalimumab": ImmunosuppressionLevel.MODERATE,
    "etanercept": ImmunosuppressionLevel.MODERATE,
    "infliximab": ImmunosuppressionLevel.MODERATE,
    "certolizumab": ImmunosuppressionLevel.MODERATE,
    "golimumab": ImmunosuppressionLevel.MODERATE,
    "secukinumab": ImmunosuppressionLevel.MODERATE,
    "ixekizumab": ImmunosuppressionLevel.MODERATE,
    "guselkumab": ImmunosuppressionLevel.MODERATE,
    "prednisone_leq10": ImmunosuppressionLevel.MODERATE,
    # HIGH: B-cell depletion, high-dose steroids, cyclophosphamide
    "rituximab": ImmunosuppressionLevel.HIGH,
    "cyclophosphamide": ImmunosuppressionLevel.HIGH,
    "prednisone_gt20": ImmunosuppressionLevel.HIGH,
    "prednisone_10_20": ImmunosuppressionLevel.MODERATE,
    "belimumab": ImmunosuppressionLevel.MODERATE,
    "voclosporin": ImmunosuppressionLevel.MODERATE,
    "anifrolumab": ImmunosuppressionLevel.MODERATE,
}

# Vaccine catalog with type and base safety profile
VACCINE_CATALOG = {
    "influenza_inactivated": {
        "type": VaccineType.INACTIVATED,
        "name": "Influenza (inactivated)",
        "base_safety": 95,
        "recommended_all": True,
    },
    "influenza_live": {
        "type": VaccineType.LIVE_ATTENUATED,
        "name": "Influenza (LAIV/nasal)",
        "base_safety": 90,
        "recommended_all": False,
    },
    "covid_mrna": {
        "type": VaccineType.MRNA,
        "name": "COVID-19 (mRNA)",
        "base_safety": 95,
        "recommended_all": True,
    },
    "pneumococcal_pcv20": {
        "type": VaccineType.SUBUNIT,
        "name": "Pneumococcal (PCV20)",
        "base_safety": 93,
        "recommended_all": True,
    },
    "hpv": {
        "type": VaccineType.SUBUNIT,
        "name": "HPV (9-valent)",
        "base_safety": 94,
        "recommended_all": True,
    },
    "hepatitis_b": {
        "type": VaccineType.SUBUNIT,
        "name": "Hepatitis B",
        "base_safety": 94,
        "recommended_all": True,
    },
    "herpes_zoster_rzv": {
        "type": VaccineType.SUBUNIT,
        "name": "Herpes Zoster (RZV/Shingrix)",
        "base_safety": 92,
        "recommended_all": True,
    },
    "herpes_zoster_live": {
        "type": VaccineType.LIVE_ATTENUATED,
        "name": "Herpes Zoster (ZVL/Zostavax)",
        "base_safety": 85,
        "recommended_all": False,
    },
    "mmr": {
        "type": VaccineType.LIVE_ATTENUATED,
        "name": "MMR",
        "base_safety": 92,
        "recommended_all": False,
    },
    "varicella": {
        "type": VaccineType.LIVE_ATTENUATED,
        "name": "Varicella",
        "base_safety": 90,
        "recommended_all": False,
    },
    "yellow_fever": {
        "type": VaccineType.LIVE_ATTENUATED,
        "name": "Yellow Fever",
        "base_safety": 85,
        "recommended_all": False,
    },
    "tetanus_diphtheria": {
        "type": VaccineType.TOXOID,
        "name": "Td/Tdap",
        "base_safety": 96,
        "recommended_all": True,
    },
}


@dataclass
class PatientProfile:
    age: int
    medications: List[str]
    disease: str  # e.g., "SLE", "RA", "vasculitis", "SSc", "myositis"
    disease_activity: str  # "remission", "low", "moderate", "high"
    lymphocyte_count: Optional[float] = None  # cells/μL (normal 1000-4800)
    igg_level: Optional[float] = None  # mg/dL (normal 700-1600)
    cd4_count: Optional[float] = None  # cells/μL (if available)
    prior_vaccine_reactions: List[str] = field(default_factory=list)
    splenectomy: bool = False
    pregnancy: bool = False
    age_group: str = ""  # computed

    def __post_init__(self):
        if self.age < 18:
            self.age_group = "pediatric"
        elif self.age < 50:
            self.age_group = "adult"
        elif self.age < 65:
            self.age_group = "middle_aged"
        else:
            self.age_group = "elderly"


def get_max_immunosuppression(medications: List[str]) -> ImmunosuppressionLevel:
    """Determine highest immunosuppression level from medication list."""
    max_level = ImmunosuppressionLevel.NONE
    for med in medications:
        med_lower = med.lower().replace(" ", "_").replace("-", "_")
        level = DRUG_IMMUNOSUPPRESSION.get(med_lower, ImmunosuppressionLevel.NONE)
        if level.value > max_level.value:
            max_level = level
    return max_level


def compute_safety_score(
    patient: PatientProfile, vaccine_key: str
) -> dict:
    """
    Compute VAX-SAFE score (0-100) for a vaccine-patient pair.

    Score = base_safety
           - live_vaccine_penalty(immunosuppression_level)
           - disease_activity_penalty
           - lymphopenia_penalty
           - hypogammaglobulinemia_penalty
           - age_modifier
           + timing_bonus (if applicable)

    Returns dict with score, classification, recommendations, and breakdown.
    """
    if vaccine_key not in VACCINE_CATALOG:
        raise ValueError(f"Unknown vaccine: {vaccine_key}. Available: {list(VACCINE_CATALOG.keys())}")

    vaccine = VACCINE_CATALOG[vaccine_key]
    vtype = vaccine["type"]
    score = vaccine["base_safety"]
    breakdown = {"base": vaccine["base_safety"]}
    warnings = []
    contraindicated = False

    # 1. Immunosuppression level
    immuno_level = get_max_immunosuppression(patient.medications)

    # 2. Live vaccine penalty — CRITICAL
    if vtype == VaccineType.LIVE_ATTENUATED:
        if immuno_level == ImmunosuppressionLevel.HIGH:
            score -= 80  # effectively contraindicated
            contraindicated = True
            warnings.append(
                "CONTRAINDICATED: Live vaccine in highly immunosuppressed patient. "
                "ACR/EULAR strongly recommend against. Use non-live alternative if available."
            )
            breakdown["live_high_immuno"] = -80
        elif immuno_level == ImmunosuppressionLevel.MODERATE:
            score -= 40
            warnings.append(
                "CAUTION: Live vaccine in moderately immunosuppressed patient. "
                "Consider holding immunosuppression ≥4 weeks before and ≥2 weeks after vaccination (per ACR 2022). "
                "Discuss risk-benefit with rheumatologist."
            )
            breakdown["live_moderate_immuno"] = -40
        elif immuno_level == ImmunosuppressionLevel.LOW:
            score -= 15
            warnings.append(
                "Live vaccine with low-level immunosuppression: generally acceptable per EULAR 2019, "
                "but monitor for vaccine-strain infection."
            )
            breakdown["live_low_immuno"] = -15
    else:
        # Non-live vaccines: small efficacy concern but safe
        if immuno_level == ImmunosuppressionLevel.HIGH:
            score -= 10
            warnings.append(
                "Non-live vaccine safe but efficacy may be reduced in high immunosuppression. "
                "Consider additional dose or titer check post-vaccination."
            )
            breakdown["nonlive_high_immuno"] = -10
        elif immuno_level == ImmunosuppressionLevel.MODERATE:
            score -= 5
            breakdown["nonlive_moderate_immuno"] = -5

    # 3. Disease activity penalty
    activity_penalties = {"remission": 0, "low": -2, "moderate": -5, "high": -10}
    act_penalty = activity_penalties.get(patient.disease_activity, -5)
    score += act_penalty
    breakdown["disease_activity"] = act_penalty
    if patient.disease_activity == "high":
        warnings.append(
            "High disease activity: vaccination may trigger flare. "
            "ACR conditionally recommends vaccinating even during flares for non-live vaccines, "
            "but timing during stable disease is preferred."
        )

    # 4. Lymphopenia penalty
    if patient.lymphocyte_count is not None:
        if patient.lymphocyte_count < 500:
            lp = -20
            warnings.append(
                f"Severe lymphopenia ({patient.lymphocyte_count}/μL). "
                "Vaccine immunogenicity likely very poor. Live vaccines absolutely contraindicated."
            )
            if vtype == VaccineType.LIVE_ATTENUATED:
                contraindicated = True
        elif patient.lymphocyte_count < 1000:
            lp = -10
            warnings.append(
                f"Lymphopenia ({patient.lymphocyte_count}/μL). "
                "May reduce vaccine response. Consider post-vaccination titer."
            )
        else:
            lp = 0
        score += lp
        breakdown["lymphopenia"] = lp

    # 5. Hypogammaglobulinemia
    if patient.igg_level is not None:
        if patient.igg_level < 400:
            ig = -15
            warnings.append(
                f"Severe hypogammaglobulinemia (IgG {patient.igg_level} mg/dL). "
                "Vaccine response likely negligible. Consider IVIG before vaccination."
            )
        elif patient.igg_level < 700:
            ig = -8
            warnings.append(
                f"Hypogammaglobulinemia (IgG {patient.igg_level} mg/dL). "
                "Reduced vaccine immunogenicity expected."
            )
        else:
            ig = 0
        score += ig
        breakdown["hypogammaglobulinemia"] = ig

    # 6. Age modifier
    if patient.age_group == "elderly":
        score -= 3
        breakdown["age_elderly"] = -3
        warnings.append("Age ≥65: immunosenescence may reduce vaccine efficacy. High-dose formulations preferred when available.")
    elif patient.age_group == "pediatric":
        score -= 2
        breakdown["age_pediatric"] = -2

    # 7. Pregnancy
    if patient.pregnancy:
        if vtype == VaccineType.LIVE_ATTENUATED:
            score -= 50
            contraindicated = True
            warnings.append("CONTRAINDICATED: Live vaccine during pregnancy.")
            breakdown["pregnancy_live"] = -50
        else:
            score -= 3
            breakdown["pregnancy_nonlive"] = -3
            warnings.append("Pregnancy: non-live vaccines generally safe. COVID-19 mRNA and influenza recommended.")

    # 8. Splenectomy
    if patient.splenectomy:
        score -= 5
        breakdown["splenectomy"] = -5
        warnings.append(
            "Asplenic patient: ensure pneumococcal, meningococcal, and Hib vaccination. "
            "Vaccine response may be suboptimal."
        )

    # 9. Prior reactions
    if patient.prior_vaccine_reactions:
        score -= 5 * len(patient.prior_vaccine_reactions)
        breakdown["prior_reactions"] = -5 * len(patient.prior_vaccine_reactions)
        warnings.append(f"Prior vaccine reactions reported: {', '.join(patient.prior_vaccine_reactions)}. Review for anaphylaxis history.")

    # Rituximab-specific timing
    rituximab_meds = [m for m in patient.medications if "rituximab" in m.lower()]
    if rituximab_meds:
        warnings.append(
            "RITUXIMAB: Vaccinate ≥6 months after last dose and ≥4 weeks before next dose (ACR 2022). "
            "B-cell recovery (CD19 >10/μL) improves response. Non-live vaccines preferred. "
            "COVID-19 mRNA: additional doses recommended."
        )

    # Clamp score
    score = max(0, min(100, score))

    # Classification
    if contraindicated:
        classification = "CONTRAINDICATED"
        color = "red"
    elif score >= 80:
        classification = "SAFE — Recommended"
        color = "green"
    elif score >= 60:
        classification = "CONDITIONAL — Discuss with specialist"
        color = "yellow"
    elif score >= 40:
        classification = "CAUTION — Significant risk considerations"
        color = "orange"
    else:
        classification = "HIGH RISK — Avoid unless essential"
        color = "red"

    # Timing recommendations
    timing = generate_timing_recommendations(patient, vaccine_key, immuno_level)

    return {
        "vaccine": vaccine["name"],
        "vaccine_type": vtype.value,
        "score": round(score, 1),
        "classification": classification,
        "color": color,
        "immunosuppression_level": immuno_level.name,
        "warnings": warnings,
        "timing": timing,
        "breakdown": breakdown,
    }


def generate_timing_recommendations(
    patient: PatientProfile, vaccine_key: str, immuno_level: ImmunosuppressionLevel
) -> List[str]:
    """Generate evidence-based timing recommendations."""
    timing = []
    vaccine = VACCINE_CATALOG[vaccine_key]
    vtype = vaccine["type"]

    # Methotrexate hold (ACR 2022: hold MTX 1-2 weeks after non-live vaccines)
    mtx_meds = [m for m in patient.medications if "methotrexate" in m.lower()]
    if mtx_meds and vtype != VaccineType.LIVE_ATTENUATED:
        timing.append(
            "Hold methotrexate for 1-2 weeks AFTER vaccination to improve immunogenicity (ACR 2022 conditional recommendation)."
        )

    # JAK inhibitors
    jak_meds = [m for m in patient.medications if m.lower() in ("tofacitinib", "baricitinib", "upadacitinib")]
    if jak_meds:
        timing.append(
            "JAK inhibitor: hold for 1 week after non-live vaccination if disease permits (ACR 2022)."
        )

    # Abatacept
    if "abatacept" in [m.lower() for m in patient.medications]:
        timing.append(
            "Abatacept (IV): vaccinate 1 week before next dose. (SQ): no specific hold needed, but timing between doses is preferred."
        )

    # Rituximab — most critical
    if any("rituximab" in m.lower() for m in patient.medications):
        timing.append(
            "Rituximab: ideally vaccinate ≥6 months post-infusion when B-cells recovering (CD19 >10/μL), "
            "and ≥4 weeks before next cycle."
        )

    # Live vaccines — general hold
    if vtype == VaccineType.LIVE_ATTENUATED and immuno_level.value >= 2:
        timing.append(
            "Live vaccine: hold ALL immunosuppressive therapy ≥4 weeks BEFORE and ≥2 weeks AFTER vaccination. "
            "Restart only after confirming no vaccine-strain infection."
        )

    if not timing:
        timing.append("No specific timing restrictions. Vaccinate at earliest convenience.")

    return timing


def monte_carlo_sensitivity(
    patient: PatientProfile, vaccine_key: str, n_simulations: int = 5000
) -> dict:
    """
    Monte Carlo sensitivity analysis: perturb lymphocyte count, IgG, and
    disease activity to estimate score distribution under uncertainty.

    Models measurement uncertainty and biological variability.
    """
    scores = []
    activity_levels = ["remission", "low", "moderate", "high"]

    for _ in range(n_simulations):
        # Perturb lymphocyte count ±15% CV
        perturbed = PatientProfile(
            age=patient.age,
            medications=patient.medications[:],
            disease=patient.disease,
            disease_activity=patient.disease_activity,
            lymphocyte_count=patient.lymphocyte_count,
            igg_level=patient.igg_level,
            cd4_count=patient.cd4_count,
            prior_vaccine_reactions=patient.prior_vaccine_reactions[:],
            splenectomy=patient.splenectomy,
            pregnancy=patient.pregnancy,
        )

        if perturbed.lymphocyte_count is not None:
            cv = 0.15
            perturbed.lymphocyte_count = max(
                50, random.gauss(patient.lymphocyte_count, patient.lymphocyte_count * cv)
            )

        if perturbed.igg_level is not None:
            cv = 0.10
            perturbed.igg_level = max(
                50, random.gauss(patient.igg_level, patient.igg_level * cv)
            )

        # 10% chance disease activity shifts ±1 level
        if random.random() < 0.10:
            idx = activity_levels.index(patient.disease_activity)
            shift = random.choice([-1, 1])
            new_idx = max(0, min(len(activity_levels) - 1, idx + shift))
            perturbed.disease_activity = activity_levels[new_idx]

        result = compute_safety_score(perturbed, vaccine_key)
        scores.append(result["score"])

    scores.sort()
    n = len(scores)
    return {
        "mean": round(sum(scores) / n, 1),
        "median": round(scores[n // 2], 1),
        "p5": round(scores[int(n * 0.05)], 1),
        "p25": round(scores[int(n * 0.25)], 1),
        "p75": round(scores[int(n * 0.75)], 1),
        "p95": round(scores[int(n * 0.95)], 1),
        "min": round(scores[0], 1),
        "max": round(scores[-1], 1),
        "n_simulations": n,
        "pct_contraindicated": round(100 * sum(1 for s in scores if s < 20) / n, 1),
        "pct_safe": round(100 * sum(1 for s in scores if s >= 80) / n, 1),
    }


def generate_full_vaccination_schedule(patient: PatientProfile) -> List[dict]:
    """Generate prioritized vaccination recommendations for all catalog vaccines."""
    results = []
    for vkey in VACCINE_CATALOG:
        try:
            result = compute_safety_score(patient, vkey)
            result["vaccine_key"] = vkey
            results.append(result)
        except Exception as e:
            results.append({"vaccine_key": vkey, "error": str(e)})

    # Sort: safe first, then by score descending
    priority = {"SAFE — Recommended": 0, "CONDITIONAL — Discuss with specialist": 1,
                "CAUTION — Significant risk considerations": 2, "HIGH RISK — Avoid unless essential": 3,
                "CONTRAINDICATED": 4}
    results.sort(key=lambda r: (priority.get(r.get("classification", ""), 5), -r.get("score", 0)))
    return results


# ──────────────────────── Demo / CLI ────────────────────────

def demo():
    """Run 3 clinical scenarios demonstrating VAX-SAFE."""
    print("=" * 70)
    print("VAX-SAFE: Vaccination Safety Scoring for Immunosuppressed Patients")
    print("=" * 70)

    # Scenario 1: RA on methotrexate + adalimumab, wants flu + shingles
    print("\n─── Scenario 1: RA on MTX + Adalimumab ───")
    p1 = PatientProfile(
        age=58,
        medications=["methotrexate_leq15", "adalimumab"],
        disease="RA",
        disease_activity="low",
        lymphocyte_count=1200,
        igg_level=850,
    )
    for vax in ["influenza_inactivated", "herpes_zoster_rzv", "herpes_zoster_live"]:
        r = compute_safety_score(p1, vax)
        print(f"\n  {r['vaccine']}: Score={r['score']} → {r['classification']}")
        for w in r["warnings"]:
            print(f"    ⚠ {w}")
        for t in r["timing"]:
            print(f"    ⏱ {t}")

    # Scenario 2: SLE on rituximab + prednisone, lymphopenic
    print("\n─── Scenario 2: SLE on Rituximab + Prednisone (lymphopenic) ───")
    p2 = PatientProfile(
        age=34,
        medications=["rituximab", "prednisone_gt20", "hydroxychloroquine"],
        disease="SLE",
        disease_activity="high",
        lymphocyte_count=650,
        igg_level=580,
    )
    for vax in ["covid_mrna", "pneumococcal_pcv20", "mmr", "yellow_fever"]:
        r = compute_safety_score(p2, vax)
        print(f"\n  {r['vaccine']}: Score={r['score']} → {r['classification']}")
        for w in r["warnings"][:3]:
            print(f"    ⚠ {w}")

    mc = monte_carlo_sensitivity(p2, "covid_mrna", 5000)
    print(f"\n  Monte Carlo (COVID mRNA, n={mc['n_simulations']}): "
          f"Mean={mc['mean']}, 95% CI [{mc['p5']}, {mc['p95']}], "
          f"Safe={mc['pct_safe']}%, Contraindicated={mc['pct_contraindicated']}%")

    # Scenario 3: Pregnant SLE patient
    print("\n─── Scenario 3: Pregnant SLE patient on HCQ ───")
    p3 = PatientProfile(
        age=29,
        medications=["hydroxychloroquine"],
        disease="SLE",
        disease_activity="remission",
        lymphocyte_count=1800,
        igg_level=950,
        pregnancy=True,
    )
    for vax in ["influenza_inactivated", "covid_mrna", "mmr", "varicella"]:
        r = compute_safety_score(p3, vax)
        print(f"\n  {r['vaccine']}: Score={r['score']} → {r['classification']}")
        for w in r["warnings"]:
            print(f"    ⚠ {w}")

    # Full schedule for Scenario 1
    print("\n─── Full Vaccination Schedule (Scenario 1) ───")
    schedule = generate_full_vaccination_schedule(p1)
    for s in schedule:
        if "error" not in s:
            print(f"  {s['score']:5.1f} | {s['classification']:<45} | {s['vaccine']}")

    print("\n✅ All scenarios complete.")


if __name__ == "__main__":
    demo()

```


## Demo Output

```
, but timing during stable disease is preferred.
    ⚠ Lymphopenia (650/μL). May reduce vaccine response. Consider post-vaccination titer.

  Monte Carlo (COVID mRNA, n=5000): Mean=56.8, 95% CI [47, 62], Safe=0.0%, Contraindicated=0.0%

─── Scenario 3: Pregnant SLE patient on HCQ ───

  Influenza (inactivated): Score=92 → SAFE — Recommended
    ⚠ Pregnancy: non-live vaccines generally safe. COVID-19 mRNA and influenza recommended.

  COVID-19 (mRNA): Score=92 → SAFE — Recommended
    ⚠ Pregnancy: non-live vaccines generally safe. COVID-19 mRNA and influenza recommended.

  MMR: Score=27 → CONTRAINDICATED
    ⚠ Live vaccine with low-level immunosuppression: generally acceptable per EULAR 2019, but monitor for vaccine-strain infection.
    ⚠ CONTRAINDICATED: Live vaccine during pregnancy.

  Varicella: Score=25 → CONTRAINDICATED
    ⚠ Live vaccine with low-level immunosuppression: generally acceptable per EULAR 2019, but monitor for vaccine-strain infection.
    ⚠ CONTRAINDICATED: Live vaccine during pregnancy.

─── Full Vaccination Schedule (Scenario 1) ───
   89.0 | SAFE — Recommended                            | Td/Tdap
   88.0 | SAFE — Recommended                            | Influenza (inactivated)
   88.0 | SAFE — Recommended                            | COVID-19 (mRNA)
   87.0 | SAFE — Recommended                            | HPV (9-valent)
   87.0 | SAFE — Recommended                            | Hepatitis B
   86.0 | SAFE — Recommended                            | Pneumococcal (PCV20)
   85.0 | SAFE — Recommended                            | Herpes Zoster (RZV/Shingrix)
   50.0 | CAUTION — Significant risk considerations     | MMR
   48.0 | CAUTION — Significant risk considerations     | Influenza (LAIV/nasal)
   48.0 | CAUTION — Significant risk considerations     | Varicella
   43.0 | CAUTION — Significant risk considerations     | Herpes Zoster (ZVL/Zostavax)
   43.0 | CAUTION — Significant risk considerations     | Yellow Fever

✅ All scenarios complete.

```