Respiratory

Idiopathic pulmonary fibrosis: diagnosis and antifibrotic therapy

Clinical Overview and When to Suspect Idiopathic Pulmonary Fibrosis

— Typically men >60 years, often former smokers

— Prevalence rises sharply after age 65; rare before 50 (consider familial pulmonary fibrosis or connective tissue disease if younger)

— Median survival historically 3–5 years from diagnosis without antifibrotic therapy

— Older adult with unexplained chronic dyspnea on exertion >3–6 months and a nonproductive cough

— Bibasilar fine "Velcro" inspiratory crackles on exam

— Digital clubbing (~25–50%)

— Restrictive pattern on PFTs with reduced DLCO

— HRCT showing basal, subpleural reticulation, traction bronchiectasis, and honeycombing

— Cigarette smoking, occupational dust (metal, wood), chronic microaspiration/GERD

— Genetic: telomere shortening syndromes (TERT, TERC), MUC5B promoter polymorphism

— Family history in ~20% → ask about relatives with "pulmonary fibrosis"

— Connective tissue disease (RA, scleroderma, myositis, Sjögren)

— Chronic hypersensitivity pneumonitis (bird, mold exposure)

— Drug-induced (amiodarone, methotrexate, nitrofurantoin, bleomycin)

— Pneumoconioses (asbestosis, silicosis)

Board pearl: A 68-year-old man with insidious exertional dyspnea, dry cough, clubbing, and Velcro crackles is IPF until HRCT and serologies prove otherwise — do not anchor on "CHF" or "COPD" without imaging.

Definition: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia of unknown cause, limited to the lungs, and defined histopathologically or radiographically by the usual interstitial pneumonia (UIP) pattern.

Epidemiology:

When to suspect on Step 3:

Risk factors / associations:

Step 3 framing: IPF is a diagnosis of exclusion. Before labeling, you must rule out:

Trajectory: Gradual decline punctuated by acute exacerbations (rapid hypoxemic decompensation without identifiable cause) carrying ~50% in-hospital mortality.

Presentation Patterns and Key History

— Exertional dyspnea progressing over months to years — patients often misattribute to aging or deconditioning, leading to delayed diagnosis (median 1–2 years from symptom onset)

— Chronic nonproductive cough, often refractory to antitussives, bronchodilators, PPIs, and ICS — a major quality-of-life burden

— Fatigue, weight loss in advanced disease

— Absence of fevers, hemoptysis, pleuritic pain, or systemic features should be the rule — their presence pushes you toward alternative diagnoses

— Occupational/environmental: asbestos, silica, coal, beryllium, hard metal; birds (pigeons, parakeets), down bedding, hot tubs, moldy environments → hypersensitivity pneumonitis

— Medications: amiodarone, methotrexate, nitrofurantoin, bleomycin, checkpoint inhibitors, statins (rare)

— Connective tissue review of systems: Raynaud, sicca, dysphagia, skin tightening, arthralgias, myalgias, rash (Gottron, heliotrope, mechanic's hands), proximal weakness

— Family history: pulmonary fibrosis, premature graying, cryptogenic cirrhosis, bone marrow failure (telomere syndromes)

— Smoking history and pack-years

— Reflux/microaspiration symptoms

— Quantify dyspnea (mMRC), 6-minute walk distance, oxygen requirement at rest and ambulation

— Track over visits — decline of ≥10% in FVC or ≥15% in DLCO over 6–12 months indicates progression and worse prognosis

Step 3 management: At the initial outpatient visit, document a structured exposure history and CTD review — failing to do so is the most common reason a "UIP" pattern is mislabeled as IPF when it is actually chronic HP or scleroderma-ILD, which have very different management.

Cardinal symptoms:

Targeted history (mandatory before diagnosing IPF):

Functional assessment for management decisions:

Comorbidity screen: pulmonary hypertension, OSA, emphysema (combined pulmonary fibrosis and emphysema syndrome), CAD, depression, lung cancer (3–7× risk in IPF).

Physical Exam Findings and Hemodynamic Assessment

— Bibasilar, fine, dry, end-inspiratory "Velcro" crackles — heard best at the posterior lung bases; do not clear with cough; present in >80% of IPF patients

— As disease progresses, crackles extend upward — bilateral, symmetric distribution

— Absence of wheeze or rhonchi (their presence suggests airway disease or alternative ILD)

— Digital clubbing in 25–50% — late finding, also seen in bronchiectasis, lung cancer, cyanotic heart disease

— Cyanosis with advanced hypoxemia

— No skin rashes, synovitis, sclerodactyly, telangiectasias, or muscle weakness — their presence redirects you to a CTD-ILD

— Loud P2, right-sided S3 or S4, parasternal heave, elevated JVP with prominent a wave, hepatojugular reflux

— Peripheral edema, ascites in cor pulmonale

— Disproportionate hypoxemia or DLCO reduction relative to FVC is a clue to PH out of proportion to fibrosis

— 6-minute walk test (6MWT): distance, nadir SpO2, recovery — desaturation <88% predicts mortality and qualifies for supplemental O2

— Resting and ambulatory pulse oximetry at every visit

— Fever, lymphadenopathy → infection, sarcoidosis, lymphoma

— Eye/mucosal involvement → sarcoid, vasculitis

— Acute mono- or oligoarthritis → CTD, infection

— Unilateral findings or pleural effusion → not IPF; reconsider

Key distinction: Velcro crackles in IPF are fine, dry, and gravity-dependent (bases), distinguishing them from the coarse, wet crackles of pulmonary edema (which shift with diuresis) and the mid-inspiratory squeaks of hypersensitivity pneumonitis. Bedside auscultation done well still narrows the ILD differential meaningfully on the wards.

Pulmonary exam — the classic triad:

Extrapulmonary:

Signs of pulmonary hypertension (develops in 30–50% as disease advances):

Functional bedside assessment:

Things you should NOT see (red flags for alternative diagnosis):

Diagnostic Workup — Initial Labs, Imaging, and PFTs

— Restrictive pattern: ↓ FVC, ↓ TLC, ↓ FRC, ↓ RV; FEV1/FVC normal or elevated (>0.70)

— Reduced DLCO — often the earliest and most sensitive abnormality; may be reduced before FVC drops

— 6MWT with desaturation <88% → poor prognosis, oxygen qualification

— Arterial blood gas may show hypoxemia with widened A–a gradient; hypercapnia is late

— Bibasilar reticular opacities, reduced lung volumes — insensitive; never sufficient to diagnose IPF

— Thin-slice (≤1.5 mm), supine + prone, inspiratory + expiratory cuts

— Definite UIP pattern: bilateral, basal and subpleural reticulation with honeycombing, often with traction bronchiectasis/bronchiolectasis, absence of features suggesting alternative diagnosis (extensive ground-glass, nodules, mosaic attenuation/air trapping, cysts away from honeycombing, peribronchovascular predominance)

— Categories per ATS/ERS/JRS/ALAT 2022: UIP, probable UIP, indeterminate for UIP, alternative diagnosis

— A definite UIP HRCT pattern + appropriate clinical context = no biopsy needed

— ANA, RF, anti-CCP — if positive, expand (anti-Scl-70, anti-centromere, anti-Jo-1 and myositis panel, anti-Ro/La)

— CK, aldolase if myositis suspected

— Hypersensitivity pneumonitis panel (serum precipitins) when exposure history suggestive

— CBC, CMP, urinalysis (vasculitis screen if indicated)

— Echocardiogram at baseline to screen for pulmonary hypertension and assess LV/RV function

— BNP if PH suspected

— Consider sleep study — OSA prevalent and worsens outcomes

Board pearl: A normal FEV1/FVC with reduced FVC and reduced DLCO in an older patient with basilar crackles is the PFT fingerprint of ILD. Order HRCT next — not spirometry repeat, not echo first.

Pulmonary function tests (cornerstone):

Chest X-ray:

High-resolution CT (HRCT) — the central test:

Laboratory exclusion of CTD and HP (every patient):

Ancillary:

Diagnostic Workup — Advanced and Confirmatory Studies

— Gold standard for diagnosis — pulmonologist + thoracic radiologist + pathologist (± rheumatologist)

— Integrates clinical, HRCT, serologic, and (when needed) histologic data

— Required when HRCT is probable UIP, indeterminate, or alternative, or when clinical features are atypical

— Not routinely needed if HRCT is definite UIP

— Useful when hypersensitivity pneumonitis or sarcoidosis is suspected — BAL lymphocytosis >30% argues against IPF

— Excludes infection in acute exacerbations or atypical presentations

— Indicated when HRCT is not definite UIP and diagnosis remains uncertain after MDD

— Transbronchial lung cryobiopsy (TBLC) — increasingly first-line, lower morbidity than surgical

— Surgical lung biopsy (VATS) — diagnostic gold standard but ~2% mortality; reserve for selected patients with adequate reserve (FVC, DLCO, no severe PH)

— Avoid biopsy in patients with definite UIP on HRCT, severe physiologic impairment, significant comorbidity, or active acute exacerbation

— Spatial and temporal heterogeneity — normal lung adjacent to fibrosis adjacent to honeycombing

— Fibroblast foci (active fibrogenesis)

— Subpleural and paraseptal accentuation

— Absent: granulomas, prominent inflammation, vasculitis (their presence → alternative diagnosis)

— Consider in familial pulmonary fibrosis (≥2 affected first-/second-degree relatives), early-onset disease, or extrapulmonary features of telomere syndrome (premature graying, cytopenias, cryptogenic cirrhosis)

— Refer for genetic counseling before testing

Step 3 management: When HRCT shows definite UIP in a 70-year-old with classic clinical features and negative CTD serologies, the next step is referral to a pulmonologist for antifibrotic initiation, not lung biopsy. Biopsy is reserved for diagnostic ambiguity, and only in patients who can tolerate it.

Multidisciplinary discussion (MDD):

Bronchoscopy with BAL:

Lung biopsy — when and how:

Histopathology of UIP:

Genetic testing:

Risk Stratification and Management Logic

— GAP index (Gender, Age, Physiology [FVC, DLCO]) — stratifies into stages I–III with 1-, 2-, 3-year mortality estimates; widely used and high-yield

— Stage I (0–3 points): 1-yr mortality ~6%

— Stage II (4–5): ~16%

— Stage III (6–8): ~39%

— FVC decline ≥10% or DLCO decline ≥15% over 6–12 months

— 6MWT desaturation <88% or distance <250 m

— Pulmonary hypertension on echo or RHC

— Honeycombing extent on HRCT

— Acute exacerbation history

— 1. Antifibrotic therapy — pirfenidone or nintedanib for all patients with confirmed IPF and measurable lung function; goal is to slow FVC decline (does not improve symptoms or reverse disease)

— 2. Supportive / symptom care — supplemental O2 for resting or exertional hypoxemia, pulmonary rehab, vaccinations (influenza, pneumococcal, COVID-19, RSV), GERD treatment when symptomatic, cough management

— 3. Lung transplant evaluation — refer early, at the time of diagnosis for appropriate candidates (typically <70 yrs, limited comorbidity); IPF is the leading indication for lung transplant in the US

— Triple therapy (prednisone + azathioprine + N-acetylcysteine) — PANTHER-IPF trial showed increased mortality and hospitalization → avoid

— Warfarin (without other indication) — harmful in IPF

— Ambrisentan — harmful in IPF

— Sildenafil monotherapy — not recommended routinely

Board pearl: Steroids + immunosuppression for IPF = wrong answer. Steroids for an acute exacerbation of IPF or for NSIP/CTD-ILD = often correct. Know which ILD you're treating.

Prognostic tools:

Markers of progression / poor prognosis:

Management framework — three parallel tracks:

Things NOT to use (historically tried, now contraindicated):

Shared decision-making: Discuss prognosis honestly, goals of care, advance directives — many patients are diagnosed late and decline rapidly.

Pharmacotherapy — Antifibrotic First-Line Regimens

— Mechanism: Pleiotropic antifibrotic — inhibits TGF-β–mediated fibroblast proliferation and collagen synthesis

— Dosing: Titrate over 2 weeks to 801 mg PO TID with food

— Key adverse effects:

— — Photosensitivity rash — daily broad-spectrum sunscreen, sun-protective clothing, sun avoidance — counsel at every visit

— — GI: nausea, anorexia, weight loss, dyspepsia — take with food, dose-adjust

— — Hepatotoxicity → check LFTs at baseline, monthly × 6 months, then quarterly

— — Fatigue, dizziness

— Interactions: CYP1A2 substrate — avoid strong inhibitors (fluvoxamine, ciprofloxacin); smoking induces CYP1A2 and reduces levels

— Contraindication: severe hepatic impairment

— Mechanism: Intracellular tyrosine kinase inhibitor (VEGFR, FGFR, PDGFR) → blocks fibroblast proliferation and migration

— Dosing: 150 mg PO BID with food (100 mg BID if intolerant or hepatic concerns)

— Key adverse effects:

— — Diarrhea (~60%) — loperamide PRN, hydration, dose reduction; most common reason for discontinuation

— — Nausea, vomiting, weight loss

— — Hepatotoxicity → LFTs at baseline, monthly × 3 months, then quarterly

— — Bleeding risk — caution with anticoagulation, NSAIDs

— — Arterial thromboembolic events, GI perforation (rare)

— Interactions: P-glycoprotein substrate — avoid strong inhibitors (ketoconazole, erythromycin) and inducers (rifampin, phenytoin)

— Pregnancy category: teratogenic — contraception required

— Reduce annual FVC decline by ~50% (≈ 100 mL/yr vs 200 mL/yr placebo)

— Trends toward reduced acute exacerbations and mortality

— Do not improve symptoms, cough, or quality of life directly

Step 3 management: Pick pirfenidone for a patient with significant GI disease or anticoagulation; pick nintedanib for a patient who works outdoors or cannot reliably use photoprotection. Counseling on side effects up front determines adherence.

Two FDA-approved antifibrotics; choose based on side-effect profile and comorbidities (no head-to-head superiority):

Pirfenidone:

Nintedanib:

Efficacy (both drugs):

Adjunctive Pharmacology and Non-Antifibrotic Management

— Resting SpO2 ≤88% (or PaO2 ≤55 mm Hg) → continuous supplemental O2 (Medicare criteria)

— Exertional desaturation <88% on 6MWT → ambulatory O2 — improves exercise tolerance and reduces dyspnea

— Nocturnal O2 if isolated nighttime desaturation

— Recommended for all symptomatic IPF patients regardless of severity

— Improves 6MWT distance, dyspnea, quality of life

— Re-refer periodically; benefits wane after 6–12 months

— Treat symptomatic reflux with PPI/H2RA and lifestyle measures

— Do not routinely prescribe PPIs for asymptomatic patients (recent data show possible harm and increased infection risk)

— Refer for fundoplication only in highly selected refractory cases

— Often refractory and disabling

— Trial of low-dose opioids (e.g., morphine 5 mg PO BID), gabapentin, or thalidomide in select cases

— Treat coexisting postnasal drip, GERD, and asthma

— Annual influenza, pneumococcal (PCV20 or PCV15+PPSV23), COVID-19 boosters, RSV (≥60), Tdap, zoster (≥50)

— Treat coexisting OSA with CPAP

— Screen and treat depression/anxiety

— Smoking cessation — essential

— Screen for lung cancer clinically; LDCT screening if eligible (use clinical judgment given competing mortality)

— Defined as acute (<1 month) worsening dyspnea with new bilateral ground-glass/consolidation on HRCT, not explained by infection, PE, CHF, or other identifiable cause

— High-dose corticosteroids (e.g., methylprednisolone pulse) commonly used despite weak evidence

— Broad-spectrum antibiotics empirically while workup pending

— Exclude PE, CHF, infection (BAL if feasible)

— High mortality (~50%) — discuss goals of care

CCS pearl: For an inpatient IPF exacerbation, order HRCT, blood/sputum cultures, respiratory viral PCR, CTPA, BNP, echo, and ABG; start empiric antibiotics and methylprednisolone; consult pulmonology; address code status early.

Oxygen therapy:

Pulmonary rehabilitation:

GERD management:

Cough:

Vaccinations (every patient):

Comorbidity management:

Acute exacerbation management:

Special Populations — Elderly and Renal/Hepatic Impairment

— Median age at diagnosis ~70 — most patients are elderly; "special population" considerations are essentially the default

— Polypharmacy: carefully review for interactions with antifibrotics (warfarin, NSAIDs with nintedanib bleeding risk; CYP1A2 substrates/inhibitors with pirfenidone)

— Frailty assessment before transplant referral or aggressive therapy

— Falls risk from dizziness (both drugs), hypoxemia, deconditioning — recommend home safety eval and pulmonary rehab

— Cognitive screening — ensure ability to adhere to complex titration schedules; involve caregivers

— Goals-of-care discussions are central — many elderly patients prioritize symptom control over modest FVC preservation

— Pirfenidone: No dose adjustment for mild–moderate impairment (CrCl ≥30); avoid in CrCl <30 or dialysis — limited data

— Nintedanib: No dose adjustment for mild–moderate (CrCl ≥30); not studied in severe renal impairment or dialysis — use cautiously; both drugs have low renal clearance but data are limited

— Pirfenidone:

— — Mild (Child-Pugh A): no adjustment but monitor LFTs closely

— — Moderate (Child-Pugh B): use with caution

— — Severe (Child-Pugh C): contraindicated

— Nintedanib:

— — Mild (Child-Pugh A): reduce dose to 100 mg BID

— — Moderate–severe (Child-Pugh B/C): not recommended

— Both: hold for ALT/AST >5× ULN or any LFT elevation with symptoms; restart at reduced dose if levels normalize

— Often elderly male smokers

— PFTs may show pseudo-normalized FVC (emphysema increases volumes, fibrosis decreases them) — DLCO is severely reduced and the most reliable marker

— High risk for pulmonary hypertension and lung cancer

— Antifibrotics still indicated when IPF features predominate

Board pearl: When IPF coexists with emphysema and the FVC looks "normal," do not be reassured — track DLCO and 6MWT, which reveal the true physiologic burden.

Elderly (the typical IPF demographic):

Renal impairment:

Hepatic impairment:

Combined pulmonary fibrosis and emphysema (CPFE):

Special Populations — Familial Disease, Younger Patients, and Pregnancy

— Defined as ≥2 family members (first/second degree) with idiopathic interstitial pneumonia

— Accounts for ~20% of IPF

— Genetic causes: telomere-related genes (TERT, TERC, RTEL1, PARN), surfactant protein genes (SFTPC, SFTPA2), MUC5B promoter variant

— Telomere syndrome clues: premature graying (<30), bone marrow failure, cryptogenic cirrhosis, macrocytosis, immunodeficiency

— Refer for genetic counseling before testing; implications for relatives, transplant donors, and cytotoxic therapy tolerance

— Telomere-short patients have poor tolerance of immunosuppression post-transplant (cytopenias, infections)

— IPF is unusual — work harder to exclude CTD-ILD, chronic HP, familial pulmonary fibrosis, sarcoidosis, drug-induced ILD, and pneumoconiosis

— Aggressive transplant evaluation if confirmed

— IPF rarely occurs in reproductive-age women; if so, consider familial/genetic causes

— Nintedanib: teratogenic (animal data) — contraindicated in pregnancy; effective contraception required during therapy and for at least 3 months after discontinuation; may reduce hormonal contraceptive efficacy → use barrier method or non-hormonal IUD

— Pirfenidone: limited human data, animal embryotoxicity at high doses — avoid in pregnancy

— Lactation: both drugs not recommended during breastfeeding

— Preconception counseling essential

— Not IPF — pediatric ILDs are distinct entities (surfactant disorders, neuroendocrine cell hyperplasia of infancy, ABCA3 deficiency)

— Refer to pediatric pulmonology

— Refer at diagnosis if patient is potentially eligible — waitlist times vary

— Relative contraindications: age >70 (program-dependent), severe comorbidity, active malignancy, BMI >35 or <17, active substance use, nonadherence

— Telomere syndromes complicate post-transplant immunosuppression

Key distinction: A 45-year-old with "IPF" should make you stop and rethink — familial pulmonary fibrosis, CTD-ILD, or chronic HP are far more likely, and management diverges substantially.

Familial pulmonary fibrosis (FPF):

Younger patients (<50):

Pregnancy:

Pediatric ILD:

Lung transplant candidacy:

Complications and Adverse Outcomes

— Acute (<1 month) worsening of dyspnea with new bilateral ground-glass/consolidation on HRCT, not fully explained by infection, CHF, PE, or other cause

— Triggers: infection, microaspiration, post-procedure (biopsy, surgery), idiopathic

— In-hospital mortality ~50%; 1-year mortality after AE >80%

— Major reason for early goals-of-care discussions

— Group 3 PH (due to lung disease) — develops in 30–50% of advanced IPF

— Suspect when DLCO is disproportionately low relative to FVC, with exertional desaturation or RV strain on echo

— RHC for confirmation if transplant candidate or considering targeted therapy

— Avoid ambrisentan and routine PDE5 inhibitors — ambrisentan harmful; sildenafil not routinely recommended

— Inhaled treprostinil approved for PH associated with ILD (INCREASE trial)

— 3–7× increased risk vs general population

— Often peripheral, in areas of fibrosis; harder to diagnose

— Biopsy and resection carry increased risk of acute exacerbation

— Elevated incidence; consider in any acute worsening of dyspnea or hypoxemia

— Routine prophylactic anticoagulation not indicated outside standard indications

— Late complication of chronic hypoxemia and PH

— Manage with diuretics, oxygen; avoid afterload-reducing agents that worsen V/Q mismatch

— Pneumonia (bacterial, viral, atypical) — vaccinate aggressively

— Increased COVID-19 mortality

— Pirfenidone: photosensitivity, GI upset, hepatotoxicity

— Nintedanib: diarrhea, bleeding, hepatotoxicity, rare GI perforation

— Oxygen: nasal mucosal injury, mobility limitations, psychosocial burden

— Depression, anxiety, social isolation, caregiver burden

— Refractory cough significantly impairs QOL

Board pearl: In an IPF patient with sudden worsening dyspnea, the differential is infection, PE, CHF, pneumothorax, and acute exacerbation — always rule out the first four before labeling AE-IPF.

Acute exacerbation of IPF (AE-IPF):

Pulmonary hypertension (PH):

Lung cancer:

Venous thromboembolism:

Cor pulmonale and right heart failure:

Infections:

Iatrogenic / treatment-related:

Quality of life / psychosocial:

When to Escalate Care — ICU, Consults, and Inpatient Triage

— All suspected IPF — for MDD, antifibrotic initiation, monitoring

— Co-manage with primary care

— At diagnosis for candidates: age <70 (program-specific), limited comorbidity, motivated, adequate social support

— Listing criteria: DLCO <40%, FVC decline ≥10% over 6 months, SpO2 <88% on 6MWT, hospitalization for AE, pulmonary hypertension

— Acute exacerbation with hypoxemia

— New oxygen requirement

— Pneumonia or other infection

— Suspected PE

— Cor pulmonale decompensation

— Respiratory failure requiring high-flow nasal cannula or non-invasive ventilation

— Hemodynamic instability

— Mechanical ventilation in advanced IPF carries very poor prognosis (>90% mortality) — must be discussed in context of goals of care; many patients and clinicians choose to forgo intubation

— HFNC may be preferred as a comfort-oriented bridge

— Pulmonology — always

— Thoracic radiology and pathology — MDD

— Rheumatology — if any CTD features

— Cardiology — for PH, RV dysfunction

— Palliative care — early integration improves symptom control and end-of-life outcomes; appropriate at diagnosis, not just terminal phase

— Transplant pulmonology — early referral

— Genetics — familial cases

— Stable oxygen needs for 24–48 hrs

— Tolerating oral intake and medications

— Clear follow-up plan with pulmonology within 1–2 weeks

— Home oxygen arranged, caregiver support assessed

— Advance directive reviewed

CCS pearl: For severe AE-IPF, the highest-yield early CCS orders are: HRCT, CTPA, BNP, troponin, blood and sputum cultures, respiratory viral PCR, ABG, methylprednisolone IV, broad-spectrum antibiotics, HFNC, pulmonary consult, and goals-of-care discussion documented. Forgetting the last item costs points.

Outpatient pulmonology referral (essential at diagnosis):

Lung transplant center referral:

Admit (general medicine/pulmonary):

ICU triage:

Consults:

Discharge readiness criteria after AE-IPF:

Key Differentials — Other Interstitial Lung Diseases

— More common in women, younger (40s–50s), nonsmokers, often associated with CTD (especially scleroderma, polymyositis/dermatomyositis, anti-synthetase)

— HRCT: bilateral, symmetric, basal ground-glass with reticulation; subpleural sparing; minimal/no honeycombing

— Histology: temporal and spatial homogeneity (opposite of UIP)

— Responds to corticosteroids and immunosuppression — very different management from IPF

— Exposure to organic antigens (birds, mold, hot tubs, isocyanates)

— HRCT: mid-to-upper lung predominance, mosaic attenuation, air trapping on expiration, centrilobular nodules, fibrosis in chronic stage

— BAL lymphocytosis (often >40%)

— Treatment: antigen avoidance (mandatory), steroids, immunosuppression; antifibrotics for progressive fibrotic HP

— Serologies positive; extrapulmonary features present

— Often NSIP pattern, but UIP can occur (esp. RA-ILD)

— Treatment: immunosuppression (mycophenolate, rituximab, tocilizumab in SSc-ILD); nintedanib also approved for SSc-ILD and progressive fibrosing ILDs

— Upper lobe predominance, hilar lymphadenopathy, perilymphatic nodules, granulomas

— Multisystem (skin, eye, cardiac, neurologic)

— Asbestosis: lower lobe fibrosis + pleural plaques — exposure history (shipyards, insulation, brake mechanics)

— Silicosis: upper lobe nodules, eggshell calcified lymph nodes

— Coal workers' pneumoconiosis: upper lobe nodules

— Amiodarone, methotrexate, nitrofurantoin, bleomycin, checkpoint inhibitors

— Stop offending agent; consider steroids

— Smokers; upper lobe ground-glass; smoking cessation is primary treatment

Key distinction: NSIP and CTD-ILD respond to steroids/immunosuppression; IPF does not, and immunosuppression worsens outcomes. Getting the ILD subtype right before prescribing prednisone is the most important decision in this differential.

Nonspecific interstitial pneumonia (NSIP):

Chronic hypersensitivity pneumonitis (HP):

CTD-ILD (RA, SSc, MCTD, Sjögren, myositis):

Sarcoidosis (fibrotic stage IV):

Pneumoconioses:

Drug-induced ILD:

Desquamative interstitial pneumonia (DIP) / RB-ILD:

Key Differentials — Non-ILD Mimics

— Dyspnea, bibasilar crackles, exertional limitation — overlaps clinically with IPF

— Clues: orthopnea, PND, elevated JVP, S3, peripheral edema, elevated BNP/NT-proBNP, cardiomegaly and Kerley B lines on CXR

— Echo distinguishes; HRCT in CHF shows interlobular septal thickening, ground-glass, pleural effusions — no honeycombing

— Diuretic trial clarifies in ambiguous cases

— Smokers, obstructive PFTs (FEV1/FVC <0.70), hyperinflation, decreased DLCO

— Wheezes/rhonchi rather than Velcro crackles

— May coexist with IPF (CPFE)

— Chronic productive cough with purulent sputum, recurrent infections, hemoptysis

— HRCT: airway dilation, tree-in-bud, mucous plugging — not reticulation/honeycombing

— Clubbing can occur

— Progressive dyspnea, PH out of proportion to parenchymal disease

— V/Q scan with segmental mismatched defects; CTPA for confirmation

— Subacute dyspnea, weight loss, smoking history

— HRCT: nodular interlobular septal thickening, often unilateral; mediastinal lymphadenopathy

— Tissue diagnosis required

— TB, nontuberculous mycobacteria, PJP, fungal — exposure history, immunosuppression, fevers, BAL/cultures

— "Crazy paving" on HRCT; milky BAL; whole-lung lavage treatment

— Peripheral eosinophilia, BAL eosinophilia, often steroid-responsive

— "Photographic negative of pulmonary edema" on CXR (chronic form)

— Young smokers, upper lobe cysts and nodules

Board pearl: Always order BNP and echo in an older patient with dyspnea and crackles before committing to an ILD diagnosis — CHF is the most common mimic, and treating fluid overload often dramatically clarifies the picture.

Congestive heart failure (HFpEF or HFrEF):

COPD/emphysema:

Bronchiectasis:

Chronic pulmonary thromboembolic disease:

Lung cancer (especially lymphangitic carcinomatosis):

Atypical/subacute infections:

Pulmonary alveolar proteinosis:

Eosinophilic pneumonia:

Pulmonary Langerhans cell histiocytosis:

Long-Term Plan, Secondary Prevention, and Discharge Medications

— Antifibrotic (pirfenidone or nintedanib) — indefinitely, until transplant, intolerance, or end-of-life transition

— Supplemental oxygen as needed (resting, ambulatory, nocturnal)

— Pulmonary rehabilitation — refer at diagnosis and periodically thereafter

— Vaccinations kept current

— Lung transplant evaluation — early referral

— Smoking cessation — mandatory; offer pharmacotherapy (varenicline, nicotine replacement, bupropion) and behavioral support

— Avoid occupational/environmental exposures that worsen disease (dusts, organic antigens, asbestos)

— Treat symptomatic GERD; sleep upright if microaspiration suspected

— Treat OSA with CPAP

— Resume or initiate antifibrotic (if not already)

— Steroid taper if started during admission (course varies)

— Home oxygen with appropriate flow rate, including ambulatory and nocturnal

— PPI only if symptomatic GERD

— Cough suppressant (low-dose opioid, gabapentin) if disabling

— Anxiolytic/antidepressant if indicated

— Review and reconcile — discontinue harmful agents (e.g., inappropriate immunosuppression, ambrisentan, warfarin without other indication)

— Code status, intubation preferences, hospice eligibility

— Documented in chart, shared with family

— Discuss before crisis — not in the ICU

— Pulmonary fibrosis support groups, social work involvement, financial counseling for high-cost antifibrotics (manufacturer assistance programs)

— Maintain age- and risk-appropriate cancer screening; balance against limited life expectancy

— Monitor for new pulmonary nodules on serial HRCT

Step 3 management: At every IPF clinic visit, address the "five pillars": antifibrotic adherence/tolerance, oxygen needs, pulmonary rehab, vaccination status, and goals-of-care/transplant trajectory. Missing one pillar is the most common longitudinal failure mode.

Core long-term regimen for confirmed IPF:

Modifiable risk reduction:

Discharge medications after acute exacerbation hospitalization:

Advance care planning (every patient, every major decision point):

Caregiver and psychosocial support:

Cancer surveillance:

Follow-Up, Monitoring, and Rehabilitation

— Pulmonology visits every 3–6 months for stable disease; more often if progressing or recently started on antifibrotic

— Primary care concurrent for comorbidity management

— Spirometry and DLCO every 3–6 months — track FVC, DLCO trajectory; FVC decline ≥10% or DLCO decline ≥15% over 6–12 months signals progression

— 6-minute walk test every 6 months — distance and nadir SpO2

— Symptom assessment: dyspnea (mMRC), cough, fatigue

— HRCT not routinely repeated unless clinical change or transplant evaluation

— Echo annually or with symptom change to screen for PH

— LFTs:

— — Pirfenidone: baseline, monthly × 6 months, then quarterly

— — Nintedanib: baseline, monthly × 3 months, then quarterly

— Hold for ALT/AST >3× ULN with symptoms or >5× ULN regardless; resume at reduced dose when normalized

— Pregnancy testing in women of reproductive age on nintedanib

— Adherence and tolerability — GI side effects, photosensitivity, weight loss

— Initial 8–12 week program with supervised exercise, breathing techniques, education, nutrition, psychosocial support

— Improves 6MWT, dyspnea, QOL

— Maintenance program or home-based continuation thereafter

— Sun protection (pirfenidone), GI management (nintedanib)

— Vaccination schedule

— Infection prevention (hand hygiene, masking in high-risk settings)

— Energy conservation, pacing, durable medical equipment

— Driving safety with portable oxygen

— Travel: altitude precautions, in-flight O2 needs (preflight assessment if SpO2 <95% at sea level)

— Sexual health and intimacy with chronic respiratory disease

— End-of-life conversations revisited periodically

— Early co-management (not end-stage only) improves dyspnea, cough, anxiety, and family satisfaction

Board pearl: An FVC drop of 12% over 6 months in an IPF patient on pirfenidone defines disease progression — the right move is not necessarily to switch antifibrotic, but to reassess transplant candidacy, optimize supportive care, and re-engage palliative care.

Routine follow-up cadence:

Disease monitoring at each visit:

Antifibrotic-specific monitoring:

Pulmonary rehabilitation:

Counseling topics longitudinally:

Palliative care integration:

Ethical, Legal, and Patient Safety Considerations

— Patients must understand that pirfenidone and nintedanib slow progression but do not improve symptoms or reverse fibrosis — managing expectations is core to informed consent

— Document discussion of GI, hepatic, photosensitivity, bleeding, and teratogenicity risks

— Cost — both drugs ~$100,000/year; ensure financial counseling, manufacturer assistance program enrollment before initiation to avoid mid-therapy abandonment

— IPF has a uniformly poor prognosis with rapid potential for catastrophic exacerbation

— Discuss intubation, CPR, hospice, and surrogate decision-maker at diagnosis, not in the ICU

— Mechanical ventilation in advanced IPF: mortality >90% — patients have a right to informed refusal; this conversation belongs in the outpatient clinic

— Document POLST/MOLST forms appropriate to state

— Hospital → home after AE-IPF is a high-risk transition: medication reconciliation (continue antifibrotic? steroid taper plan?), oxygen setup verified before discharge, follow-up appointment within 1–2 weeks, written instructions including warning signs

— Communicate explicitly with outpatient pulmonologist and PCP

— Counsel on smoking near oxygen (fire risk), open flames, secure tank transport

— Hypoxemia-related cognitive impairment may affect driving safety

— Pre-test counseling on implications for relatives, insurance (GINA protects health but not life/disability insurance), reproductive decisions

— Informed consent for genetic testing required

— Many IPF patients are eligible for trials; discuss as a therapeutic option, especially with progression on standard antifibrotics

— Ensure voluntary, informed participation; address therapeutic misconception

— If asbestos, silica, or other occupational exposure identified, document and report per state workers' compensation rules; patient may have legal/financial recourse

Step 3 management: A patient with FVC 45% predicted refusing intubation in advance is exercising autonomy — your job is to ensure the refusal is informed (prognosis discussed, alternatives offered, capacity intact, documented) and to mobilize palliative resources, not to override.

Informed consent for antifibrotic therapy:

Advance directives and goals of care:

Transition-of-care safety:

Driving and oxygen safety:

Genetic testing ethics (familial PF):

Clinical trial participation:

Mandatory reporting and occupational disease:

High-Yield Associations and Rapid-Fire Clinical Facts

Board pearl: If the question stem says "definite UIP pattern on HRCT" in an older patient without CTD features → diagnose IPF, start antifibrotic, refer for transplant, no biopsy needed.

Demographics: Older (>60), male predominance, smokers, white > other races

Genetics: MUC5B promoter variant (most common genetic risk factor), telomere genes (TERT, TERC, RTEL1, PARN), surfactant protein genes

Classic exam: Velcro crackles + clubbing + dry cough + insidious dyspnea

Pattern on HRCT for "definite UIP": basal, subpleural, reticulation + honeycombing + traction bronchiectasis, no atypical features

Histology buzzwords: fibroblast foci, spatial and temporal heterogeneity, honeycomb cysts

PFTs: restrictive (↓FVC, ↓TLC), preserved FEV1/FVC ratio, reduced DLCO

Worst prognostic features: ↓FVC ≥10%/6 mo, ↓DLCO ≥15%/6 mo, 6MWT SpO2 <88%, PH, AE-IPF, honeycombing extent

GAP index — Gender, Age, Physiology (FVC, DLCO) — mortality predictor

Antifibrotics: pirfenidone (CYP1A2, photosensitivity), nintedanib (TKI, diarrhea, bleeding, teratogenic)

Both reduce FVC decline by ~50%; neither improves symptoms

DO NOT USE: prednisone + azathioprine + NAC (PANTHER-IPF harm), warfarin without other indication, ambrisentan

Acute exacerbation: new bilateral GGO without identifiable cause; 50% in-hospital mortality

Transplant: leading indication for lung transplant in the US; refer at diagnosis

PH in IPF: Group 3; inhaled treprostinil (INCREASE trial) approved for PH-ILD

Vaccinations: influenza, pneumococcal, COVID-19, RSV, Tdap, zoster

GERD: treat symptomatic only; do not prescribe PPI prophylactically to all

CPFE: preserved FVC but severely reduced DLCO; high PH and lung cancer risk

Lung cancer risk: 3–7× general population; biopsy/resection risk AE-IPF

Familial PF: ≥2 relatives affected; 20% of IPF; consider telomere syndrome clues

Avoid mechanical ventilation in advanced IPF when goals align — mortality >90%

Palliative care: integrate early, not at end stage only

Refractory cough: consider low-dose opioids, gabapentin

MDD diagnosis: pulmonologist + radiologist + pathologist — gold standard

Biopsy: TBLC or VATS only when HRCT not definite UIP; avoid in poor reserve

Board Question Stem Patterns

— 68-year-old former smoker, 18-month dry cough, exertional dyspnea, Velcro crackles, clubbing; FVC 65%, DLCO 50%, FEV1/FVC 0.82; HRCT basal subpleural honeycombing

— Question: Most likely diagnosis? → IPF

— Next step? → Negative CTD serologies + multidisciplinary discussion → start nintedanib or pirfenidone; refer for lung transplant evaluation

— IPF patient asks about prednisone or is started on prednisone + azathioprine + NAC

— Correct answer: Discontinue — PANTHER-IPF showed increased mortality

— IPF patient on pirfenidone develops sunburn-like rash after gardening → photosensitivity; counsel on sunscreen, sun avoidance

— IPF patient on nintedanib with diarrhea → loperamide, hydration, dose reduction, not discontinuation

— Known IPF, abrupt worsening dyspnea over 2 weeks, new bilateral GGO on HRCT, negative infectious workup, no PE → acute exacerbation of IPF

— Manage with high-dose steroids, empiric antibiotics, exclude PE/CHF, goals-of-care discussion

— Younger woman with Raynaud, sclerodactyly, basal reticulation without honeycombing, subpleural sparing on HRCT → scleroderma-associated NSIP, treat with mycophenolate ± tocilizumab/nintedanib, not IPF protocol

— Bird owner with mid/upper-lobe fibrosis, mosaic attenuation, BAL lymphocytosis → chronic hypersensitivity pneumonitis; remove antigen first

— IPF patient with FVC 55%, DLCO 38%, ambulatory desaturation → refer to transplant center now, do not wait

— IPF with disproportionate hypoxemia, RV strain on echo → consider inhaled treprostinil; avoid ambrisentan

— Advanced IPF, family asks about intubation if exacerbation → discuss >90% mortality with mechanical ventilation, offer palliative/hospice options

— Definite UIP on HRCT + classic clinical picture → no biopsy needed

— Indeterminate HRCT + diagnostic uncertainty → TBLC or VATS after MDD

Step 3 management: The most common trap is choosing steroids/immunosuppression for IPF. If the stem clearly establishes UIP/IPF, the antifibrotic + transplant referral + supportive care triad is almost always the correct answer.

Pattern 1 — Classic diagnosis:

Pattern 2 — Avoid steroids:

Pattern 3 — Drug side effect identification:

Pattern 4 — Acute exacerbation:

Pattern 5 — Mimics:

Pattern 6 — Transplant timing:

Pattern 7 — PH-ILD:

Pattern 8 — Goals of care:

Pattern 9 — Biopsy decision:

One-Line Recap

— Diagnose: Older patient with insidious dyspnea, dry cough, Velcro crackles, clubbing; restrictive PFTs with reduced DLCO; HRCT showing basal, subpleural reticulation with honeycombing (definite UIP); exclude CTD, HP, drugs, pneumoconiosis; multidisciplinary discussion is gold standard; biopsy only when HRCT not definite

— Treat: Start pirfenidone (watch photosensitivity, LFTs, GI) or nintedanib (watch diarrhea, LFTs, bleeding, teratogenicity); both slow FVC decline ~50% but do not improve symptoms; supplemental O2 for desaturation; pulmonary rehab; vaccinate; treat symptomatic GERD; refer for lung transplant at diagnosis in eligible patients

— Avoid: Prednisone + azathioprine + NAC (PANTHER-IPF harm), warfarin without indication, ambrisentan; do not anchor on CHF or COPD without HRCT

— Escalate and plan: Track FVC, DLCO, 6MWT every 3–6 months; manage acute exacerbations (steroids, antibiotics, exclude PE/CHF/infection) with awareness of 50% in-hospital mortality; integrate palliative care early; discuss advance directives proactively given >90% mortality with mechanical ventilation in advanced disease

Board pearl: When you see "definite UIP on HRCT" in an older patient without CTD features, the reflex answers are IPF → antifibrotic + transplant referral + supportive care, and the wrong answer is almost always steroids/immunosuppression — get this trio right and the topic is yours.

Core teaching point: Idiopathic pulmonary fibrosis is a progressive, age-related, fibrotic interstitial lung disease defined by a UIP pattern on HRCT or histology — managed with antifibrotic therapy (pirfenidone or nintedanib), supportive care, early lung transplant referral, and avoidance of immunosuppression, which is harmful.

High-yield recap bullets: