Cookbook 339: Offline Clinical Infectious Disease Invasive Aspergillosis, Galactomannan & Isavuconazole Engine

"""
Cookbook 339: Offline Infectious Disease Invasive Aspergillosis, Galactomannan & Isavuconazole Engine
OpenPHR Clinical AI Working Group (https://openphr.org)
"""

import math
import numpy as np
import pandas as pd
from typing import Dict, List, Tuple, Optional
from dataclasses import dataclass

@dataclass
class AspergillosisPatientTelemetry:
    patient_id: str
    age_years: float = 49.0
    sex: str = "Male"
    patient_weight_kg: float = 74.0
    # Host Factors (EORTC/MSGERC 2020)
    absolute_neutrophil_count_cells_ul: float = 120.0 # ANC < 500 for > 10 days
    neutropenia_duration_days: int = 14 # >= 10 days = Positive Host Factor
    allogeneic_hct_recipient: bool = True
    active_graft_versus_host_disease: bool = True # Severe acute GvHD
    systemic_corticosteroid_daily_mg_pred_eq: float = 40.0 # >= 0.3 mg/kg for >= 3 weeks
    corticosteroid_duration_days: int = 28
    # Clinical & Radiological CT Chest Findings
    ct_dense_well_circumscribed_nodule: bool = True
    ct_halo_sign_present: bool = True # Classic angioinvasive ground-glass halo
    ct_air_crescent_sign: bool = False
    ct_cavitary_lesion: bool = False
    ct_wedge_shaped_consolidation: bool = True
    # Mycological Laboratory Telemetry
    serum_galactomannan_odi: float = 1.35 # ODI >= 0.5 = Positive
    bal_galactomannan_odi: float = 2.40 # ODI >= 1.0 = Positive
    aspergillus_pcr_positive: bool = True
    fungal_hyphae_on_tissue_biopsy: bool = False # Sterile biopsy pending
    # Cardiac & Hepatic Baseline Safety Telemetry
    baseline_qtc_interval_ms: float = 495.0 # ms (> 480 ms = Triazole QTc prolongation risk!)
    serum_alt_u_l: float = 42.0 # Normal < 50
    serum_total_bilirubin_mg_dl: float = 1.1 # Normal < 1.2
    baseline_egfr_ml_min: float = 44.0 # mL/min (< 50 mL/min = IV cyclodextrin risk)
    # Active Pharmacotherapy & TDM
    current_antifungal: str = "Voriconazole"
    voriconazole_trough_mcg_ml: float = 6.4 # mcg/mL (> 5.5 = Toxic range!)

@dataclass
class IPAEvaluationReport:
    patient_id: str
    eortc_msgerc_classification: str # "PROBABLE INVASIVE PULMONARY ASPERGILLOSIS (IPA)"
    host_factors_met: List[str]
    radiological_criteria_met: List[str]
    mycological_criteria_met: List[str]
    antifungal_recommendation: List[str]
    voriconazole_tdm_status: str
    safety_sentinels: List[str]
    clinical_idsa_ecil_directive: str

class InvasiveAspergillosisDecisionEngine:
    """
    Offline clinical engine for EORTC/MSGERC 2020 invasive aspergillosis staging,
    Galactomannan ODI interpretation, and Isavuconazole / Voriconazole TDM titration.
    """

    def evaluate_eortc_criteria(self, d: AspergillosisPatientTelemetry) -> Tuple[str, List[str], List[str], List[str]]:
        host_met = []
        ct_met = []
        myco_met = []

        # 1. Host Factors
        if d.absolute_neutrophil_count_cells_ul < 500.0 and d.neutropenia_duration_days >= 10:
            host_met.append(f"Host 1: Prolonged severe neutropenia (ANC {d.absolute_neutrophil_count_cells_ul:.0f} cells/uL for {d.neutropenia_duration_days} days).")
        if d.allogeneic_hct_recipient:
            host_met.append("Host 2: Allogeneic hematopoietic cell transplant recipient.")
        if d.systemic_corticosteroid_daily_mg_pred_eq >= 20.0 and d.corticosteroid_duration_days >= 21:
            host_met.append(f"Host 3: Prolonged systemic corticosteroid therapy ({d.systemic_corticosteroid_daily_mg_pred_eq:.0f} mg/day for {d.corticosteroid_duration_days} days).")

        # 2. Radiological CT Findings
        if d.ct_dense_well_circumscribed_nodule or d.ct_halo_sign_present:
            host_str = "Dense well-circumscribed nodule with Halo sign" if d.ct_halo_sign_present else "Dense pulmonary nodule"
            ct_met.append(f"CT 1: {host_str}.")
        if d.ct_air_crescent_sign:
            ct_met.append("CT 2: Air-crescent sign.")
        if d.ct_cavitary_lesion:
            ct_met.append("CT 3: Cavitary pulmonary lesion.")
        if d.ct_wedge_shaped_consolidation:
            ct_met.append("CT 4: Wedge-shaped segmental / lobar consolidation.")

        # 3. Mycological Criteria
        if d.serum_galactomannan_odi >= 0.5:
            myco_met.append(f"Myco 1: Positive Serum Galactomannan (ODI {d.serum_galactomannan_odi:.2f} >= 0.50 cutoff).")
        if d.bal_galactomannan_odi >= 1.0:
            myco_met.append(f"Myco 2: Positive BAL Galactomannan (ODI {d.bal_galactomannan_odi:.2f} >= 1.00 cutoff).")
        if d.aspergillus_pcr_positive:
            myco_met.append("Myco 3: Positive Aspergillus qPCR on blood/BAL.")

        # Staging Triage
        if d.fungal_hyphae_on_tissue_biopsy:
            stage = "PROVEN INVASIVE ASPERGILLOSIS (Histopathological / Sterile Culture Proof)"
        elif len(host_met) >= 1 and len(ct_met) >= 1 and len(myco_met) >= 1:
            stage = "PROBABLE INVASIVE PULMONARY ASPERGILLOSIS (IPA) (EORTC/MSGERC 2020 Criteria Met)"
        elif len(host_met) >= 1 and len(ct_met) >= 1:
            stage = "POSSIBLE INVASIVE PULMONARY ASPERGILLOSIS (IPA) (Host + Radiologic Features Present)"
        else:
            stage = "UNLIKELY INVASIVE ASPERGILLOSIS / NON-CLASSIFIED"

        return stage, host_met, ct_met, myco_met

    def audit_voriconazole_tdm(self, trough: float) -> str:
        if trough < 1.0:
            return f"⚠️ SUBTHERAPEUTIC VORICONAZOLE TROUGH ({trough:.1f} mcg/mL < 1.0 target) -> High risk of treatment failure. Increase total daily dose by 50%."
        elif 1.0 <= trough <= 5.5:
            return f"✅ OPTIMAL VORICONAZOLE TROUGH ({trough:.1f} mcg/mL, Target 1.0 - 5.5 mcg/mL) -> Maintain current dosage."
        else:
            return f"🚨 SUPRATHERAPEUTIC / TOXIC VORICONAZOLE TROUGH ({trough:.1f} mcg/mL > 5.5 mcg/mL) -> High risk of neurotoxicity and cholestatic hepatitis. STAT hold 1-2 doses and decrease daily dose by 30-50%."

    def generate_treatment_recommendations(self, stage: str, d: AspergillosisPatientTelemetry) -> Tuple[List[str], List[str]]:
        plan = []
        sentinels = []

        is_prolonged_qtc = d.baseline_qtc_interval_ms >= 480.0
        has_renal_impairment = d.baseline_egfr_ml_min < 50.0

        # Safety Sentinel: QTc Prolongation on Voriconazole
        if is_prolonged_qtc:
            sentinels.append(f"🚨 QTC PROLONGATION RISK SENTINEL: Baseline QTc is {d.baseline_qtc_interval_ms:.0f} ms (>= 480 ms). Voriconazole and Posaconazole cause dose-dependent QTc prolongation and risk of Torsades de Pointes. ISAVUCONAZOLE is preferred (causes QTc shortening) or Liposomal Amphotericin B.")

        # Safety Sentinel: IV Cyclodextrin Accumulation
        if has_renal_impairment and "Voriconazole" in d.current_antifungal:
            sentinels.append(f"CYCLODEXTRIN ACCUMULATION ALERT: Patient eGFR is {d.baseline_egfr_ml_min:.0f} mL/min (< 50 mL/min). IV Voriconazole vehicle SBECD accumulates and causes nephrotoxicity. Convert to oral Voriconazole or IV Isavuconazole.")

        # Treatment Plan
        if "PROBABLE" in stage or "PROVEN" in stage or "POSSIBLE" in stage:
            plan.append("1. FIRST-LINE TARGETED ANTIFUNGAL THERAPY (IDSA / ECIL-8 Guidelines):")

            if is_prolonged_qtc or has_renal_impairment:
                plan.append("   • PREFERRED: ISAVUCONAZONIUM SULFATE (Cresemba):")
                plan.append("     - Loading Dose: 372 mg IV/PO every 8 hours x 6 doses (first 48 hours).")
                plan.append("     - Maintenance Dose: 372 mg IV/PO once daily starting on Day 3.")
                plan.append(f"     - Rationales: Baseline QTc {d.baseline_qtc_interval_ms:.0f} ms (Isavuconazole shortens QTc), eGFR {d.baseline_egfr_ml_min:.0f} mL/min (no cyclodextrin), and predictable linear pharmacokinetics.")
            else:
                plan.append("   • OPTION A: VORICONAZOLE:")
                plan.append("     - Loading Dose: 6 mg/kg IV q12h x 2 doses on Day 1.")
                plan.append("     - Maintenance Dose: 4 mg/kg IV q12h or 200-300 mg PO BID.")
                plan.append("     - Mandatory TDM: Check trough serum level on Day 4-7 (Target 1.0 - 5.5 mcg/mL).")

            plan.append("   • OPTION B (ALTERNATIVE / AZOLE-REFRACTORY): Liposomal Amphotericin B (AmBisome) 3 - 5 mg/kg/day IV infusion.")
            plan.append("2. DURATION OF THERAPY: Minimum of 6 to 12 weeks, continuing until full radiological resolution and complete resolution of immunosuppression/neutropenia.")

        return plan, sentinels

    def evaluate_case(self, data: AspergillosisPatientTelemetry) -> IPAEvaluationReport:
        stage, host_list, ct_list, myco_list = self.evaluate_eortc_criteria(data)
        tdm_status = self.audit_voriconazole_tdm(data.voriconazole_trough_mcg_ml)
        rx_plan, sentinels = self.generate_treatment_recommendations(stage, data)

        directives = []
        directives.append(f"DIAGNOSIS: {stage}.")
        directives.append(f"MYCOLOGY: Serum Galactomannan {data.serum_galactomannan_odi:.2f}, BAL {data.bal_galactomannan_odi:.2f}.")
        directives.append(f"TDM: {tdm_status}")

        return IPAEvaluationReport(
            patient_id=data.patient_id,
            eortc_msgerc_classification=stage,
            host_factors_met=host_list,
            radiological_criteria_met=ct_list,
            mycological_criteria_met=myco_list,
            antifungal_recommendation=rx_plan,
            voriconazole_tdm_status=tdm_status,
            safety_sentinels=sentinels,
            clinical_idsa_ecil_directive=" ".join(directives)
        )

# Example Execution & Verification
if __name__ == "__main__":
    engine = InvasiveAspergillosisDecisionEngine()

    print("=" * 80)
    print("OpenPHR Clinical Infectious Disease Invasive Aspergillosis & TDM Engine")
    print("=" * 80)

    # Test Case 1: 49-year-old male post-allogeneic HCT with active severe GvHD, ANC 120 (Host Factors).
    # CT Chest: Dense nodule with classic Halo sign + Wedge-shaped consolidation.
    # Mycology: Serum Galactomannan 1.35 (>= 0.5), BAL Galactomannan 2.40 (>= 1.0), PCR Positive.
    # Diagnosis: Probable Invasive Pulmonary Aspergillosis (IPA).
    # Safety: Baseline QTc 495 ms + eGFR 44 mL/min + Voriconazole trough 6.4 mcg/mL (Toxic!).
    # Triage: STAT Hold Voriconazole -> Transition to Isavuconazole 372 mg IV/PO (QTc shortening)!
    ipa1 = AspergillosisPatientTelemetry(
        patient_id="ID-IPA-9901",
        age_years=49.0,
        patient_weight_kg=74.0,
        absolute_neutrophil_count_cells_ul=120.0,
        neutropenia_duration_days=14,
        allogeneic_hct_recipient=True,
        active_graft_versus_host_disease=True,
        systemic_corticosteroid_daily_mg_pred_eq=40.0,
        corticosteroid_duration_days=28,
        ct_dense_well_circumscribed_nodule=True,
        ct_halo_sign_present=True,
        ct_wedge_shaped_consolidation=True,
        serum_galactomannan_odi=1.35,
        bal_galactomannan_odi=2.40,
        aspergillus_pcr_positive=True,
        baseline_qtc_interval_ms=495.0,
        baseline_egfr_ml_min=44.0,
        current_antifungal="Voriconazole",
        voriconazole_trough_mcg_ml=6.4
    )

    rep1 = engine.evaluate_case(ipa1)

    print(f"\n[Patient {rep1.patient_id} - Invasive Aspergillosis Assessment]")
    print(f"EORTC / MSGERC 2020 Stage: {rep1.eortc_msgerc_classification}")
    print("\nHost Factors Met:")
    for h in rep1.host_factors_met:
        print(f"  • {h}")
    print("\nChest CT Imaging Criteria:")
    for c in rep1.radiological_criteria_met:
        print(f"  • {c}")
    print("\nMycological Evidence:")
    for m in rep1.mycological_criteria_met:
        print(f"  • {m}")
    print(f"\nVoriconazole TDM Audit:\n  {rep1.voriconazole_tdm_status}")
    print("\nAntifungal Therapy Recommendations:")
    for rx in rep1.antifungal_recommendation:
        print(f"  {rx}")
    if rep1.safety_sentinels:
        print("\nSafety Sentinels:")
        for s in rep1.safety_sentinels:
            print(f"  🚨 {s}")
    print(f"\nIDSA / ECIL-8 Consensus Directive:\n{rep1.clinical_idsa_ecil_directive}")