IPF (Idiopathic Pulmonary Fibrosis)
Deep-dive monograph: subtype-specific IPF. Overview อยู่ที่เพจ ILD (Interstitial Lung Disease)
1. 🧬 Etiology & Molecular Pathophysiology
IPF ขับเคลื่อนจากการบรรจบกันของ aging biology, genetic predisposition และ environmental hits ส่งผลให้เกิด self-perpetuating fibrotic loop ที่ไม่ตอบสนองต่อ immunosuppression
Genetic architecture:
- MUC5B promoter (rs35705950): ~60% familial, ~38% sporadic IPF vs ~9% population → mucociliary dysfunction → recurrent microinjury; paradoxically associated with better post-dx survival (mechanism debated)
- Telomere genes (TERT, TERC, RTEL1, PARN): ~25% familial IPF → accelerated AEC2 senescence → younger onset + extra-pulmonary telomere syndrome (macrocytosis, liver fibrosis, premature graying)
- SFTPC/SFTPA2: misfolded protein → ER stress → UPR → AEC2 apoptosis
Core cascade: AEC2 injury/senescence → TGF-β1 → TGF-βRI/II (ALK5) → SMAD2/3 phosphorylation → nuclear translocation → COL1A1/COL3A1/fibronectin/α-SMA transcription → fibroblast-to-myofibroblast transition → fibroblastic foci. Wnt/β-catenin pathway activated aberrantly (senescent AEC2 ↓Wnt inhibitor secretion). PDGFR-α/β, FGFR1-3, VEGFR1-3 amplify fibroblast proliferation/survival (nintedanib targets).
PDE4B pathway (nerandomilast target, FDA 2025): PDE4B degrades cAMP in fibroblasts/macrophages/AEC2. ↓cAMP → ↑fibrogenesis. Nerandomilast inhibits PDE4B → ↑cAMP → PKA → phospho-SMAD3 inhibition + ↓IL-6/TNF-α/IL-17 from macrophage — dual antifibrotic + immunomodulatory mechanism
2. 🩺 Clinical Phenotypes & Advanced Nuances
Typical: ชาย > หญิง (~2:1), >60 ปี, ประวัติสูบบุหรี่ (>75%), progressive exertional dyspnea + dry cough นานเฉลี่ย 1–2 ปีก่อนวินิจฉัย
3 disease trajectories:
- Slow progression: FVC decline <5%/yr
- Rapid progression: FVC decline >10%/yr
- AE-IPF: acute worsening <30 days + new bilateral GGO on UIP background + no identifiable cause; DAD superimposed on fibrotic lung; in-hospital mortality 50–80%
CPFE: upper-lobe emphysema + lower-lobe fibrosis → pseudonormal FVC (emphysema compensates restriction) — ต้อง track DLCO ไม่ใช่ FVC เพียงอย่าง; เสี่ยง group 3 PH สูง
IPF + PH: 30–40% ของ IPF; ไม่ตอบสนองต่อเกณฑ์ PAH therapy (STEP-IPF: sildenafil ไม่ improve 6MWD)
GERD/microaspiration: 80% ของ IPF มี GERD แต่ 2022 guideline ไม่แนะนำ routine antacid (RCT: ไม่ improve PFT, เสี่ยง NTM)
3. 🩻 Advanced Diagnostics & Formal Criteria
UIP HRCT tiers (2022 ATS/ERS/JRS/ALAT):
| Pattern | HRCT features | Implication |
|---|---|---|
| UIP | Subpleural+basal; honeycombing ± traction bronchiectasis; heterogeneous | dx IPF ไม่ต้อง biopsy |
| Probable UIP | Subpleural/basal; reticulation + traction bronchiectasis; no honeycombing | 2022: สนับ dx IPF ผ่าน MDD ไม่ต้อง biopsy |
| Indeterminate | Subtle reticulation, non-specific | BAL ± biopsy |
| Alternative dx | GGO/upper-lobe/peribronchovascular/mosaic | → HP/NSIP/OP |
Honeycombing physiology: end-stage cystic remodeling ที่ alveolar structure ถูกแทนด้วย bronchiolar-lined cysts — irreversible architecture, สะท้อน temporal heterogeneity ของ UIP histology
Cryobiopsy (TBLC): acceptable alternative ต่อ VATS ในศูนย์ expertise; tissue ใหญ่กว่า forceps ~10x; pneumothorax ~10%, major bleeding ~1.5% vs VATS mortality ~2%
Genomic classifier: no recommendation for or against (2022)
PFT signature:
| Parameter | Pattern | Physiology |
|---|---|---|
| FVC | ↓ | ↓lung compliance → ↓volume |
| TLC | ↓ | Restriction |
| FEV1/FVC | ≥0.70 (normal/↑) | Proportional reduction |
| DLCO | ↓↓ (most sensitive) | Membrane thickening + ↓surface area |
| 6MWD | ↓ + desaturation | Impaired gas exchange |
Annual FVC ≥10% or DLCO ≥15% → independent poor prognosis marker. Serial PFT ทุก 3–6 เดือน
4. 💊 Management & Pharmacodynamics
Guidelines: ATS/ERS/JRS/ALAT 2022, TSANZ 2023/2024, FDA approval nerandomilast (Jascayd) Oct 2025
Tier 1 — Antifibrotic (start at diagnosis):
- Nintedanib (Ofev) — TKI block VEGFR1-3/PDGFR-αβ/FGFR1-3 → ↓fibroblast proliferation; 150 mg BID กับอาหาร; SE: diarrhea (~60%) → loperamide ± dose reduce 100 mg BID; teratogenic
- Pirfenidone (Esbriet) — ↓TGF-β-mediated collagen/fibroblast (MOA partially debated); 2403 mg/day (801 mg TID) titrate; SE: photosensitivity, nausea; DDI: fluvoxamine (strong CYP1A2 inhibitor)
- Nerandomilast (Jascayd) — FDA approved Oct 2025 — oral preferential PDE4B inhibitor → ↑cAMP → PKA → ↓SMAD3 + ↓macrophage IL-6/TNF-α — dual antifibrotic + immunomodulatory; 18 mg BID (ลดเป็น 9 mg BID ถ้าใช้คู่กับ pirfenidone-DDI); ใช้ร่วมกับ nintedanib ได้; SE: diarrhea (tolerability ดีกว่า nintedanib/pirfenidone; discontinuation ~= placebo)
Tier 2 — Supportive:
- LTOT: resting SpO₂ ≤88% หรือ desaturation ≥4% ระหว่าง 6MWT
- Pulmonary rehabilitation: improve 6MWD + dyspnea (ไม่ improve survival)
- ไม่แนะนำ routine antacid, antireflux surgery (2022 conditional against)
- Sildenafil ใน pure IPF-PH: ไม่แนะนำ (STEP-IPF negative)
Tier 3 — AE-IPF:
- High-dose corticosteroid IV (expert-based, evidence very low)
- Supportive + exclude infection/PE
- Avoid IMV ถ้า prognosis แย่มาก
Tier 4 — Lung Transplantation:
- Bilateral LTx = definitive; IPF = top indication
- ส่งต่อเมื่อ: FVC <80% OR DLCO <40% OR 6MWT desaturation (ไม่ต้องรอ end-stage)
5. 📚 Landmark Trials & Literature
- INPULSIS-1/2 (2014, NEJM) — nintedanib ↓FVC ~50% vs placebo; ↓AE-IPF (INPULSIS-2)
- ASCEND (2014, NEJM) + CAPACITY 1/2 (2011, Lancet) — pirfenidone pivotal
- PANTHER-IPF (2012, NEJM) — triple therapy (pred+aza+NAC) → ↑mortality/hospitalization → immunosuppression อันตรายใน IPF
- STEP-IPF (2010, NEJM) — sildenafil ไม่ improve 6MWD primary endpoint
- FIBRONEER-IPF (2025, NEJM) — nerandomilast 18 mg: FVC −3 vs placebo −170 mL (p<0.001); pooled FIBRONEER: nominally 59% ↓risk of death (18 mg monotherapy, HR 0.41); composite secondary not met → FDA approved Oct 7, 2025
- FIBRONEER-ILD (2025, NEJM) — nerandomilast PPF: FVC −86 vs −152 mL → FDA approved Dec 2025
ข้อถกเถียงเปิด: (1) combine antifibrotics vs monotherapy: FIBRONEER แสดง combination feasible แต่ยังไม่มี head-to-head RCT; (2) senolytic therapy (dasatinib+quercetin) Phase II promising; (3) timing of antifibrotic initiation ใน mild disease (FVC ≥8 0%)
Follow-up log
- (initial creation) deep-dive IPF monograph; includes nerandomilast FDA Oct 2025